Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.Br[C:38]1[CH:39]=[N:40][CH:41]=[C:42]([CH:48]=1)[C:43]([N:45]([CH3:47])[CH3:46])=[O:44].C([O-])(O)=O.[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:38]3[CH:39]=[N:40][CH:41]=[C:42]([CH:48]=3)[C:43]([N:45]([CH3:46])[CH3:47])=[O:44])[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CN(C)C(=O)c1cncc(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cncc(C(=O)N(C)C)c3)cc12
Yield: 56.7 %

Procedure:
Into a 5 mL Personal Chemistry microwave reaction vial were added 3-(2-Methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.136 g, 0.270 mmol), 5-Bromo-N,N-dimethyl-nicotinamide (0.0756 g, 0.332 mmol; preparation described below), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (16.2 mg, 0.01 mmol), acetonitrile (2 mL) and saturated aqueous NaHCO3 (2 mL). The vial was sealed, purged with N2, and irradiated in a Personal Chemistry Optimizer at 90° C. for 15 min. The layers were separated, and the aqueous phase was extracted 3× with EtOAc. The combined organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. The crude product was dissolved in 3:1 MeOH/acetone (4 mL total) and treated with 500 μL of 50% w/w KOH(aq) for 1 h. Glacial Acetic acid was added to obtain pH 7, then the reaction mixture was concentrated. The residue was partitioned between EtOAc and water, then the layers were separated, and the organic phase was washed 2× with water. The organic phase was treated with brine, dried (Na2SO4), filtered and concentrated. Purification by flash silica gel chromatography using a gradient of ethyl acetate (containing 10% MeOH) and hexanes afforded the title compound as a tan powder (57 mg, 57%). 1H-NMR (500 MHz, d6-DMSO) δ=11.96 (br. s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.24 (d, J=2.0 Hz, 1H), 8.13 (t, J=2.0 Hz, 1H), 7.72 (d, J=3.0 Hz, 1H), 7.59 (dd, J=2.0, 5.5 Hz, 1H), 7.25 (dd, J=1, 7.5 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 3.76 (s, 3H), 2.97 (s, 3H), 2.92 (s, 3H); MS: m/z 373.1 [MH+].
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.C(N(CC)C(C)C)(C)C.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>CN(C=O)C>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([C:38]([N:37]([CH3:41])[CH3:36])=[O:39])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1CCC(c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-(1H-indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30.0 mg, 0.0679mmol), N,N-diisopropylethylamine (59.1 μL, 0.340 mmol) and DMF (100 mL) was treated with N,N-dimethylcarbamoyl chloride (6.23 μL, 0.0679 mmol) and stirred at rt for 1 h prior to semi-preparative HPLC to afford the isolated title compound. 1H NMR (400 MHz, CD3OD) ppm: 8.32 (br. s., 1H), 7.59-7.66 (m, 2H), 7.46 (d, 1H, J=8.3 Hz), 7.15-7.22 (m, 1H), 7.01-7.10 (m, 2H), 6.74 (s, 1H), 3.82 (d, 2H, J=12.6 Hz), 3.34-3.42 (m, 1H), 2.97-3.09 (m, 2H), 2.87 (s, 6H), 1.95-2.09 (m, 4H); MS (ES+): m/z 404.14 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH3:47])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)=[O:25]>>[CH2:41]([O:40][CH:39]([O:43][CH2:44][CH3:45])[C@@H:38]([N:26]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)[C:24](=[O:25])[C@@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)=[O:17])[CH3:47])[CH3:46])[CH3:42]
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 120 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[C:23]1([NH:33]N)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:33]([C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1cccc2ccccc12
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4ccccc34)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and naphthalen-1-yl-hydrazine according to the method described for example 91. MS: M=395.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Br.[C-:11]#[N:12].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1cc(Cl)ccc1Cl
Temperature: 80 °C
Yield: 83.6 %

Procedure:
A mixture of 2,5-dichlorobenzyl bromide (5.4 g, 22.5 mmol) in 16 mL of ethanol and potassium cyanide (1.63 g, 25 mmol) in 4 mL of water was heated at 80° C. overnight, then cooled, and the solids were filtered and washed with ethanol to give 3.5 g of 2,5-dichlorophenylacetonitrile as a white powder melting at 89-91° C. The nitrile was suspended in 20 red, of ethanol, and 20 mL of a 25% aqueous NaOH solution was added. The mixture was heated in a CEM Explore™ microwave reactor at 140° C. for 30 minutes, then cooled, poured into ice water and acidified to pH 1 with concentrated HCl to give a precipitate. The precipitate was filtered, washed with water and dried in a vacuum oven at 90° C. for 5 h to give the title compound as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:76])/[CH:4]=[CH:5]\[CH:6]=[CH:7]\[C@@H:8]([CH3:75])[C@@H:9]([O:67][Si:68]([C:71]([CH3:74])([CH3:73])[CH3:72])([CH3:70])[CH3:69])[CH2:10][C@H:11]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])/[CH:12]=[CH:13]\[C@H:14]([CH3:58])[C@H:15]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[C@@H:16]([CH3:49])[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@H:22]([CH3:40])[C@@H:23]([O:30]CC1C=CC(OC)=CC=1)[C@@H:24]([CH3:29])/[CH:25]=[CH:26]\[CH:27]=[CH2:28].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCOC(C)=O.CCCCCC>[CH3:1][O:2][C:3](=[O:76])/[CH:4]=[CH:5]\[CH:6]=[CH:7]\[C@@H:8]([CH3:75])[C@@H:9]([O:67][Si:68]([C:71]([CH3:74])([CH3:73])[CH3:72])([CH3:69])[CH3:70])[CH2:10][C@H:11]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:61])[CH3:62])/[CH:12]=[CH:13]\[C@H:14]([CH3:58])[C@H:15]([O:50][Si:51]([C:54]([CH3:55])([CH3:56])[CH3:57])([CH3:53])[CH3:52])[C@@H:16]([CH3:49])[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([O:41][Si:42]([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:43])[CH3:44])[C@H:22]([CH3:40])[C@@H:23]([OH:30])[C@@H:24]([CH3:29])/[CH:25]=[CH:26]\[CH:27]=[CH2:28]
Reactant: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@@H](CCCC[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/C=C\C(=O)OC)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](CCCC[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/C=C\C(=O)OC)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 81714.7 %

Procedure:
The procedure for 47 was used with 76 (0.38 g, 0.34 μmol) and DDQ (0.084 g, 0.37 mmol) to yield 77 (0.28 g, 82%) after flash column chromatography (EtOAc/hexane 1:9) as a colorless oil: IR (CHCl3) 3542, 2956, 2856, 1722, 1640, 1462, 1254, 1175, 1086, 1004, 836, 773 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.39 (dd, J=15.2, 11.2 Hz, 1H), 6.63 (ddd, J=16.9, 10.5, 10.4 Hz, 1H), 6.53 (t, J=11.3 Hz, 1H), 6.09 (t, J=1.0 Hz, 1H), 5.98 (dd, J=8.3, 7.1 Hz, 1H), 5.58 (d, J=11.3 Hz, 1H), 5.45-5.39 (m, 2H), 5.26 (dd, J=10.8, 8.4 Hz, 1H), 5.20 (d, J=16.9 Hz, 1H), 5.11(d, J=10.1 Hz, 1H), 4.53 (m, 1H), 3.95 (m, 1H), 3.76 (m, 1H), 3.71 (s, 3H), 3.47 (m, 1H), 3.40 (m, 1H), 2.82 (m, 1H), 2.55 (m, 1H), 2.20 (br, 1H), 1.72 (m, 2H), 1.60-1.35 (m, 5H), 1.32-1.10 (m, 5H), 1.04 (d, J=6.8 Hz, 3H), 0.99-0.83 (m, 48H), 0.12-0.03 (m, 24H); 13C NMR (75 MHz, CDCl3) δ 166.7, 147.1, 145.4, 135.2, 132.6, 132.5, 132.3, 130.0, 126.8, 117.7, 115.5, 80.2, 77.3, 76.2, 72.1, 66.5, 50.9, 43.4, 42.5, 38.3, 38.1, 36.1, 35.8, 34.7, 33.7, 28.3, 26.2, 25.94, 25.89, 25.5, 19.5, 18.4, 18.1, 17.7, 14.9, 13.3, 7.2, −3.0, −3.6, −3.8, −4.18, −4.20, −4.37, −4.41; LRMS (ESI) 1029.7 [M+Na]+, 875.6, 379.3; HRMS (ESI) calcd for C56H110O7Si4Na 1029.7226 [M+Na]+, found 1029.7244; [α]20D−18.7 (c 0.62, CHCl3).
Reaction SMILES: C(O)(C(F)(F)F)=O.C[O:9][C:10](=[O:24])[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:12]=1[C:20](=O)[CH2:21][Br:22].C([SiH](CC)CC)C>C(Cl)Cl>[Br:22][CH2:21][CH:20]1[C:12]2[C:11](=[C:16]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:14][CH:13]=2)[C:10](=[O:9])[O:24]1
Reactant: COC(=O)c1c(C(=O)CBr)cccc1[N+](=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OC(CBr)c2cccc([N+](=O)[O-])c21
Temperature: 70 °C
Reaction time: 48 h

Procedure:
TFA (50 mL) was added to a mixture of 2-(2-bromo-acetyl)-6-nitro-benzoic acid methyl ester (3.47 g, 11.5 mmol, Step D) and 20 mL of triethylsilane in 70 mL of anhydrous CH2Cl2. The mixture was stirred at 70° C. for 48 h, the volatiles were removed under reduced pressure, and hexanes were added to the residue. The titled compound was collected by filtration as an off-white solid.
Reaction SMILES: C([Li])CCC.[C:6]1([OH:17])[C:15]([F:16])=[C:13]([F:14])[C:11]([F:12])=[C:9]([F:10])[C:7]=1[F:8].Cl[Si:19]([CH3:22])([CH3:21])[CH3:20]>CCCCCC>[C:6]1([O:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([F:8])=[C:9]([F:10])[C:11]([F:12])=[C:13]([F:14])[C:15]=1[F:16]
Reactant: C[Si](C)(C)Cl
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C[Si](C)(C)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Yield: 59.8 %

Procedure:
n-Butyllithium (9.75 mL, 22.39 mmol, 2.5 M in hexane) was added dropwise, at 0° C., to a 200 mL hexane solution of C6F5OH (4.08 g, 22.17 mmol). After the addition of n-butyllithium was complete, the reaction mixture was allowed to warm to room temperature. Chlorotrimethylsilane (2.65 g, 24.39 mmol) was added to the reaction at −40° C. After slowly warming to room temperature, the reaction was refluxed for 19 hours. Isolation of the crude product was achieved by ether extraction. The organic was washed with ammonium chloride, water, brine, and dried over sodium sulfate. Solvent was removed in vacuo to yield 4.0 g of crude product. The resulting liquid was purified by vacuum distillation to give 3.4 g (60%) of a colorless liquid. 1H NMR (C6D6): δ 0.081 (br. s).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[S:28])[NH:6]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:36][CH3:37]>CN(C)C=O>[CH2:36]([S:28][C:5]1[NH:4][C:3]2[C:7](=[N:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[N:12]=3)=[N:10][C:2]=2[NH2:1])[N:6]=1)[CH3:37]
Reactant: CCI
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]c(=S)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c2[nH]1
Temperature: 70 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
150 mg (0.382 mmol) of the compound from example 28 were dissolved in 2 ml of dimethylformamide, and 58 mg (0.420 mmol) of potassium carbonate were added. The mixture was heated to 70° C. for 10 min and, after cooling, 31 μl (0.382 mmol) of iodoethane were added and the mixture was stirred at RT for 16 h. The mixture was concentrated, and the residue was adsorbed on silica gel and purified by means of chromatography on silica gel (eluent: dichloromethane/methanol=20:1). 91 mg of the title compound were obtained (51% of theory).
Reaction SMILES: [CH2:1]([C:10]1[C:11]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:12]([S:20]([OH:23])(=[O:22])=[O:21])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(=O)([O-])[O-].[Ca+2:37].C(=O)=O>CCCCCCC.C(O)(C)C>[CH2:1]([C:10]1[C:11]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:12]([S:20]([O-:23])(=[O:21])=[O:22])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Ca+2:37].[CH2:1]([C:10]1[C:11]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:12]([S:20]([O-:23])(=[O:21])=[O:22])[C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCc1cc2ccccc2c(S(=O)(=O)O)c1CCCCCCCCC
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: CCCCCCC
Solvent: CC(C)O
Product: CCCCCCCCCc1cc2ccccc2c(S(=O)(=O)[O-])c1CCCCCCCCC

Procedure:
Two hundred grams of dinonylnaphthalene sulfonic acid solution of the composition used in Example 1 is placed in a 1000 ml. flask fitted with a stirrer, thermometer and condenser. The flask is heated and 8.55 g. of powdered calcium carbonate (10% excess based on the sulfonic acid) is added with agitation. After a few minutes, carbon dioxide evolution ceases. The mixture is refluxed for 30 minutes, then the solids are allowed to settle. A 10 ml. sample diluted with a mixture of heptane and isopropanol as described in Example 1, and then filtered to remove the excess carbonate, has a pH of about 6.0, indicating that the carbonate/acid equilibrium has been reached. Then 2.0 g. of calcium hydroxide in 98 g. of mineral oil is prepared and 2 mls. of the mixture is added (0.02 g. of strong base). Finally, 60 g. of mineral oil is added, and the heptane and water are distilled off. The remaining fluid is filtered hot, at 130°-140° C., through a pressure filter. There is produced a completely neutral solution of calcium dinonylnaphthalene sulfonate in mineral oil.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]([CH3:40])[C:30]4[C:35]([NH:36][CH:37]([CH3:39])[CH3:38])=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)(=[O:10])=[O:9])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]([CH3:40])[C:30]3[C:35]([NH:36][CH:37]([CH3:38])[CH3:39])=[CH:34][CH:33]=[CH:32][N:31]=3)[CH2:25][CH2:24]1)=[O:22])=[CH:15]2)(=[O:9])=[O:10]
Reactant: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(NS(=O)(=O)CCN4C(=O)c5ccccc5C4=O)ccc3[nH]2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Nc1cccnc1N(C)C1CCN(C(=O)c2cc3cc(NS(=O)(=O)CCN)ccc3[nH]2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-[5-(2-phthalimidoethanesulfonamido)indole-2-carbonyl]-4-[N-methyl-N-(3-(1-methylethylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 31, 675 mg) in 95% ethanol (10 ml) under nitrogen is added hydrazine monohydrate (53 μl). The mixture is stirred at 70°-75° for 20 hrs during which additional hydrazine monohydrate (10 μl) is added, concentrated to remove ethanol, diluted with water (10 ml), acidified to pH 2 with 1M hydrochloric acid and stirred for 10 min. The mixture is then filtered, the filtrate is adjusted to pH 10-11, and the resulting precipitate is isolated by filtration to give the title compound, NMR (CDCl3) 9.86, 7.70, 7.56, 7.29, 7.10, 6.94, 6.84, 6.68, 4.60, 4.50, 3.56, 3.44, 3.40-2.80, 2.62, 1.93, 1.65 and 1.22 δ. The basic filtrate is extracted with methylene chloride (2×15 ml) which is then washed with saline (10 ml), dried over sodium sulfate, and concentrated under reduced pressure to give an additional amount of the title compound.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[C:4]([C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH3:3])=[O:20])[CH:15]=[CH:16][CH:17]=1)(=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1
Solvent: ClCCl
Product: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
1300 ml of a methylene chloride solution titrating 12.5 g/liter of diazomethane was added progressively at 10°-15° C to a solution of 50 g of m-benzoyl-phenyl acetic acid in 500 ml of methylene chloride and after stirring for 15 minutes, excess diazomethane was destroyed by the addition of acetic acid. The organic solution was washed with an aqueous saturated sodium bicarbonate solution and then with water and evaporated to dryness under reduced pressure to obtain 52.5 g of methyl m-benzoyl-phenyl-acetate which was used as is for the α-alkylation step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:7]([CH2:19][O:20][CH3:21])=[CH:6]2.Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[H-].[Na+].[I-].[Na+]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:14][CH:13]=1)[C:7]([CH2:19][O:20][CH3:21])=[CH:6]2
Reactant: ClCCCN1CCCC1
Reactant: COCc1cc2cc(OC)ccc2n1-c1ccc(O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc2cc(OC)ccc2n1-c1ccc(OCCCN2CCCC2)cc1
Temperature: 70 °C
Yield: 40 %

Procedure:
4-(5-Methoxy-2-methoxymethylindol-1-yl)phenol (0.43 mmol) was dissolved in N,N-dimethylformamide under N2. 1-(3-Chloropropyl)pyrrolidine (74 mg, 0.5 mmol), sodium hydride (20 mg, 60% wt dispersion in mineral oil, 0.5 mmol) and sodium iodide (75 mg, 0.5 mmol) were added, and the mixture was heated at 70° C. for 2 hours. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic extracts were dried over MgSO4 and concentrated. Purification by semi-prep LC-MS gave the desired product, 67.4 mg (40% yield, 2 steps). LC-MS (C24H30N2O3 calc'd 394) m/z 395 (M+H); 1H NMR (300 MHz, CDCl3) d 7.34-7.29 (m, 2H), 7.09 (d, J=2.4 Hz, 1H), 7.04-6.98 (m, 3H), 6.82 (d, J=2.4 Hz, 1H), 6.58 (s, 1H), 4.37 (s, 2H), 4.10 (t, J=6.3 Hz, 2H), 2H), 3.86 (s, 3H), 3.28 (s, 3H), 2.69-2.64 (m, 2H), 2.58-2.54 (m, 4H), 2.11-2.01 (m, 2H), 1.83-1.79 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1.Cl>CC(O)C.CC(C)=O>[ClH:1].[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([Cl:16])=[CH:18][C:19]=3[F:24])=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1Cl
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=[N+]([O-])c1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1Cl
Yield: 90 %

Procedure:
A mixture of 4,7-dichloro-6-nitroquinazoline (24.4 g, 0.1 mol), 4-chloro-2-fluoroaniline and ethereal hydrogen chloride (100 ml of a 1M solution) in 2-propanol (600 ml) was heated at reflux for 1.5 hours. The mixture was allowed to cool and diluted with acetone. The solid product was collected by filtration, washed with acetone and dried to give 7-chloro-4-(4-chloro-2-fluoroanilino)-6-nitroquinazoline hydrochloride (35.0 g, 90%) as a yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10]I>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc[nH]c(=O)c1Br
Reactant: CI
Solvent: ClCCl
Product: COc1nccc(C)c1Br
Reaction time: 144 h

Procedure:
A solution of 3-bromo-4-methyl-2-pyridone V-b (2.20 g, 11.7 mmol), in DCM (80 mL) was treated with MeI (7.29 mL, 117 mmol) and Ag2CO3 (6.47 g, 23.5 mmol). The flask was stoppered and stirred under argon for 6 days. The mixture was filtered and purified by column chromatography (SiO2, 10% EtOAc in cyclohexane) to afford the desired product V-c as a clear mobile oil (1.83 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=5.0 Hz, 1H), 6.77 (d, J=5.1 Hz, 1H), 4.00 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]Cl>CCOCC.CN(C)C=O>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: ClCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1C(=O)N(CCCCCl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (50% dispersion in oil, 1.63 g, 34 mmole) under dry nitrogen was washed with 50 ml of ether to remove the oil. The ether was separated by decantation. Dimethylformamide (25 ml) was added to the ether wet sodium hydride. A solution of 2,3-indolinedione (isatin, 5 g, 34 mmole) and 1,4-dichlorobutane (21.6 g, 18.6 ml, 0.17 mmole) in 200 ml of dimethylformamide was added dropwise over 1 hour, maintaining the temperature at 25°-28° C. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was filtered, and the filtrate evaporated to 30 ml and diluted with 50 ml of methylene chloride. The resulting mixture was again filtered, the filtrate evaporated to dryness and the residue slurried in 200 ml of ether. The ether was decanted from a drum and evaporated to yield the title product [830 mg, Rf 0.55 1:1 ethyl acetate:hexane)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.[Li]CCCC.[CH3:18][Si:19](Cl)([CH3:21])[CH3:20].Cl>CCOCC>[CH3:10][Si:9]([CH3:12])([CH3:11])[C:4]1[CH:5]=[C:6]([Br:8])[CH:7]=[C:2]([Si:19]([CH3:21])([CH3:20])[CH3:18])[CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: C[Si](C)(C)c1cc(Br)cc(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1cc(Br)cc([Si](C)(C)C)c1
Temperature: -68 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
17.18 g of 3,5-Dibromo-trimethylsilyl-benzene, 55.8 mmol, was dissolved in 380 ml Et2O. The solution was chilled to −68° C., and 22.3 mL of n-BuLi (2.5 M in hexanes), 55.8 mmol, were added within 18 minutes. The solution changed its color from clear to yellow, and was stirred for 45 minutes at −68° C. 7.5 mL TMSCl, 59 mmol, were added within six minutes. The temperature of solution rose within one hour to −33° C., and after another 30 minutes to −18° C. The solution was stirred overnight at room temperature. 60 mL of 2M HCl were added to the white suspension. Stirring for 30 minutes resulted in two clear phases. Et2O-phase was dried with MgSO4, filtered, and solvent evaporated. Raw product was distilled at a temperature of 70-76° C. and 0.1-0.2 mbar. All pure fractions were combined and gave 15.8 g of product (52.4 mmol, 94%). 1H-NMR (CHCl3=7.24 ppm): δ 7.56 (s, 2H), 7.50 (t, 1H), 0.25 (s, 6×3H).