Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][NH2:23])=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][N:23]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:18][CH:19]=1
Reactant: NCCCc1ccc(Cl)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 21.7 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-(4-chloro-phenyl)-propylamine (0.102 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(4-chloro-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.031 g, 23%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.96 (m, 2H), 2.69 (t, 2H), 3.64 (t, 2H), 4.36 (s, 2H), 7.14-7.58 (m, 7H), 7.84 (d, 1H). GC-MS: m/z 285 (M)+.
Reaction SMILES: FC(F)(OC1C=CC(N=NC2C=CC(N)=CC=2)=CC=1)[C:3]([F:6])([F:5])[F:4].[CH2:24]([O:26][C@@H:27]1[C@@H:32]([O:33][CH3:34])[C@H:31]([CH3:35])[O:30][C@@H:29]([O:36][C:37](=[O:61])[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]=[N:46][C:47]3[CH:52]=[CH:51][C:50]([O:53]C(F)(F)C(F)(F)F)=[CH:49][CH:48]=3)=[CH:41][CH:40]=2)[C@@H:28]1[O:62][CH3:63])[CH3:25]>>[CH2:24]([O:26][C@@H:27]1[C@@H:32]([O:33][CH3:34])[C@H:31]([CH3:35])[O:30][C@@H:29]([O:36][C:37](=[O:61])[NH:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]=[N:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][C:3]([F:6])([F:5])[F:4])=[CH:49][CH:48]=3)=[CH:41][CH:40]=2)[C@@H:28]1[O:62][CH3:63])[CH3:25]
Reactant: CCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)Nc2ccc(N=Nc3ccc(OC(F)(F)C(F)(F)F)cc3)cc2)[C@@H]1OC
Reactant: Nc1ccc(N=Nc2ccc(OC(F)(F)C(F)(F)F)cc2)cc1
Product: CCO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](OC(=O)Nc2ccc(N=Nc3ccc(OC(F)(F)F)cc3)cc2)[C@@H]1OC

Procedure:
4-(4-Pentafluoroethoxyphenylazo)aniline 1H NMR (300 MHz, CDCl3) δ7.89-7.79 (m, 4H), 7.32 (d, J=8.5 Hz, 2H), 6.73-6.76 (m, 2H), 4.09 (br s, 2H); ESIMS m/z 332 ([M+H]+). Step 2. Compound 22. 1H NMR (300 MHz, CDCl3) δ 7.96-7.92 (m, 4H), 7.60-7.57 (m, 2H), 7.38-7.35 (m, 2H), 6.86 (s, 1H), 6.26 (s, 1H), 3.75-3.45 (m, 11H), 3.22 (t, J=9.3 Hz, 1H), 1.33-1.26 (m, 6H); ESIMS m/z 578 ([M+H]+).
Reaction SMILES: [C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11](I)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[CH3:29][S:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])=[O:31]>>[C:1]([N:4]1[C:8]2=[CH:9][CH:10]=[C:11]([C:36]3[CH:37]=[CH:38][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:34][CH:35]=3)[C:12](=[O:13])[N:7]2[C@H:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C@@H:5]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(I)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1
Product: CC(=O)N1c2ccc(-c3ccc(S(C)(=O)=O)cc3)c(=O)n2[C@H](c2ccc(Cl)cc2)[C@@H]1c1ccc(Cl)cc1

Procedure:
rac-cis-1-Acetyl-2,3-bis-(4-chloro-phenyl)-6-(4-methanesulfonyl-phenyl)-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one was prepared according to general method D by reaction of rac-cis-1-acetyl-2,3-bis-(4-chloro-phenyl)-2,3-dihydro-6-iodo-1H-imidazo[1,2-a]pyridin-5-one with 4-(methylsulfonyl)phenylboronic acid. The compound was isolated by preparative HPLC. The expected product was characterized by LC/MS (M+H) where the mass was observed as 553.09; the expected mass is 552.1. LC/MS indicated a purity of 100% as measured by UV 214 nM.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[O:27]([C:34]1[CH:42]=[CH:41][C:37](C(Cl)=O)=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[N:43]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[NH2:54])[CH:47]=[CH:46][CH:45]=[CH:44]1>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][N:13]=[C:11]2[CH2:12][N:8]([C:6](=[O:7])[C:37]3[CH:36]=[CH:35][C:34]([O:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:42][CH:41]=3)[C@H:9]([C:24]([NH:54][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[N:43]3[CH:47]=[CH:46][CH:45]=[CH:44]3)=[O:26])[CH2:10]2)=[CH:21][CH:20]=1
Reactant: Nc1ccccc1-n1cccc1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(CON=C2C[C@@H](C(=O)Nc3ccccc3-n3cccc3)N(C(=O)c3ccc(Oc4ccccc4)cc3)C2)cc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 4-phenoxybenzoyl chloride, and 2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 55% purity by LC/MS. MS(ESI+): m/z=601.4.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:7][CH:8]=1.[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:20]=[CH:21][C:22]=1[Cl:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:3][C:4]4[N:5]=[C:6]([CH2:9][N:10]5[CH2:15][CH2:14][O:13][CH2:12][CH2:11]5)[S:7][CH:8]=4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Reactant: ClCc1csc(CN2CCOCC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1csc(CN2CCOCC2)n1
Temperature: 70 °C
Reaction time: 21 h
Yield: 55.1 %

Procedure:
4-{[4-(Chloromethyl)-1,3-thiazol-2-yl]methyl}morpholine hydrochloride (0.024 g, 0.089 mmol) and 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (0.030 g, 0.089 mmol) were suspended in DMF (2 mL) and potassium carbonate (0.062 g, 0.449 mmol) was added. The mixture was stirred at 70° C. for 21 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase HPLC to afford the title compound as a colorless solid (0.026 g, 0.049 mmol, 54% yield). 1H NMR (400 MHz; CDCl3): 2.50 (br s, 1H); 2.57-2.64 (m, 4H); 3.75 (t, 4H); 3.84 (s, 2H); 3.96 (s, 3H); 5.28 (s, 2H); 7.09 (s, 1H); 7.31 (s, 1H); 7.37 (s, 1H); 7.43 (d, 1H); 7.60 (dd, 1H); 7.97 (d, 1H); 8.61 (s, 1H); MS (EI) for C24H23Cl2N5O3S: 532 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=4[O:39][CH3:40])[CH2:28][CH2:27][C:26]([C:41]([OH:43])=O)=[CH:25][C:24]=3[CH:44]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=4[O:39][CH3:40])[CH2:28][CH2:27][C:26]([C:41]([NH:29][C:23]4[CH:24]=[CH:44][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:43])=[CH:25][C:24]=3[CH:44]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cc(OC)ccc2OC)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2cc(OC)ccc2OC)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (134 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (30 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (100 mg) and triethylamine (455 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature overnight, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(2,5-dimethoxybenzyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 65) (210 mg) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]([F:19])([F:18])[C:10](=O)[CH2:11][C:12](OCC)=[O:13]>>[F:8][C:9]([F:19])([F:18])[C:10]1[CH:11]=[C:12]([OH:13])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1ccccc1
Product: Oc1cc(C(F)(F)F)nc2ccccc12

Procedure:
A mixture of the appropriate aniline and ethyl 4,4,4-trifluoro-3-oxobutanoate may be treated with polyphosphoric acid to afford the requisite 2-(trifluoromethyl)quinolin-4-ol (see British Pat. Appl. GB 1419789 A 19751231).
Reaction SMILES: [NH2:1][C:2]1N=[CH:6][C:5]([C:8]2[N:9]([CH:26]3[CH2:29][CH2:28]C3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:11]=3)=[CH:4][CH:3]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:40]([O-])=[O:41])C=1.[CH:43]1([C@H:46]([OH:48])[CH3:47])[CH2:45][CH2:44]1.N1C=CC=C[CH:50]=1>O.C(Cl)Cl>[CH:43]1([C@H:46]([O:48][C:40](=[O:41])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]([CH:26]4[CH2:29][CH2:28]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][C:20]3[N:21]=[CH:22][CH:23]=[CH:24][N:25]=3)[CH:11]=4)=[CH:6][CH:50]=2)[CH3:47])[CH2:45][CH2:44]1
Reactant: N#Cc1c(-c2ccc(N)nc2)n(C2CCC2)c2cc(Oc3ncccn3)ccc12
Reactant: c1ccncc1
Reactant: C[C@@H](O)C1CC1
Solvent: O
Solvent: ClCCl
Product: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CC2)cc1)C1CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
A mixture of 2-(6-amino-pyridin-3-yl)-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (115 mg, 0.3 mmol), 4-nitrophenylchloroformate (91 mg, 0.45 mmol) in pyridine (1.0 mL) was stirred at 30° C. for 2 h, followed by the addition of (R)-1-cyclopropylethanol (150 μL, 1.5 mmol). The mixture was stirred at 80° C. overnight and diluted with water (10 mL) and CH2Cl2 (5 mL). The organic layer was washed with water (3×5 mL), HCl (2N, 3×5 mL), sat. aq. NaHCO3 (3×5 mL) and and purified on silica gel (CH2Cl2/EtOAc, 1:9) to provide (R)-{4-[3-cyano-1-cyclopropyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester (25 mg, 17%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.Cl[Si:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([Si:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:7][CH:2]=1
Reactant: Brc1ccccc1Br
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Brc1ccc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 66 %

Procedure:
As depicted in Reaction 2, a solution of 4 g (17 mmol) of dibromobenzene in ether was cooled. To the solution were sequentially added n-BuLi and chlorotriphenylsilane. The mixture was allowed to react at room temperature. After completion of the reaction, the reaction mixture was extracted with ether. After the solvent was removed under reduced pressure, the residue was purified by column chromatography to give the title compound. The product was collected by filtration under reduced pressure and dried. Yield: 66%. 1H-NMR (CDCl3, ppm): 7.54-7.5 (m, Ar—H), 7.45 (Ar—H), 7.40-7.35 (m, Ar—H). IR (KBr, cm−1): 1568, 1477-1376, 1110, 810, 727, 698. MS (EI) (Calcd. for C24H19BrSi: 414. Found: 414).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:21]([S:28][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: SCc1ccccc1
Reactant: CC(=O)c1cc(Br)ccc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)c1cc(SCc2ccccc2)ccc1F
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
To a solution of 1-(5-bromo-2-fluorophenyl)ethanone (Matrix Scientific, 3 g, 13.8 mmol), Xantphos (0.800 g, 1.38 mmol), and N,N-diisopropylethylamine (4.83 mL, 27.6 mmol) in 1,4-dioxane (15 mL) was added Pd2(dba)3 (0.633 g, 0.691 mmol). The vial was sparged with argon, sealed, and stirred at 80° C. for 10 minutes. After 10 minutes, the reaction was cooled to ambient temperature, and benzyl mercaptan (1.70 mL, 14.5 mmol) was added. The reaction was flushed with argon, sealed, and stirred at 80° C. After 45 minutes, the reaction mixture was concentrated, diluted with dichloromethane, and passed through a silica-gel pad, eluting with DCM. The filtrate was concentrated and purified by column chromatography, eluting with 10-60% ethyl acetate in heptane, to provide 1-(5-(benzylthio)-2-fluorophenyl)ethanone (3.6 g, quantative yield) as a yellow oil. m/z (ESI) 261.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([NH2:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1Cl>C(O)(C)C>[ClH:12].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[NH:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: Cc1cn(N)c2ccccc12
Reactant: Clc1ccncc1Cl
Solvent: CC(C)O
Product: Cc1cn(Nc2ccncc2Cl)c2ccccc12
Product: Cl

Procedure:
The title compound was prepared from 3-methyl-1H-indol-1-amine and 3,4-dichloropyridine in isopropanol at 80° C. for 5 hours in substantially the same manner as in Example 1. Recrystallized from ethanol, m.p. 278°-280° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12]O)=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.C[Si]([Br:22])(C)C.[Li+].[Br-]>CC#N>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][Br:22])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: C[Si](C)(C)Br
Reactant: CC(C)n1nc(Br)c2ccc(CO)cc2c1=O
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Product: CC(C)n1nc(Br)c2ccc(CBr)cc2c1=O
Temperature: 80 °C
Yield: 44.4 %

Procedure:
A solution of 4-bromo-7-hydroxymethyl-2-isopropyl-2H-phthalazin-1-one (0.74 g, 2.5 mmol) in MeCN (5 ml) was added dropwise to a stirred suspension of trimethylsilyl bromide (TMSBr) (0.9 g, 6.3 mmol) and LiBr (0.41 g, 5 mmol) in MeCN (15 ml). The reaction mixture was heated to 80° C. for 24 hours, after which time the reaction mixture was cooled to RT and the solvent removed under vacuum. The resulting residue was purified by flash column chromatography (elution: 85% heptane, 15% EtOAc) to give the title compound (0.4 g, 44% yield) as a white solid. 1H-NMR: (250 MHz, D6- DMSO), 8.37 (1H, s), 8.03 (1H, d), 7.94 (1 H, d), 5.26-5.09 (1H, m), 4.93 (2H, s), 1.35 (6H, d).
Reaction SMILES: C(OC([N:11]([CH2:13][C:14]1[CH:15]=[C:16]([NH:27][C:28]([O:30][CH2:31][C@@H:32]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=2[CH3:43])[CH3:33])=[O:29])[CH:17]=[C:18]([F:26])[C:19]=1[O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH3:12])=O)C1C=CC=CC=1.[NH2:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[C:51]([N:55]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:50][CH:49]=[CH:48]2.O.[C:71]([OH:75])(=[O:74])[CH:72]=O>CC#N.CN(C=O)C>[C:66]([O:65][C:63]([N:55]([C:56]([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:57])[C:51]1[C:52]2[C:47](=[CH:46][C:45]([NH:44][CH:72]([C:37]3[CH:38]=[CH:39][C:34]([C@@H:32]([CH3:33])[CH2:31][O:30][C:28](=[O:29])[NH:27][C:16]4[CH:15]=[C:14]([CH2:13][NH:11][CH3:12])[C:19]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])=[C:18]([F:26])[CH:17]=4)=[C:35]([CH3:43])[CH:36]=3)[C:71]([OH:75])=[O:74])=[CH:54][CH:53]=2)[CH:48]=[CH:49][N:50]=1)=[O:64])([CH3:69])([CH3:68])[CH3:67]
Reactant: COCCCOc1c(F)cc(NC(=O)OC[C@H](C)c2ccc(B(O)O)cc2C)cc1CN(C)C(=O)OCc1ccccc1
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CNCc1cc(NC(=O)OC[C@H](C)c2ccc(C(Nc3ccc4c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc4c3)C(=O)O)cc2C)cc(F)c1OCCCOC
Temperature: 85 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a flask was added 28D (208 mg, 0.349 mmol), Intermediate 1 (138 mg, 0.384 mmol), glyoxylic acid monohydrate (32.1 mg, 0.349 mmol) in CH3CN (3 ml) and DMF (0.5 ml). The mixture was stirred at 85° C. for 2 h. The mixture was concentrated and purified by prep HPLC. The desired fractions were combined, concentrated. The residue was dissolved in MeOH (8 mL), and 10% Pd/C was added. The mixture was hydrogenated at 40 psi for 6 h. The mixture was filtered and concentrated to give 28E (188 mg, 0.225 mmol, 64.6% yield). MS (ESI) m/z: 834.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([OH:7])=O.CC(C)=O.ClC(OCC)=O.[CH:28]1([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:41][NH2:42])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(N(CC)CC)C.O>[CH:28]1([CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH:37]2[CH2:41][NH:42][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:10]=[C:11]([O:12][CH3:13])[C:3]=2[O:2][CH3:1])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: NCC1CCCN1CC1CCCCCC1
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(S(N)(=O)=O)cc(C(=O)NCC2CCCN2CC2CCCCCC2)c1OC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
13 g of 2,3-dimethoxy-5-sulphamoyl benzoic acid, 150 ml of acetone, 28 ml of water and 7 ml of triethylamine (density 0.726) are placed in a 250 ml flask fitted with an agitator, a thermometer, a condenser and a dropping funnel. The resultant solution is cooled from 0° to +5° C. 5.4 g of ethyl chloroformate is added drop by drop and the reaction medium is agitated for 45 minutes at room temperature and cooled to 0° C. again. 13.7 g of 1-cycloheptylmethyl-2-aminomethylpyrrolidine is added drop by drop. The medium is agitated for 1 hour at room temperature then left to stand. The crystals formed are drained, washed with water and dried in an oven at 30° C.
Reaction SMILES: [K].Cl.O.[NH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([CH:16]=[CH:17][NH:18]2)=[CH:14][CH:13]=1>CO>[CH3:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([C:7]3[CH2:6][CH2:5][NH:4][CH2:9][CH:8]=3)=[CH:17][NH:18]2)=[CH:14][CH:13]=1
Reactant: O=C1CCNCC1
Reactant: Cc1ccc2cc[nH]c2c1
Agent: Cl
Agent: [K]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 92.7 %

Procedure:
To a solution of potassium hydroxyde (16 g) in methanol were added at 5° C. 4-piperidone hydrate hydrochloride (30 g) and a solution of 6-methyl-1H-indole (10 g) in methanol (50 ml). The mixture was refluxed for 16 hours. After cooling precipitated inorganic salts were filtered off. Methanol was evaporated and the remaining oil was dissolved in ethyl acetate (200 ml) and subsequently washed with brine (2×100 ml). After drying (anh. MgSO4) the solvent was evaporated leaving 15 g of crude 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole, which was used without further purification. The pure tetrahydropyridyl derivative crystallized from diethyl ether. Mp: 150°-152° C. To a solution of 1-(2-chloroethyl)-3-(2-propyl)-2-imidazolidinon (32 g)in MIBK (500 ml) were added 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (15 g), potassium carbonate (16 g) and potassium iodide (5 g). The mixture was refluxed for 19 hours and finally filtered while still hot. MIBK was evaporated and the resulting oil was dissolved in ethyl acetate (500 ml) and washed with brine (2×100 ml). After drying (anh. Na2SO4) ethyl acetate was evaporated. The remaining oil was stirred with diethyl ether (200 ml) and the precipitated, crystalline 3-[1-[2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl]-1,2,3,6-tetrahydro-4-pyridyl]-6-methyl-1H-indole was filtered off. Yield: 14.5 g. Mp: 170°-174° C. To a solution of the thus prepared imidazolidinon derivative (14 g) in acetic acid (300 ml) was added PtO2 (600 mg). This mixture was hydrogenated in a Parr apparatus at 3 ato. for 72 hours. The catalyst was filtered off and most of the acetic acid was evaporated in vacuo. The remaining oil was dissolved in H2O and pH was adjusted to 9-10 by addition of dil. NaOH solution. The title compound 14a was extracted with dichloromethane (2×200 ml) and isolated as above. The crude product was purified by eluting (eluent:ethyl acetate/dichloromethane/ethanol/triethyla-mine 40:40:20:5) through silica gel. Yield: 4.5 g. Mp: 185° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[K+].O>CO.O>[N+:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)([O-:17])=[O:16]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 108.4 %

Procedure:
5-Nitro-1H-indole-2-carboxylic acid ethyl ester 15 (194 mg, 0.83 mmol) and KOH (342 mg, 5.25 mmol) were stirred in MeOH/water (8 mL/4 mL) at room temperature for 21.5 h. More water was added to dilute the solution. The mixture was concentrated to remove the organic solvent. The remaining solution was washed with DCM (100 mL). The aqueous solution was adjusted with 1 N HCl to pH 2.9, extracted with EtOAc (2×15 mL). The combined EtOAc extraction was washed with brine, dried over sodium sulfate, concentrated to afford the product as solid (185.5 mg, 97% yield). 1H-NMR (DMSO-d6): 8.718 (d, J=2.0-2.5 Hz, 1 H, Ar—H), 8.116 (dd, J=2.0-2.5 Hz and 9.0-9.5 Hz, 1 H, Ar—H), 7.583 (d, J=9.0-9.5 Hz, 1 H, Ar—H), 7.378 (d, J=1.5 Hz, 1 H, Ar—H). LC-MS: 207.1 (MH+).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.Cl.[NH:31]1[CH2:34][CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32]1>ClCCl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:31]3[CH2:34][CH:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32]3)[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCOC(=O)C1CNC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)C1

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.45 g, 1.57 mmol) was dissolved in dichloromethane (15 ml), then diisopropylethylamine (0.6 ml, 3.53 mmol) and ethyl azetidine-3-carboxylate hydrochloride (I-147) (0.55 g) were added. After heated under reflux for 3 hours, this was diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a brown oil (0.60 g, quant).