Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[C:26]([Cl:25])[CH:31]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4ccc(NC(=O)OC(C)(C)C)c(Cl)c4)c4c(N)ncnc43)CC2)CC1

Procedure:
A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.20 g, 0.00498 mol), tert-butyl N-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (1.93 g, 0.00548 mol), sodium carbonate (1.32 g, 0.01245 mol) in 1,2-dimethoxyethane (50 mL) and water (100 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred 6 hours at 80° C., after which time additional tetrakis(triphenylphosphine)palladium(0) (0.345 g, 0.00030 mol) was added. The reaction mixture was stirred an additional 16 hours at 80° C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate (200 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×75 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (90:10:0.5). The solvent was removed in vacuo to give trans tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)carbamate as a white solid (1.993 g, 0.00368 mol):
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Br)=[O:8])=[CH:5][CH:4]=1.[C:12]([O:16][C:17](=[O:31])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:21][C:20]=1[NH2:30])([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl.Cl>[C:12]([O:16][C:17](=[O:31])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:21][C:20]=1[NH:30][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C(Br)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
4-Bromomethyl-benzoyl bromide (0.70 g, 2.52 mmol) was made 0.21 M in anhydrous DCM and cooled to −78° C. To this stirring solution was added (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert-butyl ester (0.73 g, 2.52 mmol) followed by DIPEA (0.98 g, 7.56 mmol). The resulting solution was warmed to ambient temperature and stirred for 18 hours. The reaction mixture was then diluted with 0.1 N HCl and extracted with EtOAc. The organic layer was then washed with saturated aqueous sodium bicarbonate, brine, dried (MgSO4), and concentrated in vacuo to afford the title compound: 1H NMR (DMSO-d6, 600 MHz) 9.90 (s, 1H), 8.72 (s, 1H), 7.94 (d, J=7.8. Hz, 2H), 7.78-7.80 (m, 1H), 7.57-7.62 (m, 3H), 7.47-7.51 (m, 2H), 7.42-7.44 (m, 1H), 7.09-7.12 (m, 1H), 4.77 (s, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[N:7][C:6]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:54][CH:55]([CH3:57])[CH3:56])[CH2:52][OH:53]>CN(C=O)C.C(O)=O>[OH:53][CH2:52][C@@H:51]([NH:50][C:11]([C:9]1[CH:8]=[N:7][C:6]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[N:10]=1)=[O:13])[CH2:54][CH:55]([CH3:57])[CH3:56]
Reactant: CCCOc1nc(C(=O)O)cnc1N1CCCC1
Reactant: CC(C)C[C@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
A mixture of 6 mg (0.024 mmol) 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid, 9.3 mg (0.029 mmol) TBTU, 9.3 mg (0.072 mmol) DIPEA and 4.2 mg (0.036 mmol) (S)-2-amino-4-methyl-pentan-1-ol (commercially available) in 1 mL DMF was shaken at room temperature for 16 h. After addition of formic acid the mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The combined product fractions were evaporated to yield 2 mg (24%) of the title compound. m/z (ES+): 351.5 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:17]=1>CC(N(C)C)=O.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([O:8][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: CC(C)NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)NC(=O)c1cc(Oc2ccc(N)nc2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A solution of 2-amino-5-hydroxypyridine (0.446 g, 4.05 mmol) in DMA (6.75 mL) was treated with potassium tert-butoxide (0.511 g, 4.55 mmol), stirred at RT for 1 h, treated with DMA (2 mL) and a solution of 4-chloro-N-isopropylpicolinamide (0.67 g, 3.37 mmol) in DMA (6.75 mL) and stirred at RT overnight under Ar. The mixture was diluted with EtOAc, washed with 1N NaOH, then brine and the organic layer was dried over Na2SO4, concentrated to dryness and purified by silica gel chromatography (MeOH/EtOAc) to afford 4-((6-aminopyridin-3-yl)oxy)-N-isopropylpicolinamide (0.523 g, 57%). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (t, J=5.6 Hz, 2H), 7.82 (d, J=2.9 Hz, 1H), 7.33 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.9, 3.0 Hz, 1H), 7.12 (dd, J=5.6, 2.6 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.08 (s, 2H), 4.05-4.04 (m, 1H), 1.14 (d, J=6.6 Hz, 6H); MS (ESI) m/z: 273.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([CH2:15][NH2:16])[CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH2:15][CH:12]2[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCC1CC1
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(Br)cc1
Yield: 26.5 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and cyclopropylmethylamine (0.35 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(cyclopropylmethyl)benzenesulfonamide (0.12 g) was provided after purification. MS (ESI) m/z 290. HPLC purity 100.0% at 210-370 nm, 9.0 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2.[Cl:12][C:13]1[C:22]2[C:17](=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([CH3:25])[CH:14]=1>>[ClH:12].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:13]1[C:22]3[C:17](=[C:18]([O:23][CH3:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH3:25])[CH:14]=1)=[CH:8][C:7]([CH3:11])=[CH:6][CH:5]=2
Reactant: Cc1ccc2[nH]c(C)cc2c1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Product: COc1cccc2c(-c3c(C)[nH]c4ccc(C)cc34)cc(C)nc12
Product: Cl

Procedure:
The sub-title compound was prepared by the method of Example 15 step a), using 2,5-dimethylindole and 4-chloro-8-methoxy-2-methylquinoline.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]([N:28]1[CH2:33][CH2:32][C:31]([CH2:34][C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[CH:30][CH2:29]1)/[CH:10]=[CH:11]/[C:12]1[CH:13]=[C:14]2[C:24](=[N:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:16]1([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:15]2.C(N(CC)CC)C.[C:47](=O)([O:49]C1C=CC=CC=1)[NH2:48]>CS(C)=O>[O:27]=[C:22]1[C:16]2([CH2:21][CH2:20][N:19]([C:47]([NH2:48])=[O:49])[CH2:18][CH2:17]2)[CH2:15][C:14]2[C:24](=[N:25][CH:26]=[C:12](/[CH:11]=[CH:10]/[C:9](=[O:8])[N:28]3[CH2:33][CH2:32][C:31]([CH2:34][C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[CH:30][CH2:29]3)[CH:13]=2)[NH:23]1
Reactant: NC(=O)Oc1ccccc1
Reactant: O=C(/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2)N1CC=C(Cc2nccs2)CC1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: NC(=O)N1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc1NC2=O
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
To a stirred solution of (E)-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydro pyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naph-thyridine-3,4′-piperidin]-2(4H)-one 2,2,2-trifluoroacetate (Compound 34) (150 mg, 0.26 mmol) in DMSO (2 mL) were added triethylamine (110 mg, 1.04 mmol) and phenyl carbamate (44 mg, 0.32 mmol) at 20-35° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was poured into ice water (50 mL), obtained solid was filtered, washed with water and dried under vacuum to get the desired compound as a yellow solid (40 mg, 31%); 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.37 (d, J=2.0 Hz, 1H), 8.10 (s, 1H), 7.71 (d, J=3.4 Hz, 1H), 7.61 (d, J=3.4 Hz, 1H), 7.45 (d, J=15.2 Hz, 1H), 7.28-7.14 (m, 1H), 5.93 (s, 2H), 5.68-5.65 (m, 1H), 4.28-4.20 (m, 1H), 4.08-4.02 (m, 1H), 3.76-3.72 (m, 3H), 3.66-3.62 (m, 1H), 3.60-3.52 (m, 2H), 3.18 (t, J=10.0 Hz, 2H), 2.95 (s, 2H), 2.20-2.06 (m, 2H), 1.76-1.66 (m, 2H), 1.34-1.24 (m, 2H); ES-MS: 493.3 (M+1)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[Mg]Br.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([OH:24])([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: Br[Mg]c1ccc2ccccc2c1
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C1(O)c1ccc2ccccc2c1
Temperature: -25 °C
Reaction time: 4 h

Procedure:
A solution of 2-naphthylmagnesium bromide in tetrahydrofuran (0.5 M, 8.26 mL, 4.13 mmol) (Aldrich) was added dropwise with magnetic stirring to a suspension of 6-chloroisatin (0.3 g, 1.67 mmol) in tetrahydrofuran (10 mL) with cooling in a −25° C. bath at such a rate that reaction temperature was kept below −10° C. Cooling bath was then removed and mixture was allowed to warm to room temperature. After stirring for an additional 4 hours, 15% aqueous ammonium chloride solution was added and mixture extracted with ethyl acetate. The combined organic layers were then washed with water, brine, combined, dried (Na2SO4), filtered and concentrated. Residue was stirred in dichloromethane at room temperature for 15 minutes and filtered to give crude rac-6-chloro-3-hydroxy-3-naphthalen-2-yl-1,3-dihydro-indol-2-one as a red solid. This was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)[CH:12]=[CH:11][C:9]=2[N:10]=1.[Cl:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[ClH:27].[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:29]4[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=4[Cl:27])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1.[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[S:7][C:8]2[CH:14]=[C:13]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:29]4[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:28]=4[Cl:27])=[CH:19][CH:18]=3)=[O:24])[CH:12]=[CH:11][C:9]=2[N:10]=1
Reactant: Cc1ccc(B(O)O)c(Cl)c1
Reactant: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1
Product: Cc1ccc(-c2ccc(C(=O)Nc3ccc4nc(N(C)CCN(C)C)sc4c3)cc2)c(Cl)c1
Product: Cl

Procedure:
The title compound is prepared by following a procedure analogous to Example 113, Step 1, using N-{2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-4-iodo-benzamide (0.40 g, 0.83 mmol) and 2-chloro-4-methyl-phenyl boronic acid (0.17 g, 0.10 mmol) to afford 2′-chloro-4′-methyl-biphenyl-4-carboxylic acid {2-[(2-dimethylamino-ethyl)-methyl-amino]-benzothiazol-6-yl}-amide (0.21 g, 0.44 mmol, 53%). The material is dissolved in EtOH, treated with 1.0 M HCl in EtOH (0.44 mL), concentrated and recrystallized from EtOH/Heptane to give 0.20 g (88%) as the hydrochloride salt. LC/MS, Retention time=5.04 min; (m/z): calcd for C26H27ClN4OS (M+H)+: 479.4; found: 479.0.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[CH:4]=[O:5].C(N[CH:15]([CH3:17])C)(C)C.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I.O1CCOCC1>[CH3:31][Si:32]([CH3:34])([CH3:33])[C:35]#[C:36][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:17]#[C:15][Si:32]([CH3:34])([CH3:33])[CH3:31])[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)NC(C)C
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: N#Cc1ccccc1
Solvent: C1COCCO1
Product: C[Si](C)(C)C#Cc1cccc(C#C[Si](C)(C)C)c1C=O
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 37 %

Procedure:
Following the method described by Buchwald and Fu (Hundertmark, T. et al., Org. Lett. 2000, 12, 1729-1731), samples of 2,6-dichlorobenzaldehyde (3.56 g, 20.4 mmol), Pd(PhCN)2Cl2 (468 mg, 1.22 mmol), and CuI (155 mg, 814 μmol) were placed in a Schlenk flask. Diisopropylamine (6.7 mL), dioxane (30 mL), and P(t-Bu)3 (494 mg, 2.44 mmol) were placed in a Schlenk flask and sparged of oxygen for 10 min, then added to the Schlenk flask. The flask was placed in an oil bath heated to 70° C. After 5 min, (trimethylsilyl)acetylene (7.19 mL, 50.9 mmol) was added and the mixture was stirred at 70° C. for 4 h. Removal of an aliquot and analysis by GC showed mono and di-coupled products in a nearly 1:1 ratio. An additional equivalent of (trimethylsilyl) acetylene (2.9 mL, 20.4 mmol) was added. After 24 h at 70° C., GC analysis showed no mono-coupled product. The mixture was cooled to room temperature, then filtered through a pad of silica. Kugelrohr distillation (110° C., 0.1 Torr) followed by column chromatography (silica, toluene) afforded a yellow oil (2.22 g, 37%): 1H NMR δ0.27 (s, 18H), 7.40-7.43 (m, 1H), 7.51 (d, J=8.0Hz, 2H), 10.63 (s, 1H); 13C NMR δ−0.0, 101.5, 102.5, 125.2, 132.3, 134.4, 137.2, 190.6; FAB-MS obsd 299.1267, calcd 299.1287; Anal Calcd. for C17H22OSi2: C, 68.40; H, 7.43; Found: C, 67.94; H, 7.36.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[Br:15]Br.O>C(O)(=O)C>[NH2:1][C:2]1[C:9]([Br:15])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: N#Cc1ccc(N)nc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cnc(N)c(Br)c1
Reaction time: 0.08 h
Yield: 71.5 %

Procedure:
To a solution of 6-aminonicotinonitrile (3.6 g, 300 mmol) in glacial acetic acid (50 mL) at RT was added sodium acetate (30 mmol). To the resulting well stirred mixture was added bromine (2.58 mL, 30 mmol) dropwise. After 5 min, a precipitate started to form and the mixture became very thick. Acetic acid (10 mL) was added and the mixture was stirred vigorously for 1 h, poured into cold water (100 mL). The mixture was filtered; the solid was washed with water and dried in vacuo to afford 6-amino-5-bromonicotinonitrile (4.25 g) as a solid. LC/MS; (M+H)+=199. Additional solid precipitated from the filtrate after some time which upon filtration and drying gave less pure compound (1.21 g).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]3[C:14]([C:25]([OH:27])=O)=[CH:15][N:16](COCC[Si](C)(C)C)[C:11]3=[N:10][CH:9]=2)[CH:5]=[N:4]1)[CH3:2].C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1.[CH3:51][C:52]1([CH3:59])[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]1[NH2:58].Cl.NC1(C(O)(C)C)CCCC1>>[CH3:51][C:52]1([CH3:59])[CH2:57][CH2:56][CH2:55][CH2:54][CH:53]1[NH:58][C:25]([C:14]1[C:12]2[C:11](=[N:10][CH:9]=[C:8]([C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=3)[N:13]=2)[NH:16][CH:15]=1)=[O:27]
Reactant: CC1(C)CCCCC1N
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Agent: CC(C)(O)C1(N)CCCC1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)NC4CCCCC4(C)C)c3n2)cn1

Procedure:
2-(1-Ethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2,2-dimethyl-cyclohexyl)-amide was prepared according to the procedure outlined in Example 1, steps 4-5 substituting 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid and 2,2-dimethylcyclohexylamine [Example 21, steps 1-2] for 2-(1-amino-cyclopentyl)-propan-2-ol hydrochloride in step 4. MS: (M+H)+=367.
Reaction SMILES: [Cl:1]C1C2C(=CC(OC)=C(OC)C=2)N=CN=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]2[NH:30][C:31]1[CH:32]=[C:33]([S:40]([NH:43][CH3:44])(=[O:42])=[O:41])[CH:34]=[CH:35][C:36]=1[N:37]([CH3:39])[CH3:38]>>[ClH:1].[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[N:24]=[CH:23][N:22]=[C:21]2[NH:30][C:31]1[CH:32]=[C:33]([S:40]([NH:43][CH3:44])(=[O:42])=[O:41])[CH:34]=[CH:35][C:36]=1[N:37]([CH3:38])[CH3:39]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: CNS(=O)(=O)c1ccc(N(C)C)c(Nc2ncnc3cc(OC)c(OC)cc23)c1
Product: Cl

Procedure:
The following compounds were prepared with procedures analogous to that described in Example 1 using 4-chloro-6,7-bis(methyloxy)quinazoline and the specified aniline as starting materials:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[N:9]2)=[C:4]([O:23][CH3:24])[CH:3]=1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[CH3:22][O:21][N:19]([CH3:20])[C:17]([C:10]1[C:11](=[O:16])[C:12]([O:14][CH3:15])=[CH:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:3][C:4]=2[O:23][CH3:24])[N:9]=1)=[O:18]
Reactant: c1cn[nH]c1
Reactant: COc1cc(I)ccc1-n1cc(OC)c(=O)c(C(=O)N(C)OC)n1
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(=O)N(C)OC)n1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A suspension of 1-(4-iodo-2-methoxyphenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (10.7 g, 24 mmol), pyrazole (1.63 g, 24 mmol), Cu2O (0.343 g, 2.4 mmol), salicylaldoxime (1.32 g, 9.6 mmol), and Cs2CO3 (15.6 g, 48 mmol) in CH3CN (100 mL) was refluxed for 4 h under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt/THF (1/0-0/1) to give the title compound (6.32 g, 68% yield) as a pale yellow amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 3.39 (3H, s), 3.73 (3H, s), 3.91 (3H, s), 3.99 (3H, s), 6.53 (1H, dd, J=1.9, 2.3 Hz), 7.27 (1H, dd, J=2.3, 8.7 Hz), 7.58 (1H, d, J=8.7 Hz), 7.61 (1H, d, J=1.9 Hz), 7.77 (1H, d, J=1.5 Hz), 7.84 (1H, s), 7.98 (1H, d, J=2.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H](C)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To 200 g (1.00 mol) (S)-1-(4-bromophenyl)ethylamine in 800 mL DCM are slowly added 94.5 mL (1.00 mol) acetic anhydride while cooling the mixture to 20-30° C. Then the cooling is removed and the reaction mixture is stirred at r.t. over night. Afterwards the mixture is consecutively washed with water, sat. aq. NaHCO3 solution, water, diluted aq. citric acid solution and again water. The org. layer is dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[O:20][CH:17]1[CH2:16][CH2:15][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OC2CCN(C3CCNCC3)CC2)cc1Cl

Procedure:
The product of Step 2 (10.15 g, 23.6 mmol) was dissolved in dichloromethane (150 ml) and trifluoroacetic acid (40 ml, 519 mmol) added and the resultant solution stirred. After 90 minutes the dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The resultant oil was partitioned between ethyl acetate (100 ml) and 2M aq NaOH (100 ml). The layers were separated and the organics extracted with 10% aq citric acid (10 ml). The layers were separated and the aqueous basified with 2M aq NaOH and extracted with ethyl acetate (200 ml). The organics were dried (MgSO4), filtered and the solvent removed to give the sub-titled product as a pale oil which solidified on standing (4.62 g, 59%; MS: (M+H) 329).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].F[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].Cl>CN(C=O)C.O>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:19]([O-:21])=[O:20])[C:12]=1/[C:2](=[C:3](\[OH:4])/[CH3:5])/[C:1]([O:7][CH3:8])=[O:6]
Reactant: O=[N+]([O-])c1cccc(Cl)c1F
Reactant: COC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C(=C(\C)O)c1c(Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
Methyl acetoacetate (59.82 mmol, 2.1 equiv.) was added dropwise at 0° C. to a suspension of NaH (65.52 mmol, 2.3 equiv.) in DMF (40 ml). Then the mixture was stirred for 10 min and subsequently heated to 25° C. 2-Fluoro-3-chloronitrobenzene (28.49 mmol, 1.0 equiv.) was cooled with an ice bath in a reaction flask, and the NaH suspension was added. Then stirring was carried out for 16 h at 25° C. 2 M HCl (5 ml) and water (10 ml) were then added, and extraction with diethyl ether (3×20 ml) was carried out. The combined organic phases were washed with water (10 ml) and sat. NaCl solution (20 ml), dried over Na2SO4 and reduced under reduced pressure. The residue was purified by column chromatography (5% ethyl acetate in hexane). Yield: 51%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH2:12])=[S:11].[C:13]([N:17]=[C:18]=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:18](=[O:19])[NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[S:11]
Reactant: NC(=S)Nc1c(Cl)cccc1Cl
Reactant: CC(C)(C)N=C=O
Solvent: Cc1ccccc1C
Product: CC(C)(C)NC(=O)NC(=S)Nc1c(Cl)cccc1Cl

Procedure:
To a mixture of 11 g (0.05 mole) of 1-(2,6-dichlorophenyl)thiourea and 10 ml of xylene is added 5 g of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dichlorophenyl)-3-(t-butylcarbamyl)thiourea.