Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:18][CH2:19][CH3:20])(=[O:17])[C:8]1[CH:16]=[CH:15][C:13]([OH:14])=[C:10]([O:11][CH3:12])[CH:9]=1.CS(O[CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O.C(OCC)C>CN(C)C=O>[F:28][C:27]([F:30])([F:29])[CH2:26][O:14][C:13]1[CH:15]=[CH:16][C:8]([C:7]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1ccc(OCC(F)(F)F)c(OC)c1
Temperature: 120 °C
Yield: 51.5 %

Procedure:
Potassium carbonate (62.2 g, 450 mmol) was added to a solution of ethyl vanillate (58.9 g, 300 mmol) in dimethylformamide (400 ml) and the reaction heated to 120° C. 2,2,2-Trifluoroethyl methanesulphonate (63.4 g, 360 mmol) was added over 15 minutes and the reaction heated at 120° C. for 15 hours. The reaction was cooled to ambient temperature, diethyl ether (400 ml) was added and the reaction was filtered. The filtrate was evaporated in vacuo and the residue was taken up in a mixture of diethyl ether (375 ml) and isohexane (375 ml). The organic layer was concentrated in vacuo to a total volume of 250 ml and the solid which crystallised out was collected by suction filtration. Drying of the solid in vacuo yielded ethyl 4-(2,2,2-trifluoroethoxy)-3-methoxybenzoate (43.0 g, 52% yield) as a white crystalline solid:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].Cl>C(O)C>[CH3:8][CH:7]([CH3:9])[C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:10]([N:12]1[CH2:16][C@@H:15]([CH3:17])[CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH3:49])[CH2:46][NH:45]3)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)[nH]2)ccc1-4)C(C)C
Agent: Cl
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2ccc3cc4c(cc3c2[nH]1)OCc1cc(-c2cnc([C@@H]3C[C@H](C)CN3)[nH]2)ccc1-4)C(C)C
Temperature: 60 °C

Procedure:
Tert-butyl (2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (200 mg, 0.262 mmol) was treated with 2 mL 1.25N HCl in ethanol and heated at 60° C. for 2 h, then it was concentrated under reduced pressure and pumped dry under high vacuum and used directly in the next step.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CC1N(C2C=CC([N+]([O-])=O)=CC=2C#N)C=NC=1>>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH:18]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: Cc1c[nH]cn1
Agent: Cc1cncn1-c1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2C#N)cn1

Procedure:
In analogy to example 5a, 2-fluoro-5-nitro-benzonitrile was reacted with 4-methylimidazole and potassium carbonate for 1 h at 20° C. Aqueous workup afforded a 3.6:1 mixture of the title compound and its regioisomer [2-(5-methyl-imidazol-1-yl)-5-nitro-benzonitrile] as a light brown solid (yield: 69%). MS: m/e=229.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[C:4]=1[C:10]#[N:11].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].Br[CH:21]([CH2:23][CH3:24])[CH3:22]>C(=O)([O-])O.[Na+].COCCOC>[CH:21]([N:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]1=[O:9])([CH2:23][CH3:24])[CH3:22]
Reactant: COc1cc[nH]c(=O)c1C#N
Reactant: CCC(C)Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCC(C)n1ccc(OC)c(C#N)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a mixture of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (500 mg), cesium carbonate (2.17 g), potassium iodide (553 mg) N,N-dimethylformamide (10 mL) and 1,2-dimethoxyethane (10 mL) was added 2-bromobutane (776 mg) at room temperature, and the mixture was stirred overnight at 60° C. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted threetimes with ethyl acetate. The extracts were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (330 mg).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[O:17]=[C:18]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH:19]=[CH:20][CH3:21]>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH:20]([CH3:21])[CH2:19][C:18]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:17])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC=CC(=O)N1CCCC1
Solvent: CO
Product: CC(CC(=O)N1CCCC1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
Following the procedure of Example 4, 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.Og, 0.008 mole) and 1-(1-oxo-2-butenyl)pyrrolidine (1.llg, 0.008 mole) were dissolved in methanol (20ml) under an argon atmosphere and refluxed for 24 hours. The solvent was removed and the product isolated by chromatography on silica, and recrystallized from hexane to yield the product as a white solid, m.p. about 95°-99° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][N:20]=1>>[NH2:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:21][N:20]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cnc(N)nc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (20 mg, 26%), MS (ISP) m/z=312.5 [(M+H)+], mp 310° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 2-amino-pyrimidin-5-ylboronic acid (45.1 mg, 0.325 mmol).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[S:19][C:18]([CH2:20][C:21]([O:23]CC)=[O:22])=[N:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Li+].[OH-]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[S:19][C:18]([CH2:20][C:21]([OH:23])=[O:22])=[N:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cc1nnc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CC(=O)O)s2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
To a solution of compound 118E (128 mg, 0.33 mmol) in THF (15 mL) was added 0.1 M aqueous LiOH (3.75 mL) and the mixture was stirred at room temperature. After 24 h, the resultant solution was acidified to pH 4 and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (20 mL) and concentrated to give the crude product, which was further purified by chromatography on 70-230 mesh silica gel eluted with CH2Cl2:methanol:water 40:10:1 to afford 104 mg (0.29 mmol, 88%) of the product as a solid, mp 206-207° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.05 (s, 3H), 3.81 (s, 2H), 7.65 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 24.8, 37.3, 119.0, 127.5, 137.9, 142.6, 153.3, 169.4, 169.5, 170.9; MS (LCQ, ESI+) Calcd for C12H13N4O5S2 357.0, found 357.0 (M+H)+; HRMS (ESI+, m/z) Calcd for C12H13N4O5S2 357.0327, found 357.0326 (M+H)+.
Reaction SMILES: C1C(=O)N(Br)C(=O)C1.[Cl:9][C:10]1[N:15]=[C:14]([CH2:16][C:17]([C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)=O)[CH:13]=[CH:12][N:11]=1.[NH2:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]1)=[S:40].O>CC(N(C)C)=O>[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[S:40][C:39]([N:41]3[CH2:42][CH2:43][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:45][CH2:46]3)=[N:38][C:17]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[C:20]=2[F:37])[CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
NBS (0.21 g, 1.2 mmol) was added to a stirring solution of N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (0.50 g, 1.13 mmol) in DMA (5.5 ml) at rt. The reaction was allowed to stir for 15 min, then 1,1-dimethylethyl 4-(aminocarbonothioyl)-1-piperazinecarboxylate (0.55 g, 2.26 mmol) was added and the reaction was allowed to stir for 1 h. LCMS analysis indicated the reaction had progressed sufficiently, the reaction was poured into water and the bright yellow precipitate was collected by filtration. The filter cake was dissolved in DCM, dried over MgSO4, filtered and the filtrate was concentrated onto silica gel. Purification by flash chromatography afforded the title compound of Step B (0.36 g, 45% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.79 (s, 1H), 8.32 (d, J=5.5 Hz, 1H), 7.25-7.64 (m, 6H), 6.47 (d, J=5.5 Hz, 1H), 3.53-3.58 (m, 4H), 3.43-3.51 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([NH:16][C:17]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][N:18]=1)(=[O:15])[CH3:14].O>O1CCCC1>[C:13]([NH:16][C:17]1[CH:22]=[C:21]([CH2:23][O:24][S:9]([CH3:8])(=[O:11])=[O:10])[CH:20]=[CH:19][N:18]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1cc(CO)ccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(COS(C)(=O)=O)ccn1
Reaction time: 0.33 h
Yield: 87 %

Procedure:
A solution of triethylamine (1.7 mL, 12 mmol) and methanesulfonyl chloride (0.70 mL, 9.0 mmol) in anhydrous tetrahydrofuran (3.0 mL) was added to a solution of (2-acetylaminopyridin-4-yl)methanol (Reference compound No. 12-1, 1.0 g, 6.0 mmol) in anhydrous tetrahydrofuran (9.0 mL) under ice-cooling, and the mixture was stirred for 20 minutes. Water (30 mL) was added to the reaction mixture, the whole was extracted with ethyl acetate (40 mL) three times, and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was filtered off with hexane. The solid was dried under reduced pressure at 40° C. to give 1.3 g of the title reference compound as a pale yellow solid. (Yield 87%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17][CH2:18]O>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1F
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(I)ccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 2-fluoro-5-iodobenzoic acid (Oakwood, 0.99 g, 3.72 mmol) in EtOH (7.4 mL) was added H2SO4 (198 μL, 3.72 mmol). The resulting reaction mixture was stirred at 100° C. overnight and then concentrated in vacuo. The crude oil was purified using flash column chromatography (gradient from 0% to 10% EtOAc/hexanes) to give the title compound (916 mg, 84%) as a colorless oil. 1H NMR (CDCl3) δ 8.24 (dd, J=6.8, 2.4 Hz, 1H), 7.81 (ddd, J=8.8, 4.5, 2.4 Hz, 1H), 6.93 (dd, J=10.3, 8.6 Hz, 1H), 4.41 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.[C:18]1([C:24]([CH3:44])([CH3:43])[C:25]([NH:27]C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO>[N:12]1([C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([NH:27][C:25](=[O:26])[C:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:44])[CH3:43])=[CH:3][CH:4]=3)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccccc1
Reactant: Brc1ccc2ncc(N3CCOCC3)nc2c1
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: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C(=O)Nc1ccc2ncc(N3CCOCC3)nc2c1)c1ccccc1
Temperature: 120 °C
Yield: 168.8 %

Procedure:
A mixture of 7-bromo-2-morpholin-4-yl-quinoxaline [intermediate example 2.1] (50 mg), 2-phenyl-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isobutyramide (87 mg, 0.24 mmol) and Pd(PPh3)4 in 1:1 Toluene/EtOH (2 mL) was treated with 1M aq. sodium carbonate solution and heated at 120° C. under microwave irradiation for 15 minutes. The reaction was partitioned between EtOAc and water, the phases separated and the organic layer concentrated in vacuo. The reaction was repeated and the combined crude products were purified by trituration with DMSO to give the title compound (108 mg). UPLC-MS: RT=1.36 min; m/z (ES+) 453.27 [MH+]; required MW=452.56.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][C:27]=3[Cl:28])[NH:24][CH:23]=[C:22]4[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:28][C:27]1[CH:26]=[C:25]2[C:21]([C:22]([C:29]([OH:31])=[O:30])=[CH:23][NH:24]2)=[CH:20][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCNC4)cc3)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 129.1 %

Procedure:
To a mixture of 5-{4-[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]phenyl}-6-chloro-1H-indole-3-carboxylic acid (15 mg, 0.0341 mmol) in dichloromethane (2 mL) was added TFA (0.213 g, 1.87 mmol) and the resulting mixture was stirred for 45 min at room temperature. The reaction mixture was concentrated in vacuo to give 6-chloro-5-[4-(pyrrolidin-3-yl)phenyl]-1H-indole-3-carboxylic acid (15 mg) as an off-white solid. MS (ES+) 341.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.99 (br, 1 H), 8.92 (br, 1 H), 8.09 (d, 1 H), 7.94 (s, 1 H), 7.65 (s, 1 H), 7.43 (m, 4 H), 3.70 (m, 1 H), 3.50 (m, 4 H), 3.17 (m, 1 H), 2.04 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[C:25]([O:28]C(=O)C)(=[O:27])[CH3:26]>O>[C:25]([OH:28])(=[O:27])[CH3:26].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: CC(=O)OC(C)=O
Agent: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: O
Product: CC(=O)O

Procedure:
In a manner similar to Example 12, a mixture of 8-chloro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine and acetic anhydride was heated on the water bath to give 8-chloro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine acetate (ester).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:16]=2[C:17](O)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:16]=2[C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])[CH2:14][CH2:13]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C1CC1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1ccc(C(F)(F)F)cc1C1CC1

Procedure:
The title compound, white solid, MS: m/e=367.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-cyclopropyl-4-trifluoromethyl-benzoic acid (intermediate K).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:4]=1[CH:5]=O.CN.[BH3-][C:15]#[N:16].[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[F:11][C:9]1[CH:8]=[CH:7][C:4]([CH2:5][NH:16][CH3:15])=[C:3]([S:2][CH3:1])[CH:10]=1
Reactant: [BH3-]C#N
Reactant: CSc1cc(F)ccc1C=O
Agent: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(F)cc1SC
Reaction time: 20 h

Procedure:
A solution of 2-methylthio-4-fluorobenzaldehyde (2.04 g, 12 mmol) and 2M methylamine in methanol (24 mL, 48 mmol) was stirred at room temperature for 2 h. To this was added a solution of ZnCl2 (0.818 g, 6 mmol) and NaCNBH3 (0.754 g, 12 mmol) in methanol (30 mL). After stirring for 20 h, the reaction mixture was concentrated and the resulting residue was taken up in aqueous NaOH (0.5 M, 20 mL), extracted with CH2Cl2 (5×50 mL). The combined organic layers were concentrated and the resulting residue was taken up in 1N HCl (25 mL). This solution was extracted with ethyl acetate (3×25 mL). The organic layers were discarded and aqueous layer was brought to pH 9 by adding Na2CO3 and extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 layers were dried over MgSO4, filtered and concentrated to give the desired benzylamine as a viscous pale yellow oil (1.4 g, 60% pure).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([CH:21]=[C:22](Br)Br)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:30]#[N:31].C1N2CCN(CC2)C1>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:25])[C:5]([CH2:21][C:22]2[NH:35][C:34]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=3[N:26]=2)=[C:6]2[C:10]=1[N:9]([S:11]([C:14]1[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=C(Br)Br)c(C)cc(Cl)c32)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: C1CN2CCN1CC2
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Cc4nc5cc(C#N)ccc5[nH]4)c(C)cc(Cl)c32)cc1
Reaction time: 8 h

Procedure:
A solution of 7-chloro-4-(2,2-dibromovinyl)-5-methyl-1-tosyl-1H-indole (67 mg, 0.133 mmol), 3,4-diaminobenzonitrile (26.6 mg, 0.200 mmol) and DABCO (44.8 mg, 0.399 mmol) in NMP (0.5 mL) was stirred at 110° C. After stirring overnight, the reaction mixture was loaded onto silica gel and was purified by flash chromatography (0-100% EtOAc in heptanes) to provide 2-((7-chloro-5-methyl-1-tosyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile. The obtained compound was dissolved in EtOH (5.0 mL), and KOH (0.118 g, 2.105 mmol) and isoamylamine (0.489 mL, 4.21 mmol) were added, and the mixture was stirred at 100° C. in the microwave for 30 minutes. The reaction mixture was loaded onto silica gel and was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (s, 1H) 11.33 (br. s., 1H) 7.93 (s, 1H) 7.57 (d, J=8.84 Hz, 1H) 7.47 (dd, J=8.34, 1.52 Hz, 1H) 7.33 (t, J=2.78 Hz, 1H) 7.06 (s, 1H) 6.52-6.63 (m, 1H) 4.45 (s, 2H) 2.39 (s, 3H). HRMS calcd. for C18H13ClN4 (M+H)+ 321.0902. found 321.0906.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][C:7]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:6][CH:5]=2.[H-].[Na+].[C:22](=O)([O:26]C1C=CC=CC=1)[O:23][CH2:24][CH3:25].O>CN(C)C=O.C(O)(=O)C>[C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:8]=2)[NH:3][C:2]=1[NH:1][C:22](=[O:26])[O:23][CH2:24][CH3:25])#[N:12]
Reactant: CCOC(=O)Oc1ccccc1
Reactant: N#Cc1c(N)[nH]c2ccc(Sc3ccccc3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Nc1[nH]c2ccc(Sc3ccccc3)cc2c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of 2-amino-3-cyano-5-(phenylthio)indole (1.5 g., 5.7mM.) in dimethyl formamide (20 ml.) was added sodium hydride (0.27 g., 50% w/w dispersion in mineral oil, 5.7mM.) followed by ethyl phenyl carbonate (0.94 g., 5.7mM.). The mixture was stirred overnight and allowed to warm to room temperature. T.l.c. indicated the reaction was complete. The reaction mixture was poured into rapidly stirred water and neutralised with acetic acid. The cream-coloured precipitate was filtered off and dried to give the crude product (1.62 g.) m.p. 181°-2° C. Recrystallisation from ethanol gave colourless crystals of ethyl 3-cyano-5-(phenylthio)indol-2-ylcarbamate, m.p. 190.5°-191.5° C. (0.82 g., 43%). ##STR2##
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][CH:22]=[C:14]([F:13])[CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 3-fluorobenzoic acid (256 mg, 1.83 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) were placed in DCM (5 mL) and stirred at room temperature for 30 minutes. 3M LiOH (3 mL) was then added. The reaction was stirred for 10 minutes and then poured into water. The aqueous layer was extracted several times with DCM, and the combined organic phases were dried, filtered, and concentrated to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluorobenzamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][N:28]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([F:24])[CH:21]=1)[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[N:9]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3cc(F)cc(F)c3)cc1)nn2C[C@H]1CCCN1
Yield: 99.5 %

Procedure:
Into a 100 mL, round-bottom flask, was placed a solution of tert-butyl (2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (230 mg, 0.44 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by the addition of trifluoroacetic acid (10 mL) dropwise with stirring over 10 mM. The resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum to give 0.185 g (crude) of 3-[4-(3,5-difluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a brown oil.