Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].CN(C=O)C.[H-].[Na+].F[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:23]=2[CH:24]=1>O>[F:1][CH:2]([F:5])[CH2:3][O:4][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[C:20]1[O:21][C:22]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][C:23]=2[CH:24]=1
Reactant: OCC(F)F
Reactant: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)COc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
A mixture of 75 mg of 2,2-difluoroethanol and 0.5 ml of DMF was added to a mixture of 36 mg of sodium hydride (60%, oil-based) and 3 ml of DMF under ice-cooling. This mixture was stirred at room temperature for 15 minutes, and then ice-cooled. Subsequently, 0.20 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine was added thereto, and the mixture was stirred at room temperature for 3.5 hours. Thereto was added a mixture of 29 mg of 2,2-difluoroethanol, 0.5 ml of DMF and 14 mg of sodium hydride (60%, oil-based), and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 3-(2,2-difluoroethoxy)-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 10”).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[N:6]=1.CCN(CC)CC.[CH3:32][C:33](OC(C)=O)=[O:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:33]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[N:6]=1)(=[O:34])[CH3:32]
Reactant: COC(=O)c1ccc(Cn2c(CCCN)nc3ccccc32)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2c(CCCNC(C)=O)nc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 34.8 %

Procedure:
To a round bottom flask charged with methyl 4-((2-(3-aminopropyl)-1H-benzo[d]imidazol-1-yl)methyl)benzoate 34 (135 mg, 0.417 mmol) in DCM (5 mL) was added Et3N (0.076 mL, 0.543 mmol) and catalytic DMAP (5 mg, 0.042 mmol). The reaction was cooled to 0° C. and then Ac2O (0.051 mL, 0.543 mmol) was added dropwise. The resulting solution was allowed to warm to RT and stirred for 18 h after which the reaction was quenched with H2O (10 mL) and extracted with chloroform (3×10 mL). Combined extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified using automated column chromatography method 2 and isolated as a white, waxy solid (53 mg, 35%). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.0 Hz, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.24 (m, 3H), 7.07 (d, J=8.0 Hz, 2H), 6.73 (br s, 1H), 5.38 (s, 2H), 3.88 (s, 3H), 3.33 (m, 2H), 2.89 (t, J=7.2H, 2H), 2.05 (m, 2H), 1.86 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.44, 166.32, 154.48, 141.76, 140.60, 134.98, 130.26, 129.91, 126.00122.81, 122.49, 118.89, 109.42, 52.12, 46.60, 38.91, 26.42, 24.92, 22.97. ESI-LRMS: [M+H]+=366 m/z.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+]>C1COCC1.CO.[Pd]>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOC(=O)c1ncc2ccc(Oc3ccc(N)cc3)cc2c1O
Yield: 69.8 %

Procedure:
100 mg of 1-chloro-4-hydroxy-6-(4-nitro-phenoxy)-isoquinoline-3-carboxylic acid butyl ester was dissolved in 3 ml THF and 3 ml methanol. 20 mg of sodium acetate and 25 mg of 10% palladium on carbon were added to the mixture, and the stirring reaction was placed under hydrogen atmosphere (balloon) overnight. The resultant solution was filtered through a pad of celite and concentrated to a residue. The crude material was purified by column chromatography on silica gel, eluting the product with a gradient of 0-20% ethyl acetate in dichloromethane, to produce 59 mg of product; MS (−): m/z 351.27 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[OH:13])[C:6]3[CH2:20][CH2:21][NH:22][CH2:23][C:5]=3[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30]([O:32][C:33](=[O:36])[CH2:34]Br)[CH3:31]>C(#N)C.O>[CH2:30]([O:32][C:33](=[O:36])[CH2:34][N:22]1[CH2:21][CH2:20][C:6]2[N:7]([CH2:11][CH:12]([OH:13])[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]=2[CH2:23]1)[CH3:31]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (200 mg, 0.651 mmol) in acetonitrile (4 mL), potassium carbonate (270 mg, 1.953 mmol) and bromo-acetic acid ethyl ester (163 mg, 0.977 mmol) were added and the reaction mixture was stirred at RT for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to yield [5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-acetic acid ethyl ester (220 mg). To a solution of [5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-acetic acid ethyl ester (120 mg, 0.305 mmol) in ethanol (2 mL), 1N NaOH (3 mL) was added and the reaction mixture stirred at RT for 1 h. The progress of reaction was monitored by LCMS. The reaction mixture was neutralized with aq HCl. The solvent was removed under reduced pressure and the residue diluted with 90% MeOH in DCM and filtered. The filtrate was concentrated and residue was purified by reverse phase HPLC to yield [5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-acetic acid. 1H NMR (CD3OD, formate salt) δ (ppm): 8.42 (d, 2H), 7.4 (d, 2H), 7.2 (d, 2H), 6.9 (d, 1H), 5.03 (t, 1H), 4.6 (bs, 1H), 4.57 (bs, 2H), 4.3 (m, 2H), 3.8 (s, 2H), 3.7 (bs, 2H), 3.0 (m, 1H), 2.3 (s, 3H). Separation by chiral HPLC provides enantiomers II-65a-b.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].I[C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:17]=2)[N:12]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:11]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH:28]([S:25]([C:22]1[CH:23]=[CH:24][C:19]([C:16]2[N:17]=[C:18]3[C:10]([C:2]#[C:1][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:11][N:12]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:33])=[O:32])[C:13]3=[N:14][CH:15]=2)=[CH:20][CH:21]=1)(=[O:27])=[O:26])([CH3:30])[CH3:29]
Reactant: C#Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C#Cc3ccccc3)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 67.2 %

Procedure:
Ethynylbenzene (34.26 mg, 36.92 μL, 0.3354 mmol) was added dropwise to a stirred solution of 7-iodo-2-(4-isopropylsulfonylphenyl)-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine (150 mg, 0.2580 mmol), triethylamine (130.5 mg, 179.8 μL, 1.290 mmol), copper(I) iodide (5.896 mg, 0.03096 mmol) and Pd(PPh3)4 (14.91 mg, 0.01290 mmol) in DMF (1.3 mL) and the resulting solution stirred at ambient temperature for 64 hours. The solution was added dropwise to a mixture of EtOAc/ice water and the layers separated. The organic layer was washed with brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 12 g column, eluting with 2 to 20% EtOAc/DCM, loaded in DCM) to give the sub-title product as an off-white solid (96.4 mg, 67% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.19 (d, 6H), 2.38 (s, 3H), 3.49 (s, 1H), 7.50 (t, 5H), 7.64 (t, 2H), 8.01 (d, 2H), 8.10 (d, 2H), 8.44 (d, 2H), 8.81 (s, 1H) and 9.24 (s, 1H) ppm; MS (ES+) 556.1.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[OH:10][CH2:9][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:8]=1
Reactant: Nc1ccc(CO)cc1Br
Reactant: COc1ccc(B(O)O)cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cc(CO)ccc2N)cc1
Yield: 138 %

Procedure:
To a degassed solution of crude 2-bromo-4-hydroxymethylaniline (3.2 g, 15.8 mmol), 4-methoxybenzeneboronic acid (2.89 g, 19 mmol) and potassium carbonate (4.77 g, 34.8 mmol) in toluene/ethanol 2/1 (45 mL) a catalytic amount of Pd(PPh3)4 (0.2 g, 1 mmol %) was added and the mixture was heated at 90 C for 5 hours. The residue was extracted into ethyl acetate and washed with water and then saturated brine and dried over sodium sulphate. The solvent was removed under reduced pressure to afford 5 g of crude product. C14H15BNO2 Mass (calculated) [229.28]; (found) [M+H+]=230 Lc Rt=0.88, 89%. NMR (400 MHz, CDCl3): 3.75 (3H, s, MeO); 4.5 (2H, s, CH2O); 6.65 (1H, d, J=8.5 Hz, aryl-H); 6.9 (2H, d, J=8.5 Hz, aryl-H); 7-7.1 (2H, m, aryl-H); 7.25 (2H, d, J=8.5 Hz, aryl-H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.CCN(C(C)C)C(C)C.[C:41]([O:45][C:46]([N:48]([CH2:50][C:51](O)=[O:52])[CH3:49])=[O:47])([CH3:44])([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:41]([O:45][C:46](=[O:47])[N:48]([CH2:50][C:51](=[O:52])[NH:1][CH2:2][C@H:3]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2)[CH3:31])[CH3:49])([CH3:44])([CH3:42])[CH3:43]
Reactant: C[C@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](CNC(=O)CN(C)C(=O)OC(C)(C)C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reaction time: 18 h

Procedure:
5-[(1R)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 65, preparation of starting materials, 868 mg) was stirred in DCM (40 ml) with DIPEA (1 ml). N-(tert-butoxycarbonyl)sarcosine (400 mg) and HATU (800 mg) were added and mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue was purified by chromatography, eluting with increasing concentrations of methanol in ethyl acetate (0-10%). Evaporation of the appropriate fractions gave the title compound as a froth (0.50 g); NMR spectrum (DMSO-d6 @ 373k) 1.10 (s, 6H), 1.20 (s, 3H), 1.40-1.42 (d, 3H), 2.72 (s, 3H), 3.40-3.60 (d, 1H, (masked by H2O), 3.60-3.75 (q, 2H), 3.75-3.80 (d, 1H), 4.90-5.00 (bs, 1H), 5.30 (s, 2H), 7.28-7.34 (q, 2H), 7.34-7.40 (m, 1H), 7.42-7.46 (d, 1H), 7.50-7.62 (m, 2H), 7.85-7.91 (dt, 1H), 7.91-7.99 (m, 2H), 8.24-8.34 (bs, 1H), 8.57-8.62 (d, 1H), 8.75 (s, 1H), 10.60-10.70 (bs, 1H); Mass spectrum MH+ 607.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:17].O.O.[C:20](O)(=[O:24])[C:21](O)=[O:22]>Cl>[OH:22][C:21]1[C:20]([OH:24])=[N:17][C:4]2[CH:5]=[CH:6][C:7]3[C:8]([S:13](=[O:14])(=[O:15])[NH2:16])=[CH:9][CH:10]=[CH:11][C:12]=3[C:3]=2[N:2]=1
Reactant: Nc1ccc2c(S(N)(=O)=O)cccc2c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: NS(=O)(=O)c1cccc2c1ccc1nc(O)c(O)nc12
Temperature: 25 °C
Yield: 122.6 %

Procedure:
A mixture of 5,0 g (21,0 mmol) 1,2-diamino-naphthalene-5-sulphonamide hydrochloride salt and 6,0 g oxalic acid dihydrate in 200 ml 2N hydrochloric acid was refluxed for 2,5 h. After cooling to 25° C., the precipitate was filtered off and washed with water. The crude product was recrystallized (dimethylformamide-water) to give 7,5 g (69%) 2,3-dihydroxy-7-sulphamoyl-benzo[f]quinoxaline.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]2[NH:7][C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3cc(F)c(Cl)cc3c2C1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)c(F)cc3n2CCc2ccc(C(F)(F)F)nc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.5 %

Procedure:
To a solution of 8-Chloro-7-fluoro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.0041 mol) in N-methyl 2-pyrolidone (0.5 mL) was added powdered potassium hydroxide (0.08 g, 0.00143 mol) and allowed to stir for 10 min at RT. 2-trifluoromethyl-5-vinyl pyridine (0.079 g, 0.00046 mol) was added and stirred for further 15 h. at rt, After completion (TLC), reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through preparative HPLC to give the desired compound 10 as light yellow solid (0.02 g, 12% yield), 8-Chloro-7-fluoro-2-methyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.02 g, 0.0000485 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.006 g, 0.0000485 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as white solid (0.015 g, 62% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F-].[K+].[CH:21]1([NH2:24])[CH2:23][CH2:22]1.O>CC1C=CC=CC=1C>[Cl:18][C:12]1[C:11]([NH:10][C:8]([C:7]2[C:2]([NH:24][CH:21]3[CH2:23][CH2:22]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[C:16]([CH3:17])[CH:15]=[CH:14][N:13]=1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Reactant: NC1CC1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1NC1CC1
Temperature: 135 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (50 g), potassium fluoride (30.85.g), cyclopropylamine (40.43 g) were suspended in o-xylene (150 ml) and heated to 130-140° C. in autoclave for 5-8 h. Then the reaction mass was cooled to 25-30° C., diluted with o-xylene (250 ml) and further heated the reaction mass to 70-75° C. Thereafter, DM water (150 ml) added and stirred for 10 min at 70-75° C. The aqueous layer was separated at hot condition and organic layer was washed with DM water (150 ml) at 70-75° C. and organic layer was concentrated at 60-63° C. under reduced pressure up to residual weight attained is approximately 200 g. The concentrated mass was cooled to 25-30° C. and stirred for 15 min and further cooled to 5-10° C. and stirred for 30 min. Filtered the solid obtained and washed with chilled o-xylene (50 ml, 5-10° C.). Dried the obtained solid at 45-50° C. under reduced pressure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11](O)[CH:10]([NH:14][CH2:15][CH2:16][OH:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>S(=O)(=O)(O)O.O>[CH2:1]([N:8]1[CH2:12][CH:11]2[CH:10]([NH:14][CH2:15][CH2:16][O:17]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCNC1CN(Cc2ccccc2)CC1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CN2CC3NCCOC3C2)cc1

Procedure:
15.6 g (66 mmol) of 1-benzyl-4-hydroxy-3-(2-hydroxyethylamino)-pyrrolidine are heated under reflux in a mixture of 60 ml of concentrated sulphuric acid and 20 ml of water for 6 hours. The mixture is rendered alkaline with concentrated sodium hydroxide solution, the sodium sulphate which has precipitated is filtered off with suction and the filtrate is extracted with chloroform. The extract is dried over potassium carbonate and concentrated and the residue is distilled.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH:16]=[N:15][C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][C:5]=3[NH:6][C:7]=2[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1.B1([O-])O[O:23]1.O.O.O.O.[Na+].Cl>C(O)C.O>[Br:1][C:2]1[C:3]2[C:4]3[CH:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:5]=3[NH:6][C:7]=2[C:8]([C:11](=[O:23])[NH2:12])=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1cc2[nH]c3c(C#N)ccc(Br)c3c2cn1
Reactant: [O-]B1OO1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C(=O)O)ncc12
Temperature: 100 °C
Yield: 79.2 %

Procedure:
A suspension of crude ethyl 9-bromo-6-cyano-5H-pyrido[4,3-b]indole-3-carboxylate (0.78 g, 2.266 mmol) and sodium perborate tetrahydrate (1.395 g, 9.07 mmol) in ethanol-water (3:2, 99 mL) was heated at 100° C. for 3 h. The mixture was cooled to room temperature and the ethanol was removed under vacuum to give a suspension. The pH was adjusted to about 5-6 with 1 M aqueous HCl. The precipitate was collected by filtration, washed with water and air-dried to afford the desired product (0.60 g). The filtrate was concentrated under vacuum to provide additional desired product (70 mg, total of 88% yield). LCMS (M+H)+ m/z 334.0, 335.9.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:4]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:27]1[S:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1.O>CS(C)=O>[S:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[N:15]1[CH2:16][CH2:17][CH:12]([N:5]2[C:6]3=[N:7][CH:8]=[CH:9][N:10]=[C:11]3[C:3]([CH3:19])([CH3:2])[C:4]2=[O:18])[CH2:13][CH2:14]1
Reactant: Clc1nc2ccccc2s1
Reactant: CC1(C)C(=O)N(C2CCNCC2)c2nccnc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C(=O)N(C2CCN(c3nc4ccccc4s3)CC2)c2nccnc21
Temperature: 110 °C
Yield: 46.7 %

Procedure:
A mixture of 7,7-dimethyl-5-(piperidin-4-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one hydrochloride (Intermediate 78) (0.107 g, 0.378 mmol), potassium carbonate (0.183 g, 1.324 mmol), and 2-chlorobenzo[d]thiazole (0.077 g, 0.454 mmol) in DMSO (3 mL) was heated at 110° C. in 2 h. The reaction mixture was cooled, H2O was added, and extracted with DCM (3×). The organic extracts were dried over Na2SO4, filtered, concentrated, and purified by reverse phase HPLC. The pure fractions were concentrated to minimal H2O, neutralized with saturated aqueous NaHCO3. The white solid was collected, washed with H2O, and dried to afford the title compound (67 mg, 47%). MS (M+1): 380. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.04-8.19 (2 H, m), 7.77 (1 H, d, J=7.4 Hz), 7.46 (1 H, d, J=8.0 Hz), 7.21-7.35 (1 H, m), 6.98-7.14 (1 H, m), 4.46-4.65 (1 H, m), 4.18 (2 H, d, J=13.1 Hz), 3.32-3.41 (2 H, m), 2.52-2.62 (2 H, m), 1.83 (2 H, d, J=10.8 Hz), 1.33 (6 H, s)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:16]([CH3:18])[CH3:17]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH:16]([CH3:18])[CH3:17])[CH:3]=1
Reactant: CC(C)I
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Sc1cccc(Br)c1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
3-Bromobenzenethiol (1 g, 5.3 mmol) was added to acetone (25 mL). Next was added potassium carbonate (1.46 g, 10.58 mmol) and 2-iodopropane (1.17 g, 6.88 mmol). This was refluxed for 5 h. Reaction was then cooled to rt and filtered through a pad of Celite. The organic was then concentrated in vacuo and taken up in ether at which time a white precipitate crashed out. The organic was then re-filtered through the same celite plug and concentrated in vacuo to provide 1.14 g (93.17%) of 1-bromo-3-isopropylsulfanyl-benzene as an oil. 1H-NMR (methylene chloride -d2) δ 7.54 (s, 1H), 7.37-7.31 (m, 2H), 7.18 (t, J=7.9 Hz, 1H), 3.50-3.36 (m, 1H), 1.31 (d, J=6.1 Hz, 6H); LC-MS RT: 4.15, [M+H]+: 233.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]=[C:8]=[O:9])=[CH:2]1.[N+:10](=[C:12]1[N:16]=[CH:15][N:14]=[C:13]1[C:17]([NH2:19])=[O:18])=[N-:11]>CS(C)=O>[O:9]=[C:8]1[N:7]([CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:11]=[N:10][C:12]2=[C:13]([C:17]([NH2:19])=[O:18])[N:14]=[CH:15][N:16]12
Reactant: O=C=NCc1ccsc1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: NC(=O)c1ncn2c(=O)n(Cc3ccsc3)nnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophen-3-ylmethyl isocyanate (0.306 g, 2.2 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (off-white) removed by filtration, washed with water and ethyl acetate and air dried. Yield: 0.235 g, 42%. IR vmax/cm−1 3094, 1728, 1688, 1604. 1H NMR δH (DMSO-d6) 5.50 (2H, s, CH2Ar), 7.17 (1H, dd, J 4.9, 1.3, ArH), 7.55-7.58 (2H, m, ArH), 7.70 (1H, br s, NH), 7.83 (1H, br s, NH), 8.85 (1H, s, 6-H). δC (DMSO-d6) 48.0, 124.4, 127.3, 128.0, 129.5, 131.4, 134.9, 136.7, 139.5, 162.0.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH:5](=[N:3][CH2:2][CH2:1][N:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: NCCN
Solvent: Cc1ccccc1
Product: C(=NCCN=Cc1ccccc1)c1ccccc1

Procedure:
A mixture of ethylene diamine (12.02 g; 0.2 mole) and benzaldehyde (42.44 g; 0.4 mole) in toluene (200 ml) was refluxed for 4 hours using a Dean-Stark trap. The toluene was then removed under vacuum. The residual oil crystallized on cooling. The resulting product was dried in a vacuum oven for 24 hours at room temperature and had a melting point of 52°-54° C.