Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:38]2[CH:50]=[CH:49][C:41]([CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:40][CH:39]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:38]2[CH:39]=[CH:40][C:41]([CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:49][CH:50]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
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: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 55 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The solution was heated at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.065 g, 55%). LCMS: 559.35 (M+1)+; HPLC % 99.26 (@254 nm) (Rt; 3.983; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.15 (t, 1H), 7.58 (d, 2H, J=8 Hz), 7.36 (d, 3H, J=8.4 Hz), 7.18 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.84 (d, 2H, J=11.2 Hz), 3.57 (m, 3H), 3.48 (m, 3H), 3.24 (m, 2H), 3.40 (m, 1H), 2.63 (s, 3H), 2.36 (m, 4H), 2.23 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.60 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([OH:12])[C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.C(OCC)C>[CH2:16]([NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([OH:12])[C:3]=1[N+:13]([O-:15])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)cc(C(F)(F)F)nc1O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1O
Temperature: 25 °C
Yield: 115 %

Procedure:
4-Chloro-3-nitro-6-trifluoromethyl-pyridin-2-ol (65.1 gm 268 mmol) was dissolved in tetrahydrofuran (350 mL) and stirred at room temperature under N2. Benzylamine (86.3 gm 805 mmol) in tetrahydrofuran (50 mL) was added drop wise over 30 minutes to give a bright yellow solution. The reaction was heated in an oil bath at 50° C. for 18 hours, (a solid formed during the reaction). The resulting mixture was then cooled to ambient temperature, diluted with diethyl ether (200 mL) and the resulting solid (benzylamine hydrochloride) was then filtered off. The filtrate was evaporated to low bulk under reduced pressure to give a thick yellow slurry. Added diethyl ether (300 mL) and filtered off the yellow solid, dried on the filter pad to give the benzylamine salt (96.5 gm). The desired product was liberated by partition of the solid between aqueous 2N HCl and dichloromethane and crystallization from ethyl acetate/n-pentane gave the title compound as a pale yellow solid (61.7 gm 73.4% yield).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[P:9](Cl)(Cl)([O:11][CH3:12])=[O:10].C(#N)C>C(N(CC)CC)C>[P:9]1([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)([O:11][CH3:12])=[O:10]
Reactant: COP(=O)(Cl)Cl
Reactant: Oc1ccccc1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COP1(=O)Oc2ccccc2O1
Temperature: -25 °C
Yield: 129.5 %

Procedure:
To 1.418 g of pyrocatechol were added 1.917 g of methyl dichlorophosphate and 11 ml of acetonitrile. The mixture was cooled to -25° C. and 2.605 g of triethylamine was added dropwise at -25° C. to -20° C. with stirring. The dropping funnel was washed with 1 ml of acetonitrile and the washings were added to the mixture. After stirring at the same temperature for 10 minutes, the reaction mixture was allowed to return to 10° C. and then filtered. The filtration residue was washed with a 5-ml and 3-ml portion of acetonitrile. The filtrate and washings were concentrated under reduced pressure on a water bath at 15° C. to 20° C. to give 3.102 g of methyl o-phenylene phosphate as a slightly turbid oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[N:10]([O-])=[O:11].[Na+]>C(O)(=O)C>[OH:11][N:10]=[C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)[C:8]#[N:9]
Reactant: N#CCc1cnccn1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#CC(=NO)c1cnccn1
Yield: 88 %

Procedure:
Pyrazineacetonitrile (32 g), prepared as described in British Patent Specification No. 1 021 397, was dissolved in glacial acetic acid (250 ml). The solution was stirred and 1.2 equivalents of sodium nitrite (22.3 g) were added in small portions, while the temperature was kept under 20° C. After the addition, the reaction mixture was stirred at room temperature for another two hours. The title compound separated partly from the reaction mixture. On evaporation of the solvent under reduced pressure, a solid was obtained which on recrystallization from hot water yielded α-hydroxyiminopyrazineacetonitrile (35 g, 88%). Melting point >192° C. (dec.).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.[N:18]1([CH2:24][C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[NH4+].[OH-].CO>C(Cl)Cl>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][N:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)[CH:26]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: OB(O)c1cccc(CN2CCCCC2)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(CN4CCCCC4)c3)nc12

Procedure:
2,2-Dimethyl-1-[2-(3-piperidin-1-ylmethyl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-(piperidin-1-ylmethyl)phenylboronic acid hydrochloride following general procedures as described in these Examples. Silica gel chromatography using 0-20% [5% NH4OH:MeOH]/DCM as eluant gave a brown solid which was washed with 1:2 Et2O/Hexanes to provide 70 mg (36%) of a pale brown solid. MP 176-177° C., M+H=377.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[Cl:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10]>O.[OH-].[Na+]>[NH2:10][C:9]1[CH:8]=[C:7]([Cl:6])[CH:13]=[CH:12][C:11]=1[S:1]([OH:3])(=[O:5])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: Nc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)ccc1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 48.2 %

Procedure:
Concentrated sulphuric acid (specific gravity. 1.84) (13.9 ml, 250 mmol) was diluted with 100 ml of water. 3-Chloro-aniline (31.9 g, 250 mmol) was added over 30 minutes while temperature was kept at 85° C. During the addition some precipitation occurred. The suspension was allowed to cool to room temperature and heavy precipitation was formed. The solid is filtered with suction to yield white crystalline solid. The solid was heated slowly to 200° C. under vacuum (water pump) and fitted with a water trap. The solid was kept at 200° C. for 7 hours. Water was lost from the crystalline material. The solid was allowed to cool and then dissolved in dilute aqueous NaOH and precipitated with hydrochloric acid. Yielded 25 g (48%) of the title compound as a white crystalline solid (m.p. >250° C.).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Br:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:24][CH2:23][N:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([Br:15])[CH:17]=4)[CH2:27][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Brc1cccc(N2CCNCC2)c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCN(c2cccc(Br)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(3-bromophenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 84% overall yield. mp 144°-145°. FDMS m/e=429 (M+ of free base). α[D]589 =-8.12 (c=0.81, methanol).
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH2:2]1.[C:16]1([CH3:40])[CH:21]=[CH:20][C:19]([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)=[O:25])=[CH:18][CH:17]=1>>[C:16]1([CH3:40])[CH:17]=[CH:18][C:19]([C:22]2[CH:39]=[CH:38][CH:37]=[CH:36][C:23]=2[C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([N:7]3[C:8]4[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=4[C:10](=[O:11])[N:4]4[CH2:3][CH2:2][CH2:1][C@H:5]4[CH2:6]3)=[O:32])=[CH:29][CH:28]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: O=C1c2ccccc2NC[C@@H]2CCCN12
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)O)cc2)cc1
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3C[C@@H]4CCCN4C(=O)c4ccccc43)cc2)cc1
Yield: 74.4 %

Procedure:
The same procedures used in Example 25 were repeated using (11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one prepared in Reference Example 24 and 4-[[2-(4-tolyl)benzoyl]amino]benzoic acid to give the title compound. Yield 74.4%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])#[CH:18]>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]#[C:18][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: C#Cc1ccccc1OC
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: COc1ccccc1C#Cc1ccnc2[nH]c(=O)c3ccccc3c12
Yield: 72 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and 1-ethynyl-2-methoxy-benzene (86 mg, 0.65 mmol) to provide 164 (101 mg, 71% yield) as a white solid. LC-MS (M+H=327, obsd.=327).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:19]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:14][N:15]=2)=[O:9])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: ClCCN1CCCCC1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCN2CCCCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 1-(2-chloroethyl)-piperidine
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][C:21]([NH:20][CH2:19][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=3)=[O:22])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc2c(Cl)nccc12
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c(Cl)nccc12

Procedure:
Prepared from 1-chloroisoquinolin-5-amine (1Description 48) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to the procedure of Description 61. m/z (ES+) 380, 382 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([CH3:8])(=[O:7])[OH:6].[C:9]([O:14][CH:15]([O:17][C:18](OC1CC(=O)NC1=O)=[O:19])[CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11]>C(#N)C.O>[C:9]([O:14][CH:15]([O:17][C:18]([NH:1][CH2:2][CH2:3][CH2:4][P:5]([CH3:8])(=[O:6])[OH:7])=[O:19])[CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CP(=O)(O)CCCN
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Solvent: CC#N
Solvent: O
Product: CC(OC(=O)NCCCP(C)(=O)O)OC(=O)C(C)C

Procedure:
A solution of 3-aminopropylmethylphosphinic acid (137 mg, 1 mmol) and compound (17) (301 mg, 1 mmol) in acetonitrile (5 mL) and water (0.5 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to afford the title compound (111) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.69 (br, 1H), 6.77 (q, 1H, J=5.2 Hz), 3.27 (t, 2H, J=6 Hz), 2.53 (m, 1H), 1.83-1.73 (m, 4H), 1.45 (m, 6H), 1.15 (d, 6H, J=7.2 Hz). MS (ESI) m/z 296.1 (M+H)+, 294.1 (M−H)−.
Reaction SMILES: [CH2:1]([N:5]1[C:12]([NH2:13])=[CH:11][C:9](=[O:10])[N:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(=O)C.Cl.[N:23]([O-])=[O:24].[Na+]>O>[NH2:13][C:12]1[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:7])[N:8]([CH2:14][CH2:15][CH2:16][CH3:17])[C:9](=[O:10])[C:11]=1[N:23]=[O:24]
Reactant: CCCCn1c(N)cc(=O)n(CCCC)c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCn1c(N)c(N=O)c(=O)n(CCCC)c1=O
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a mixture of 1,3-di-n-butyl-6-amino-uracil g, 112.8 mmol), glacial acetic acid (10 ml), and 6N HCl (18.8 ml) in water (500 ml) was added dropwise a solution of sodium nitrite (7.78, g, 112.8 mmol) in water (30 ml) on ice bath. The reaction mixture was stirred for 30 min. The violet solid was collected by filtration and washed with water (2×20 ml), dried for 2 days at 60° C. in a vacuum oven to yield 6-amino-1,3-di-n-butyl-5-nitroso-uracil (24.99 g, 82.6%), m.p. 199°-205° C.; 1H NMR (CDCl3) δ0.97-1.01 (m, 6H, 2×CH3), 1.36-1.49 (m, 4H, 2×CH2), 1.62-1.74 (m, 4H, 2×CH2), 3.94 (t, J=7.8 Hz, 2H, N--CH2), 4.08 (t, J=7.5 Hz, 2H, N--CH2), 6.46 (br s, 2H, NH2). Anal. Calc'd for C12H20N4O3 : C, 53.72; H, 7.51; N, 20.88; Found: C, 54.37; H, 7.67; N, 20.65.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([O:29]C)=[O:28])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([OH:33])[C:6]=2[CH:34]=1.[OH-].[Na+].O.Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:32])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([OH:29])=[O:28])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([OH:33])[C:6]=2[CH:34]=1
Reactant: COC(=O)c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a suspension of 7-chloro-5-hydroxy-1-[6-(2-methoxycarbonyl-benzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in methanol (4 ml) is added 5% aqueous sodium hydroxide solution (1.5 ml), and the mixture is stirred at room temperature for one hour. To the reaction solution are added water and diluted aqueous hydrochloric acid solution in order to make the mixture weak acidic. The mixture is extracted with dichloromethane, and the extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from dichloromethane-methanol to give 7-chloro-5-hydroxy-1-[6-(2-carboxybenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (150 mg) as white powder.
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(OC)=[O:2].C1COCC1.[BH4-].[Na+]>O>[OH:2][CH2:1][C:5]1[N:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2c(cn1)[nH]c1ccccc12

Procedure:
3-carbomethoxy-β-carboline or a derivative thereof (J in Scheme VII above) is dissolved in a polar solvent (e.g., THF), and a reducing agent (e.g., NaBH4) is added to the solution. The mixture is stirred for a few hours and cooled. An excess of water is then added, and the mixture is stirred for another few hours. The solvent is thereafter evaporated and the resulting residue is dissolved in water, washed several times with one or more non-polar solvents such as dichloromethane and ethyl acetate, and the combined organic extracts are then evaporated. The remaining residue is purified by column chromatography (e.g., on a silica gel with elution by a 9:1 mixture of ethylacetate and methanol), to give a 3-hydroxymethyl-β-carboline intermediate.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:7]1[CH:8]=[N+:9]([O-:13])[CH:10]=[CH:11][CH:12]=1)#[N:6].[N+]([O-])([O-])=O.[K+]>>[N+:1]([C:12]1[CH:11]=[CH:10][N+:9]([O-:13])=[CH:8][C:7]=1[C:5]#[N:6])([O-:4])=[O:2]
Reactant: N#Cc1ccc[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: N#Cc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 7.5 °C
Reaction time: 0.25 h

Procedure:
One hundred fifty mL of stirred 15% fuming nitric acid is cooled to 5-10° C., and 20.4 grams (0.17 mole) of 3-cyanopyridine N-oxide is added portionwise. Upon completion of addition, the reaction mixture is stirred for about 15 minutes, and then 34.4 grams (0.340 mole) of potassium nitrate is added portionwise. Upon completion of addition, the reaction mixture is warmed to about 100° C. where it is stirred for six hours. The reaction mixture is then poured into about 1000 mL of ice-water. The mixture is stirred until the ice melts, and then the resultant solid is collected by filtration. The solid is dried under reduced pressure at about 100° C., yielding 4-nitro-3-cyanopyridine N-oxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Br
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1ccc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a solution of 2-bromo-4-(trifluoromethyl)benzenesulfonyl chloride (10 g, 0.031 mol) in CH2Cl2 (100 mL) was added t-butylamine (8.0 mL, 0.076 mol) at 0° C. The reaction mixture was allowed to warm to room temperature, and stirred for 30 min. A white precipitate formed and was filtered, and the filtrate was concentrated in vacuo to afford the title compound as a yellow oil (11 g, 100%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].Cl.Cl[CH:12]([C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[O:21])[C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>O1CCCC1.O>[NH2:1][C:2]1[S:3][C:12]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:4]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)C(Cl)C(=O)c1ccccn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N)sc1C(=O)c1ccccn1
Reaction time: 2 h
Yield: 20.7 %

Procedure:
To a solution of thiourea (4.5 g) and sodium acetate (5 g) in a mixture of tetrahydrofuran (50 ml) and water (15 ml) was added ethyl 3-chloro-4-(2-pyridyl)-2,4-dioxo-butyrate hydrochloride (5.6 g). After the mixture was stirred at 45° C. to 50° C. for 2 hours, water (50 ml) was added thereto. The resulting mixtures was acidified to pH 1.0 with 10% hydrochloric acid. The precipitate was collected by filtration. The precipitate was added to a mixture of water and ethyl acetate, and adjusted to pH 6.0 with 10% potassium carbonate. The separated ethyl acetate layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give ethyl 2-amino-5-(2-pyridinecarbonyl)-4-thiazolecarboxylate (1.1 g).
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[F:22])[N:3]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[Cl:21][C:17]1[C:16]([F:22])=[C:15]([CH2:14][S:13][C:4]2[N:3]=[C:2]([NH:26][CH2:25][CH2:23][OH:24])[C:11]3[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=3[N:5]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(Cl)c3F)nc2[nH]1
Reactant: NCCO
Product: O=c1cnc2c(NCCO)nc(SCc3cccc(Cl)c3F)nc2[nH]1

Procedure:
The titled compound (51 mg) was prepared by the method of Example 6, step (f) using the product from Example 6, step (e) (75 mg) and ethanolamine (25 μl).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][O:14][C:15]1[N:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3([C:33](O)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[C:17]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=2)[N:16]=1.[CH3:50][S:51]([NH2:54])(=[O:53])=[O:52]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][O:14][C:15]1[N:20]=[C:19]([C:21]2[CH:22]=[C:23]([C:27]3([C:33]([NH:54][S:51]([CH3:50])(=[O:53])=[O:52])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[CH:24]=[CH:25][CH:26]=2)[CH:18]=[C:17]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=2)[N:16]=1
Reactant: COc1nc(NCCc2ccc(OC(F)(F)F)cc2)cc(-c2cccc(C3(C(=O)O)CCOCC3)c2)n1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1nc(NCCc2ccc(OC(F)(F)F)cc2)cc(-c2cccc(C3(C(=O)NS(C)(=O)=O)CCOCC3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (39 mg, 0.2 mmol) is added to a stirred ice cold solution of N-[4-(3-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid (100 mg, 0.19 mmol), methanesulfonamide (19.3 mg, 0.2 mmol) and 4-dimethylaminopyridine (23.6 mg, 0.19 mmol) in dry DCM under nitrogen. The reaction mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with 0.1 N HCl, brine and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2 packed column), eluting with ethyl acetate/heptane to afford N-[4-(3-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carbonyl]-methanesulfonamide [86 mg, Example 84(a)]. LCMS: RT=2.52 minutes, LCMS: 595 (M+H). IC50=0.7 nM