Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:65]=[C:64]([Cl:66])[C:63]([Cl:67])=[C:62]([Cl:68])[CH:61]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].[NH2:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:78])([CH3:77])[CH3:76]>C(Cl)Cl>[Br:43][C:44]1[CH:52]=[C:51](/[CH:53]=[CH:54]/[CH:55]([C:60]2[CH:61]=[C:62]([Cl:68])[C:63]([Cl:67])=[C:64]([Cl:66])[CH:65]=2)[C:56]([F:59])([F:58])[F:57])[CH:50]=[CH:49][C:45]=1[C:46]([NH:69][CH2:70][CH2:71][NH:72][C:73](=[O:79])[O:74][C:75]([CH3:76])([CH3:78])[CH3:77])=[O:47]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.7 %

Procedure:
PyBOP (420 mg, 0.82 mmol) and DIPEA (0.410 mL, 2.46 mmol) were added to a stirred solution of (E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic acid (400 mg, 0.82 mmol) and tert-butyl 2-aminoethylcarbamate (130 mg, 0.82 mmol) in CH2Cl2 (10 mL) and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was partitioned between water and CH2Cl2 (25 mL). The organic layer was washed with 2N HCl followed by saturated NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 40% EtOAc in petroleum ether to afford the title compound as a brown solid (200 mg, 39%): 1H NMR (400 MHz, DMSO-d6) δ 8.38 (t, J=5.2 Hz, 1H), 7.91-7.89 (m, 3H), 7.58 (d, J=6.8 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 6.99 (dd, J=15.6, 9.2 Hz, 1H), 6.84 (t, J=6.0 Hz, 1H), 6.76 (t, J=15.6 Hz, 1H), 4.84-4.80 (m, 1H), 3.24-3.20 (m, 2H), 3.11-3.08 (m, 2H), 1.30 (s, 9H); ESIMS m/z 628.80 ([M+H]+); IR (thin film) 3365, 1701, 1167, 699, 555 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+:29]>C(O)C.O>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+:29]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])c(F)c1
Reaction time: 4 h

Procedure:
A mixture of 3.62 g. of 2-fluoro-4-(hexadecylamino)-benzoic acid and 25 ml of ethanol-water (9:1) containing 0.400 g of sodium hydroxide is stirred for 4 hours. The mixture is filtered and the residue washed with 10 ml of ethanol-water (9:1) and dried, in vacuo, over P2O5 for 24 hours to yield sodium 2-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:16][CH2:17][CH3:18])=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH3:19][NH:20][CH3:21]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:16][CH2:17][CH3:18])=[N:8][C:9]([N:20]([CH3:21])[CH3:19])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1OCC
Reactant: CNC
Solvent: CC#N
Product: CCOC(=O)c1cnc(N(C)C)nc1OCC
Temperature: 80 °C
Reaction time: 3 h

Procedure:
4-Ethoxy-2-methanesulfonyl-pyrimidine-5-carboxylic acid ethyl ester (60 mg, 0.22 mmol) was dissolved in acetonitrile. Dimethylamine (0.6 mL, 2.0 M in methanol) was added and reaction mixture was stirred in seal tube at 80° C. for 3 h. The reaction progress was checked by LC-MS. After the reaction was completed, it was concentrated to give 2-dimethylamino-4-ethoxy-pyrimidine-5-carboxylic acid ethyl ester as a white solid (50 mg). LR-MS: 239 [(M+H)+]
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[Na+]>C(O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8](=[N:12][OH:13])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)c1ccnc(N)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=NO)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a suspension of 1-(2-aminopyrimidin-4-yl)ethanone (3a) (4 g) in ethanol (70 mL) and water (14 mL) was added hydroxylamine hydrochloride (4.05 g) followed by sodium acetate (7.18 g) and the mixture was stirred at room temperature for one hour. After this time the reaction mixture was concentrated in vacuo, water was added and stirred for 15 minutes. The precipitate was collected by filtration and washed with water and dried in vacuo at 40° C. overnight to afford the title product (4.29 g) as a light yellow solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:21]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([Cl:32])=[O:31])=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[ClH:32].[CH2:21]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:31])=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 69.6 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 0.94 ml (4.96 mmol) of 4-n-butoxybenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.10 g of the desired compound (free base) (76.9%, colorless powder), mp: 98.0°-99.0° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:24][C:25]1([F:32])[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:31][CH:28]4[CH2:29][CH2:30][C:25]([F:32])([F:24])[CH2:26][CH2:27]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCC(F)(F)CC1
Temperature: 110 °C
Yield: 82.3 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.433 g, 1.28 mmol), 4,4-difluorocyclohexyl amine hydrochloride (0.242 g, 1.41 mmol), diisopropylethylamine (0.491 ml, 2.82 mmol) in propan-2-ol (10 ml) was heated at 110° C. in a microwave reactor for 20 min. The mixture was then cooled to 25° C. and was partitioned between water (50 ml) and CH2Cl2 (2×100 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the resulting yellow solid by column chromatography on silica gel (gradient: 0 to 60% EtOAc in heptanes) afforded (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(4,4-di fluoro-cyclohexyl)-amine (0.46 g, 82%) as a yellow solid. LCMS (Method G, ESI): RT=1.21 min, m+H=437; 1H NMR (400 MHz, DMSO) δ 8.91 (s, 1H), 8.83 (d, J=8.1 Hz, 1H), 8.13 (d, J=7.5 Hz, 2H), 7.84 (d, J=4.2 Hz, 1H), 7.77 (t, J=7.4 Hz, 1H), 7.66 (t, J=7.8 Hz, 2H), 7.17 (d, J=4.3 Hz, 1H), 4.39-4.26 (m, 1H), 2.29-1.98 (m, 6H), 1.83-1.68 (m, 2H).
Reaction SMILES: C1C=CN=CC=1.F.[Si]([O:15][CH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[N:25][C:26]=1[CH:27]([O:30][CH3:31])[O:28][CH3:29])[N:23]([C:32]([NH:34][C:35]1[CH:40]=[C:39]([O:41][CH:42]([CH3:44])[CH3:43])[C:38]([C:45]#[N:46])=[CH:37][N:36]=1)=[O:33])[CH2:22][CH2:21][CH2:20]2)(C(C)(C)C)(C)C>C1COCC1>[C:45]([C:38]1[C:39]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:40][C:35]([NH:34][C:32]([N:23]2[C:24]3[C:19](=[CH:18][C:17]([CH2:16][OH:15])=[C:26]([CH:27]([O:30][CH3:31])[O:28][CH3:29])[N:25]=3)[CH2:20][CH2:21][CH2:22]2)=[O:33])=[N:36][CH:37]=1)#[N:46]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(OC)c1nc2c(cc1CO)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Reaction time: 0.33 h

Procedure:
HF-Pyridine (300 μL, 3.33 mmol) was added to a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-isopropoxypyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 165, 861 mg, 1.549 mmol) in THF (8 ml) at room temperature. The reaction mixture was stirred for 5 h and 20 min, quenched with saturated aqueous NaHCO3 and partitioned with ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried using Na2SO4, filtered and concentrated to yield the title compound as a white solid. (UPLC-MS 3) tR 1.11 min; ESI-MS 442.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 13.92 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.55 (s, 1H), 5.46 (s, 1H), 4.90-4.79 (m, 1H), 4.72 (d, 2H), 4.08-4.00 (m, 2H), 3.54 (s, 6H), 2.86 (t, 2H), 2.07-1.95 (m, 2H), 1.57 (br s, 1H), 1.44 (d, 6H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:4]([OH:26])[CH2:5][N:6]([CH2:18][C:19]([CH3:25])([CH3:24])[CH2:20][CH2:21][C:22]#[N:23])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(N(C(C)C)CC)(C)C.[C:43](=O)([O:51]C1C=CC([N+]([O-])=O)=CC=1)[O:44][CH:45]1[CH2:50][O:49][CH2:48][O:47][CH2:46]1>C(Cl)Cl>[O:47]1[CH2:46][CH:45]([O:44][C:43](=[O:51])[NH:2][C@@H:3]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C@H:4]([OH:26])[CH2:5][N:6]([CH2:18][C:19]([CH3:25])([CH3:24])[CH2:20][CH2:21][C:22]#[N:23])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH2:50][O:49][CH2:48]1
Reactant: COc1ccc(S(=O)(=O)N(C[C@@H](O)[C@@H](N)Cc2ccccc2)CC(C)(C)CCC#N)cc1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COCOC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC2COCOC2)CC(C)(C)CCC#N)cc1
Yield: 64.7 %

Procedure:
N-(2R,3S)-(3-Amino-2-hydroxy-4-phenyl-butyl)-N-(4-cyano-2,2-dimethyl-butyl)-4-methoxy-benzenesulfonamide hydrochloride (0.111 g, 0.22 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.120 ml, 0.67 mmol) and 1,3-dioxan-5-yl 4-nitrophenyl carbonate (0.066 g, 0.25 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by column chromatography (1% to 3% MeOH in CH2Cl2) gave 0.084 g of a white solid. MS (ES): 590 (M+1).
Reaction SMILES: C(N(C(=O)CC)CC[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)C.[H-].[Na+].C(O[CH2:23][CH3:24])(=O)C>O1CCCC1>[C:24]1([O:12][C:9]2[CH:8]=[CH:7][CH:6]=[CH:11][CH:10]=2)[CH:23]=[CH:8][CH:7]=[CH:6][CH:11]=1
Reactant: CCOC(C)=O
Reactant: CCC(=O)N(CC)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(Oc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a stirred solution of N-ethyl,N-propionyl tyramine (2.84 g, 12.83 mmole) in tetrahydrofuran (32.1 ml) was added 60% sodium hydride dispersion (0.56 g, 14.11 mmole). After stirring for 10 minutes, the compound of Example 42(E) (4.70 g, 12.83 mmole) was added. The reaction was allowed to stir at room temperature for 5 hours, poured into ethyl acetate, and extracted with 10% sodium sulfate, then brine. The organic layer was dried over sodium sulfate, evaporated to dryness, and chromatographed on silica gel using a hexane-ethyl acetate gradient. Further chromatography on silica gel using toluene-acetone gradients yielded the intermediate phenyl ether (2.10 g, 32%):
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:17]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]([CH3:17])[S:13]([CH3:16])(=[O:15])=[O:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(I)ccc1NS(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)ccc1N(C)S(C)(=O)=O
Reaction time: 24 h
Yield: 92.4 %

Procedure:
To a solution of methyl 5-iodo-2-((methylsulfonyl)amino)benzoate (Preparation 49, 0.50 g) and K2CO3 (0.41 g) in DMF (10 mL) is added iodomethane (0.10 mL) at ambient temperature. After 24 hrs, the solvent is removed in vacuo and the residue is partitioned between Et2O (20 mL) and water (20 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude yellow liquid is purified by silica gel column chromatography (4/1, hexanes/EtOAc) to afford 0.48 g (92%) of the title compound as a white solid. Physical characteristics: m.p. 105-106° C.; 1H NMR (300 MHz, CDCl3) δ 8.22, 7.86, 7.18, 3.91, 3.27, 2.96; IR (diffuse reflectance) 1718, 1443, 1330, 1289, 1258, 1150, 1056, 970, 964, 957, 888, 839, 772, 732, 712 cm−1; MS (ESI+) m/z 370 (MH+). Anal. Found: C, 32.74; H, 3.30; N, 3.81.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[OH-].[Na+]>O1CCOCC1.C(O)C>[CH3:13][S:10]([C:8]1[CH:7]=[CH:6][C:5]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[C:4]([CH:9]=1)[C:3]([OH:19])=[O:2])(=[O:11])=[O:12]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1-c1nccs1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Yield: 50 %

Procedure:
5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid is prepared by saponification of 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid methyl ester in the presence of sodium hydroxide (2N) in a mixture of dioxane and ethanol at 80 deg for 30 minutes. Brow solid, 50% yield, MS (m/e): 282.2 (M−H, 100%)
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1>CO.[C].[Pd]>[NH2:12][C:11]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cnc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc(N)c(N)c1

Procedure:
1 Gram of methyl 6-amino-5-nitronicotinate was dissolved in 10 ml of methanol. To this solution was added 0.1 g of 5%-palladium-carbon, then hydrogen gas was absorbed at room temperature under a normal pressure. The reaction was stopped when the stoichiometric amount of hydrogen was absorbed. The catalyst was removed from the reaction mixture by filtration, and the solvent was removed by evaporation. The residue thus obtained was recrystallized from ethanol to yield 0.8 g of methyl 5,6-diaminonicotinate in the form of yellow needle-like crystals. Melting point: 154°-155° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:16]([O-])=O.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:16][S:24]([C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)(=[O:26])=[O:25]
Reactant: O=[N+]([O-])c1cccc2cc(-c3ccccn3)[nH]c12
Reactant: O=S(=O)(Cl)c1cccs1
Product: O=S(=O)(Nc1cccc2cc(-c3ccccn3)[nH]c12)c1cccs1

Procedure:
2-Pyridin-2-yl-7-nitro-1H-indole prepared in Preparation 9 and 2-thiophenesulfonylchloride were reacted according to the same procedures as Step A of Example 1 and Example 22 sequentially to give the title compound.
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]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=2)[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]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1cccc(F)c1
Product: Cc1c2n(c3c(-c4cccc(F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (73 mg, 89%), MS (ISP) m/z=329.5 [(M+H)+], mp 239° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:18][C@@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:20]2)[C@H:16]([C:30](OCC)=[O:31])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>O1CCCC1>[CH2:7]([N:14]1[CH2:18][C@@H:17]([C:19]2([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:20][CH2:21]2)[C@H:16]([CH2:30][OH:31])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1C1(NC(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC1([C@@H]2CN(Cc3ccccc3)C[C@H]2CO)CC1
Reaction time: 4 h
Yield: 101.7 %

Procedure:
Under a nitrogen atmosphere, lithium aluminum hydride (381 mg, 9.54 mmol) was suspended in anhydrous tetrahydrofuran (30 ml) to which, while cooling in an ice bath, was subsequently added dropwise an anhydrous tetrahydrofuran (10 ml) solution of ethyl trans-1-benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine-3-carboxylate (1.24 g, 3.18 mmol) over a period of 15 minutes. After 4 hours of stirring at the same temperature, ice-cooled water was gradually added to the reaction solution. The reaction suspension was subjected to celite filtration (chloroform washing) to separate the organic layer. The aqueous layer was extracted with chloroform (50 ml×2), and the organic layers were combined and dried over anhydrous sodium sulfate. By evaporating the solvent, 1.12 g (>99%) of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)=[CH:14][C:6]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl>CN(C=O)C>[Cl:1][C:2]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:19]=[N:18][N:17]([CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])[CH:16]=3)=[CH:14][C:6]1=2
Reactant: CN(C)CCCl
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4cn[nH]c4)cc32)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(-c2cnc3c(c2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cn1
Temperature: 25 °C
Reaction time: 312 h
Yield: 9 %

Procedure:
Anhydrous DMF (2 mL) was added to a mixture of 1-(2-chloro-3,6-difluorobenzyl)-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (57 mg, 0.000158 mol), cesium carbonate (0.110 g) and 2-dimethylaminoethyl chloride HCl (0.025 g). The reaction mixture was stirred at room temperature under nitrogen for 13 days and then concentrated and dissolved in methylene chloride. The organic phase was washed with water, dried with magnesium sulfate, filtered, and concentrated. The residue was purified on normal phase silica gel chromatography to give the title compound as an off-white solid (9% yield). LCMS: m/z=433.13 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.30 (6H, s), 2.79 (2H, t, J=6.8 Hz), 3.29 (2H, t, J=4.7 Hz), 3.51 (2H, m), 4.24 (2H, t, J=6.8 Hz), 4.50 (2H, s), 4.77 (1H, bs), 6.97 (1H, s), 7.02 (1H, m), 7.12 (1H, m), 7.60 (1H, s), 7.63 (1H, d, J=1.5 Hz), 7.66 (1H, s).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[S:29]1[CH2:33][C:32](=[O:34])[NH:31][C:30]1=[O:35].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:33]2[S:29][C:30](=[O:35])[NH:31][C:32]2=[O:34])=[CH:23][CH:22]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(OCCN(Cc2ccccc2)c2nc3ccccc3s2)cc1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc(OCCN(Cc3ccccc3)c3nc4ccccc4s3)cc2)S1

Procedure:
4-(2-(N-(2-Benzothiazolyl)-N-benzylamino)ethoxy)benzaldehyde (3 g) and 2,4-thiazolidinedione (1 g) were dissolved in toluene (200 ml) containing piperidine (0.2 ml) and benzoic acid (0.2 g) and heated to reflux for 4 h. in a Dean and Stark apparatus. On cooling, the solution was concentrated under vacuum to 50% of its volume and the title compound, which crystallised, was collected by filtration and dried in vacuo (m.p. 185°-188° C.). It was used in Example 27 without further purification.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][C:7]1([CH3:21])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[N:8]1.CI>O1CCCC1>[CH3:6][C:7]1([CH3:21])[CH2:11][O:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][C:13]=2[CH3:1])=[N:8]1
Reactant: CC(C)c1ccc(C2=NC(C)(C)CO2)cc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C(C)C)ccc1C1=NC(C)(C)CO1
Reaction time: 2 h

Procedure:
n-Butyllithium (52.8 ml of a 2.5M solution in hexanes) was added dropwise to a stirred solution of the product of step (i) (27.6 g) in tetrahydrofuran (100 ml)at -20° C. After 2 hours methyl iodide (85.3 g) was added and the mixture was stirred for 2 hours at this temperature then 0.5 hours at room temperature. The reaction mixture was partitioned between brine and ethyl acetate. The aqueous solution was extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 5% ethyl acetate inisohexane. Used without further purification.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f21) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[I-].[K+].[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O.O>[O:15]([CH:2]([CH3:6])[C:3](=[O:5])[CH3:4])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)C(C)Br
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(=O)C(C)Oc1ccccc1

Procedure:
A mixture of 3-bromobutan-2-one (75.5 g.) and finely-powdered potassium iodide (1 g.) in ethyl methyl ketone (50 ml.) was added dropwise, over 25 minutes, to a stirred, refluxing mixture of phenol (47 g.) and dry potassium carbonate (82 g.) in ethyl methyl ketone (100 ml.) Stirring and refluxing were continued for a total of 5 hours and the mixture was cooled, poured into water (cs. 500 ml.) and extracted with ether. The ether extract was washed exhaustively with 5N-sodium hydroxide, dried over anhydrous sodium sulphate and evaporated. The residue was distilled to give pure 3-phenoxybutan-2-one, b.p. 110°-112°/14 mm.