Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([N:35]3[CH:47]=[CH:46][N:38]4[C:39]5[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=5[CH:45]=[C:37]4[C:36]3=[O:48])[N:30]=[CH:29][CH:28]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:34][CH2:33][C:32]1[C:31]([N:35]2[CH:47]=[CH:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:30][CH:29]=[CH:28][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
A mixture of 151g (89 mg, 0.14 mmol), NaBH4 (22 mg, 0.60), and methanol (10 mL) was stirred at 25° C. for 1 h. The mixture was quenched with water (8 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 151 (35 mg, 39%). MS-ESI: [M+H]+649. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=2.0 Hz, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.46 (s, 1H), 7.83 (d, J=2.5 Hz, 1H), 7.50-7.48 (m, 2H), 7.38-7.36 (m, 1H), 7.26-7.24 (m, 2H), 6.83-6.80 (m, 2H), 4.98 (bs, 1H), 4.57-4.54 (m, 2H), 4.48-4.33 (m, 4H), 3.67-3.66 (m, 1H), 3.60 (s, 3H), 3.39-3.38 (m, 2H), 3.09-3.08 (m, 1H), 2.96-2.94 (m, 1H), 2.76-2.74 (m, 2H), 2.64-2.62 (m, 2H), 2.36-2.31 (m, 2H), 2.20-2.17 (t, J=7.5 Hz, 1H), 1.88-1.86 (m, 2H), 1.75-1.74 (m, 2H), 0.93 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH2:32][CH:33]([CH3:36])[CH2:34][OH:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:32][CH:33]([CH3:36])[CH2:34][OH:35])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: CC(N)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC(C)CO)c4)cc23)CC1
Yield: 7.8 %

Procedure:
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), 2-amino-1-propanol (6.5 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (3.4 mg, 6.0%).
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][NH:25][NH2:26].CO.O>CO>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:14])[N:3]([C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17])[C:2]1[N:25]([CH3:24])[N:26]=[CH:11][C:10]2=1
Reactant: CNN
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Solvent: CO
Solvent: O
Product: Cn1ncc2c3cc(Cl)c(Cl)cc3n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 82 mg, 0.22 mmol) was dissolved in methanol (4 mL) to which was added methylhydrazine (0.5 mL). The solution was stirred at room temperature for 16 h, then the solvent was removed under vacuum. The residue was suspended in 20 mL of brine and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a yellow oil. The oil was subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/water. Fractions containing product were pooled and evaporated to yield 29 mg (33%) of 4.36 as a pale yellow solid: mp 135-138° C.; Rf 0.6 (20% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.94 (s, 1H), 7.73 (s, 1H), 5.95 (d, 1H), 5.38 (d, 1H, D2O exch.), 5.25 (m, 2H, D2O exch.), 4.21 (q, 1H), 4.13 (m, 1H), 4.05 (s, 3H), 3.97 (m, 1H), 3.74 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 146.23, 139.94, 128.98, 123.94, 122.80, 120.16, 119.24, 115.28, 109.15, 88.91, 85.71, 71.94, 68.75, 60.89, 37.81. HRMS (ES) m/z calcd. for C15H15Cl2N3O4.Na.MeOH 426.0599, found 426.0593. Anal calcd for C15H15Cl2N3O4: C, 48.40; H, 4.06; N, 11.29. Found: C, 48.13; H, 4.16; N, 11.12.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([O:30]CC)=[O:29])=[O:21])=[CH:14][C:13]=3[C:33]([F:36])([F:35])[F:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[Na+].CCO>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[C:28]([OH:30])=[O:29])=[O:21])=[CH:14][C:13]=3[C:33]([F:35])([F:34])[F:36])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by hydrolysis of the compound of Example 249 under basic conditions (aq. NaOH/EtOH), resulting in a white solid, mp 90° C. (dec.). 1HNMR (DMSO-d6, 300 MHz) δ 1.15-1.50 (m, 2H), 1.50-1.70 (m, 2H), 2.16 (m, 1H), 2.56 (m, 1H), 3.15 (m, 1H), 4.30 (s, 4H), 4.32 (m, 1H), 5.20 (m, 1H), 7.02 (m, 4H), 7.30-7.52 (m, 2H), 7.84 (m, 1H), 8.15 (s, 1H). MS (APCI) m/z 494 (M+H)+. Anal. calcd. for C24H22F3NO5.0.3 H2O: C, 57.78; H, 4.57; N, 2.81. Found: C, 57.87; H, 4.5 7; N, 2.76.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][O:13]1.I[CH3:29]>C1COCC1>[O:11]=[C:12]1[NH:16][C@@H:15]([C@@H:17]([CH3:29])[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][O:13]1
Reactant: O=C(C[C@H]1COC(=O)N1)OCc1ccccc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)OCc1ccccc1)[C@H]1COC(=O)N1
Temperature: -78 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of sodium bis(trimethylsilyl)amide (1M in THF; 68.0 mL) under argon atmosphere was added THF (40.4 mL). The mixture was cooled to −78° C. and a solution of (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate (7.80 g, 33.2 mmol) in THF (85 mL) was added slowly over ˜15 min. The mixture was stirred for 1 hr at −78° C. and a solution of iodomethane (4.25 mL, 68.0 mmol) in THF (40.4 mL) was added slowly over ˜10 min. The reaction mixture was stirred for 1 hr at −78° C. and ˜1 hr at −40° C. The mixture was quenched with saturated aqueous ammonium chloride solution (˜100 mL) and allowed to warm to room temperature. The mixture was extracted with DCM (3×). The combined organic layers were dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 220 g, EtOAc/heptane] to provide (R)-benzyl 2-((S)-2-oxooxazolidin-4-yl)propanoate (7.47 g) as a colorless oil. MS m/z 250.1 (M+H)+; Rt-0.65 min. 1H NMR (400 Mhz, DMSO-d6) δ ppm 7.85 (s, 1H), 7.44-7.28 (m, 5H), 5.10 (s, 2H), 4.36 (t, J=1.0 Hz, 1H), 4.11 (dd, J=5.4, 8.9 Hz, 1H), 4.06-3.98 (m, 1H), 2.69 (quin, J=6.9 Hz, 1H), 1.08 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[NH:22][N:21]=[N:20][N:15]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
To 4-methyl-2'-cyanobiphenyl (53 mg, 0.274 mmol) dissolved in toluene (0.5 mL) was added trimethylsilyl azide (100 μL, 0.73 mmol) and dibutyltin oxide (74 mg, 0.300 mmol). The reaction mixture was heated at ~105° C. for 91 hours, cooled to ambient temperature, concentrated under reduced pressure and flash chromatographed on silica gel eluting with methanol in methylene chloride to give the title compound (61.2 mg). The 300 MHz 1H NMR spectrum was found to be consistent with the desired product.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH:27]([OH:28])[C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[CH:24]=4)[N:19]=[CH:18][C:17]=3[O:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[O:32]=[C:33]1[NH:38][C:37]2[CH:39]=[C:40](C(O)=O)[CH:41]=[CH:42][C:36]=2[S:35][CH2:34]1>>[OH:28][CH:27]1[C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:29][CH3:30])[CH:24]=3)[N:19]=[CH:18][C:17]=2[O:16][CH2:15][CH:14]1[C@H:11]1[CH2:10][CH2:9][C@H:8]([NH:7][C:6]([C:40]2[CH:41]=[CH:42][C:36]3[S:35][CH2:34][C:33](=[O:32])[NH:38][C:37]=3[CH:39]=2)=[O:5])[CH2:13][CH2:12]1
Reactant: COc1ccc2ncc3c(c2c1)C(O)C([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2c1)C(O)C([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 15 using [trans-4-(4-hydroxy-6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]1[C:15]([NH2:16])=[C:8]2[C:9]([NH2:14])=[N:10][S:11](=[O:13])(=[O:12])[C:7]2=[CH:6][CH:5]=1.[CH3:17][N:18]([CH2:20][C:21]1[O:25][C:24]([CH2:26]O)=[CH:23][CH:22]=1)[CH3:19]>Cl>[CH3:17][N:18]([CH2:20][C:21]1[O:25][C:24]([CH2:26][S:1][CH2:2][CH2:3][C:4]2[C:15]([NH2:16])=[C:8]3[C:9]([NH2:14])=[N:10][S:11](=[O:13])(=[O:12])[C:7]3=[CH:6][CH:5]=2)=[CH:23][CH:22]=1)[CH3:19]
Reactant: CN(C)Cc1ccc(CO)o1
Reactant: NC1=NS(=O)(=O)c2ccc(CCS)c(N)c21
Agent: Cl
Product: CN(C)Cc1ccc(CSCCc2ccc3c(c2N)C(N)=NS3(=O)=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N3 -[2-mercapto ethyl]-1,2-benzoisothiazole-3,4-diamine-1,1-dioxide (D.9, 0.11 g) in concentrated hydrochloric acid (0.4 ml) under nitrogen at -10° C. was added 5-dimethylaminomethyl-2-furanmethanol (0.08 g). After stirring at room temperature overnight, the reaction mixture was worked-up as described in Example 2 to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C)C=O.O>[CH2:21]([O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH:20]=[CH2:19]
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-chloro-5-trifluoromethyl-phenol (10.00 g, 0.05 mol) in N,N-dimethylformamide (500 mL) was added potassium carbonate (28.12 g, 0.209 mol) followed by allyl bromide (7.38 g, 0.061 mol) and the reaction was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (500 mL) to dissolve any solids and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with water (4×500 mL), saturated aqueous sodium chloride (400 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give 2-(allyloxy)-1-chloro-4-(trifluoromethyl)benzene as a colorless oil. The oil was re-dissolved in mesitylene (35 mL) and heated at reflux for 12 h. Removal of the solvent in vacuo provided a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:8) provided 9.6 g (96%) of 2-allyl-6-chloro-3-(trifluoromethyl)phenol as a amber oil. Rf=0.66 (silica, ethyl acetate:hexanes 1:4); 1H NMR (DMSO-d6) δH 9.84 (s, 1H); 7.43 (d, 2H); 7.16 (d, 1H); 5.84 (m, 1H); 4.95 (d, 1H); 4.89 (d, 1H); 3.46 (d, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([CH:24]2[CH2:28][S:27][CH:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[N:25]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:23])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([CH:24]3[CH2:28][S:27][CH:26]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[N:25]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:23])=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)NCCc2ccc(O)cc2)CSC1c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C(C(=O)NCCc2ccc(OCCCCc3ccccc3)cc2)CSC1c1cccnc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 51 %

Procedure:
A solution of 280 mg of 1-bromo-4-phenylbutane in 5 ml of N,N-dimethylformamide was added to a mixture of 540 mg of N-[2-(p-hydroxyphenyl)ethyl]-3-tert-butoxycarbonyl-2(3-pyridyl)thiazolidine-4-carboxamide, 180 mg of potassium carbonate and 10 ml of N,N-dimethylformamide at room temperature. The mixture was stirred at 80° C. for 3 days. After cooling, 20 ml of water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. The organic layer was washed in sequence with water and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (eluent: hexane-ethyl acetate=1:3) gave 360 mg of N-[2-[p-(4-phenylbutoxy)phenyl]ethyl]-3-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxamide. Trifluoroacetic acid (5 ml) was added to the compound obtained, and the mixture was stirred at room temperature for 1.5 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give 230 mg of N-[2-[p-(4-penylbutoxy)phenyl]ethyl]-2-(3-pyridyl)-thiazolidine-4-carboxamide. This compound was dissolved in ethyl acetate, and 1 ml of 2N hydrogen chloride solution in dioxane was added. The resultant solid was collected by filtration, washed with ethyl acetate and dried to give 130 mg of N-[2-[p-(4-phenylbutoxy)phenyl]ethyl]-2-(3-pyridyl) thiazolidine-4-carboxamide dihydrochloride. Melting point 102° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:31]=[CH:30][S:29][CH:28]=1)=O>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:24]=[C:25]([C:27]3[CH:31]=[CH:30][S:29][CH:28]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: O=C(CBr)c1ccsc1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Product: O=C(O)c1cc(-c2nc(-c3ccsc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 19 %

Procedure:
2′-Nitro-4-(4-thiophen-3-yl-thiazol-2-yl)-biphenyl-2-carboxylic acid (50 mg, 19%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromo-1-(3-thienyl)-1-ethanone (available from Maybridge) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.54 (d, J=1.7 Hz, 1H), 8.23 (dd, J=7.8, 1.8 Hz, 1H), 8.04-8.15 (m, 3H), 7.78 (t, J=6.8 Hz, 1H), 7.62-7.69 (m, 3H), 7.44 (t, J=8.1 Hz, 2H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][N:26]=1>ClCCl>[Cl:24][C:25]1[N:26]=[CH:27][C:28]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:32][CH:33]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Reaction time: 1 h

Procedure:
A solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (100 mmol) and N,N-diisopropylethyl amine (130 mmol) in dichloromethane (500 mL) was cooled to 0° C. 6-Chloronicotinoyl chloride (130 mmol) was added dropwise under nitrogen. The solution was stirred for one hour as it returned to room temperature. The reaction mixture was filtered through a sica gel pad, washed with 0.5 N sodium hydroxide and water, dried over anhydrous magnesium sulfate. The solution was again filtered through a silica gel pad and evaporated to dryness in vacuo. The residual oil crystallized from diethyl ether to provide the title compound as a colorless crystalline solid, m.p. 165–167° C.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19]O)=[N:17][CH:18]=1)([O-:12])=[O:11].C(N(CC)CC)C>C(Cl)Cl>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:5][S:2]([CH3:1])(=[O:4])=[O:3])=[N:17][CH:18]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CO)nc1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cn1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Methanesulfonic anhydride (1.79 g, 10.3 mmol, 1.1 equiv) was added portionwise to a cold (5° C.) mixture of (5-nitro-pyridin-2-yl)-methanol (Step 112.4) (1.44 g, 9.4 mmol) and triethylamine (1.57 mL, 11.3 mmol, 1.2 equiv) in DCM (20 mL), under an argon atmosphere. The reaction mixture was allowed to stir for 0.5 h at 5° C., quenched with H2O and extracted with DCM. The organic phase was washed with H2O, dried (Na2SO4), filtered and concentrated to provide 2.16 g of the title compound as a brown solid: ESI-MS: 231.1 [M−H]−; tR=2.85 min (System 1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O>[CH2:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(O)cn1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C

Procedure:
The solution of 32.7 g of 2-methyl-5-hydroxy-pyridine in 300 ml of dimethylformamide is added to a suspension of 12.8 g of sodium hydride (57% mineral oil dispersion) in 150 ml of dimethylformamide, with stirring. Then the mixture is heated to 100° and maintained at 100° for 18 hours. After that, the mixture is cooled to room temperature and to the cooled mixture is added a solution of 49.8 g of benzyl chloride in 100 ml of dimethylformamide over a period of 30 minutes. The mixture is then refluxed for 7 hours, cooled and then evaporated to a residue. The residue is partitioned between water and ether, the layers are separated and the water layer extracted with ether. The ether layer is combined with ether extract, dried over sodium sulfate, filtered and the ethereal filtrate is distilled off. The residue is distilled to yield 5-benzyloxy-2-methyl-pyridine, boiling at 100°-102°/0.02 mm/Hg.
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[O:10])=CC=1)([O-])=O.C(#N)C.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH:42][C:43]([NH2:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[CH2:30][CH2:29]1>CCOC(C)=O>[NH2:45][C:43]([NH:42][C:38]1[CH:37]=[C:36]([CH2:35][CH2:34][CH:31]2[CH2:32][CH2:33][N:28]([C:9]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=3)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[CH2:29][CH2:30]2)[CH:41]=[CH:40][CH:39]=1)=[O:44]
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: NC(=O)Nc1cccc(CCC2CCNCC2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(NC(N)=O)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (228 mg) was added to an acetonitrile (5 ml) solution of 1-{3-[2-(4-piperidinyl)ethyl]phenyl}urea hydrochloride (185 mg) and TEA (0.2 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted with EtOAc, washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain methyl 5-({[4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidyl]carbonyl}oxy)nicotinate (183 mg).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:6][C:7]1[C:8]([N:22]2[C:26]([CH3:27])=[N:25][N:24]=[C:23]2Br)=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[N:13]=[C:12]([O:18][CH3:19])[C:11]([O:20][CH3:21])=[N:10]2>>[Cl:6][C:7]1[C:8]([N:22]2[C:26]([CH3:27])=[N:25][N:24]=[C:23]2[N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:17])[N:13]=[C:12]([O:18][CH3:19])[C:11]([O:20][CH3:21])=[N:10]2
Reactant: COc1nc2cc(Cl)c(Cl)c(-n3c(C)nnc3Br)c2nc1OC
Reactant: c1c[nH]cn1
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(C)nnc3-n3ccnc3)c2nc1OC
Temperature: 100 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
A mixture of imidazole (78 mg, 1.15 mmol) and 6,7-dichloro-2,3-dimethoxy-5-(3-bromo-5-methyl-4H-1,2,4-triazol-4-yl)quinoxaline (48 mg, 0.115 mmol) was heated at 100° C. for 1 hour then at 120° C. for 3 hours. After being cooled the mixture was partitioned between water (15 mL) and dichloromethane (2×15 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (98:2 changing to 95:5, by volume) to give the title compound (15 mg, 32%) as a brown solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([F:25])=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH:6]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[O:15])=[C:9]3[N:8]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([F:25])=[C:20]([C:21]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:22])[CH:24]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(F)c(C(=O)O)c3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(F)c(C(=O)N4CCOCC4)c3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)-2-fluorobenzoic acid (75 mg, 0.22 mmol 0 in DMF (3 mL) was added EDCI (46 mg, 0.24 mmol), HOBt (33 mg, 0.24 mmol), and morpholine (21 mg, 0.24 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed 1× with saturated sodium bicarbonate, 2× with brine, dried over MgSO4, filtered and evaporated to dryness to provide 92 mg of 7-(cyclopropylamino)-5-(4-fluoro-3-(morpholine-4-carbonyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=410)