Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]\[CH:34]=O)=[CH:4][N:3]=1.[CH3:36][N:37]1[C:43](=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]\[CH2:34][N:40]2[CH2:41][CH2:42][C:43](=[O:44])[N:37]([CH3:36])[CH2:38][CH2:39]2)=[CH:4][N:3]=1
Reactant: CN1CCNCCC1=O
Reactant: COc1cc(-c2csc3c(/C=C\C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Product: COc1cc(-c2csc3c(/C=C\CN4CCC(=O)N(C)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using N-(4-{4-amino-7-[(1Z)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide, 4-methyl-1,4-diazepan-5-one (trifluoroacetic acid salt), and General Procedure B. 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 8.01 (m, 1H), 7.98 (s, 1H), 7.70 (d, 1H), 7.62 (s, 1H), 7.59 (d, 1H), 7.36 (s, 1H), 7.32 (d, 1H), 7.20 (m, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 6.69 (d, 1H), 6.21 (m, 1H), 5.65 (br, 2H), 4.04 (s, 3H), 3.91 (s, 3H); 3.47 (m, 2H), 3.32 (m, 2H), 3.02 (m, 2H), 2.85 (s, 3H), 2.58 (m, 4H); MS: (M−H)− 593.
Reaction SMILES: C([O:4][CH2:5]/[CH:6]=[CH:7]/[CH2:8][N:9]1[C:14]([C:15](=[O:24])[C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]1=[O:29])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[OH:4][CH2:5]/[CH:6]=[CH:7]/[CH2:8][N:9]1[C:14]([C:15](=[O:24])[C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[C:13]([CH:25]([CH3:26])[CH3:27])[C:12](=[O:28])[NH:11][C:10]1=[O:29]
Reactant: CC(=O)OC/C=C/Cn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2C/C=C/CO)c1
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a stirred solution of 80 mg (0.2 mmol) of the compound obtained from Example 75 in 5 ml of methanol was added 20 mg (0.37 mmol) of sodium methoxide at room temperature. After 1 hour, the reaction mixture was neutralized with acetic acid and evaporated under reduced pressure to give a yellow-colored residue, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (4:1) as an eluent to afford 60 mg (yield 82%) of the title compound as a colorless syrup.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[CH2:51][CH2:50][N:42]2[C:43]3[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=3[CH:49]=[C:41]2[C:40]1=[O:52])(=[O:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:39]2[CH2:51][CH2:50][N:42]3[C:43]4[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=4[CH:49]=[C:41]3[C:40]2=[O:52])=[CH:26][CH:27]=[CH:28][C:29]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)nc(Nc2cnn(C3CC3)c2)c1=O
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: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3cnn(C4CC4)c3)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 114b (200 mg, 0.645 mmol), 114a (0.903 mmol), Pd(PPh3)4, Na2CO3 aqueous solution (1.0 N, 2.13 mL, 2.13 mmol), DME (2.0 mL) were added. The mixture was reacted in microwave at 135° C. for 15 min. DCM (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:DCM=5:95) gave 2-(6-(1-cyclopropyl-1H-pyrazol-4-ylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 114c, it was directly used in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:21]1CCOCC1.C(Cl)(=O)OCC(C)C.N>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:19])[NH2:21])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCOCC1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10.5 g) in tetrahydrofuran (100 ml) were dropwise added N-methylmorpholine (4.6 ml) and isobutyl chlorocarbonate (5.4 ml) with ice-cooling and under an argon atmosphere, and the mixture was stirred at the same temperature for 10 min. Then, 28% aqueous ammonia (100 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated and water was added. The mixture was extracted with ethyl acetate and washed successively with aqueous sodium hydrogencarbonate solution, 10% aqueous citric acid solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and dried under reduced pressure to give the title compound (8.3 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[Cl-:15]>>[CH3:1][C:2]1[C:7]([C:8]([Cl:15])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14]
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)O
Reactant: [Cl-]
Product: Cc1c(F)c(F)c(F)c(F)c1C(=O)Cl

Procedure:
To 6-methyl-2,3,4,5-tetrafluorobenzoic acid (5.60 g) is added thiony chloride (9.8 ml) and the mixture is refluxed for 1 hour. After concentrating, 6-methyl-2,3,4,5-tetrafluorobenzoyl chloride (5.20 g) is obtained as a colorless oil, b.p. 82° C./23 mmHg.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[C:16]2[CH2:15][CH2:14][CH:13](Br)[C:12](=O)[C:11]=2[CH:10]=[CH:9][CH:8]=1)C.[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([NH2:29])=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]2[S:28][C:13]3[CH2:14][CH2:15][C:16]4[C:11](=[CH:10][CH:9]=[CH:8][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:19])[C:12]=3[N:29]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)COc1cccc2c1CCC(Br)C2=O
Reactant: NC(=S)C(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1CCc1sc(C(c3ccccc3)c3ccccc3)nc1-2
Yield: 31 %

Procedure:
Using ethyl[(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate and diphenylthioacetamide, the procedure of Example 52 was otherwise repeated to synthesize the title compound. Yield 31%. Amorphous solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cccnc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(-c2cccnc2)cc1
Yield: 72.7 %

Procedure:
Prepared according to the method as described in Example 33b) from 3-(4-methoxyphenyl)pyridine (2.5 g), 48% aqueous hydrobromic acid (25 ml) and acetic acid (25 ml) to give the sub-title compound as a pale orange solid (1.68 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:20])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[C:9]([C:10]1[CH:26]=[CH:25][C:24](=[O:27])[N:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[NH:12][C:11]=12)=[O:20]
Reactant: O=C(Cc1nc2c([nH]1)CCCC2)c1ccc(F)c(F)c1
Reactant: C#CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: O=C(c1ccc(F)c(F)c1)c1ccc(=O)n2c3c([nH]c12)CCCC3

Procedure:
The compound is prepared as described in example 20 with 200 mg (0.72 mmol) of 1-(3,4-Difluorophenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone (example XXXVII), 78.2 mg (1.45 mmol) of sodium methylate and 60.9 mg (0.72 mmol) methyl propiolate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44]([OH:46])=O)=[O:10])C1C=CC=CC=1.[CH3:47][NH:48][CH3:49]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:44](=[O:46])[N:48]([CH3:49])[CH3:47])=[O:10])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:33]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CNC
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC(=O)N(C)C)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 6a, 80.0 mg of (2R,4R,5R)-2-(2-carboxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 19b) are reacted with dimethylamine to afford the title compound as a yellow oil. Rf=0.35 (dichlormethane-methanol 9:1); Rt=4.93.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.CN(C)C([N:14]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][O:22][Si](C)(C)C)[N:16]=[CH:15]1)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:16]2[C:17]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:18][N:14]=[CH:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)n1cnc(CCCO[Si](C)(C)C)c1
Reactant: BrCc1cccc(Br)c1
Solvent: CC#N
Product: OCCCc1cncn1Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 250 parts of 1-bromo-3-bromomethylbenzene, 168.5 parts of N,N-dimethyl-4-[3-[(trimethylsilyl)oxy]propyl]-1H-imidazole-1-carboxamide and 869 parts of acetonitrile was refluxed for 18 hours. After cooling to 0° C., ammonia was bubbled through the reaction mixture for 5 min. The solvent was evaporated and the residue was stirred for 1 hour in 1700 ml of hydrochloric acid 1N. The mixture was extracted with ethyl acetate. The aqueous layer was basified with Na2CO3 (sat.) and reextracted with ethyl acetate (5×450 parts). The combined extracts were washed with water, dried, filtered and evaporated, yielding 210 parts (100%) of 1-[(3-bromophenyl)methyl]-1H-imidazole-5-propanol (interm. 1).
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[N:14]([C:22]1[C:27]([C:28]2[O:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:31][N:32]=2)=[N:26][C:25]([C:39]#[C:40][CH2:41][OH:42])=[CH:24][N:23]=1)C(OC(C)(C)C)=O)(C)(C)C>CO>[NH2:14][C:22]1[N:23]=[CH:24][C:25]([C:39]#[C:40][CH2:41][OH:42])=[N:26][C:27]=1[C:28]1[O:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:32]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C#CCO)nc1-c1nnc(-c2ccccc2)o1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncc(C#CCO)nc1-c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.2 %

Procedure:
4M HCl in dioxane (101.3 μL, 0.405 mmol) was added to a stirred solution of tert-butyl(5-(3-hydroxyprop-1-yn-1-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)(tert-butoxycarbonyl)carbamate (40 mg, 0.08105 mmol) in MeOH (1 mL) and the reaction allowed to stir at ambient temperature for 20 hours then concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an yellow solid (22.4 mg, 94% Yield). MS (ES+) 294.2.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][C@H:6]([C:8]([O:10][CH3:11])=[O:9])[NH2:7].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH3:25])=[O:23]>ClCCl.O>[Br:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][C@H:6]([C:8]([O:10][CH3:11])=[O:9])[NH:7][C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)[C@H](N)Cc1ccccc1Br
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)N[C@H](Cc1ccccc1Br)C(=O)OC
Reaction time: 2.5 h
Yield: 99.8 %

Procedure:
Dissolve methyl 2-bromo-D-phenylalaninate hydrochloride (27.2 g, 92.3 mmol) in dichloromethane (923 mL) and water (185 mL). Add sodium bicarbonate (31.0 g, 369.4 mmol) and methyl chloroformate (7.86 mL, 101.6 mmol) at room temperature. Stir the mixture 2.5 hours. Dilute with water and extract with dichloromethane. Dry the dichloromethane extracts over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with ethyl acetate:hexanes (10-75% gradient) to give the title compound (29.1 g, 92.1 mmol). MS (m/z): 316 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[S:41])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCC(=S)N[C@@H](CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A solution of 14.8 g (33.9 mmol) of 4-benzyl 1-tert-butyl N-[(1-tert-butoxyformamido)acetyl]-L-aspartate and 6.9 g (17 mmol) of Lawesson reagent in 140 ml of dry toluene is heated to 100° for 2.5 hours. Thereafter, the solvent is distilled off under reduced pressure and the residue is boiled up three times with 500 ml of a 9:1 mixture of hexane and ether. The combined organic phases are evaporated and, for purification, the residue is chromatographed on silica gel using a 9:1 mixture of hexane and ether as the eluent, whereby there is obtained 4-benzyl 1-tert-butyl N-[(1-tert-butoxyformamido)thioacetyl]-L-aspartate as a viscous oil; MS: 452 (M)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([C:30](O)=[O:31])=[CH:24]2>>[CH2:13]([C@H:3]([NH:2][C:30]([C:25]1[NH:26][C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([F:20])=[CH:29][CH:28]=2)=[O:31])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2cc(F)ccc2[nH]1

Procedure:
(S)-2-Amino-1-(4-hydroxy-piperidin-1-yl)-3-phenyl-propan-1-one hydrochloride (0.65 mmol) and 5fluoro-1H-indole-2-carboxylic acid (0.73 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) and the product purified by chromatography on silica gel eluted with 20, 30, 40, 50, 75 and 100% ethyl acetate in hexanes. Yield 228 mg, 84%; HPLC (60/40) 3.57 minutes (98%); PBMS 410 (MH+, 100%);
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH:5]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[F:15][B-:16]([F:19])([F:18])[F:17].[Na+]>O.Cl>[F:15][B-:16]([F:19])([F:18])[F:17].[NH:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:14]#[N:1])[C:8]=2[CH:7]=[N:6]1
Reactant: Nc1cccc2[nH]ncc12
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: N#[N+]c1cccc2[nH]ncc12
Reaction time: 0.5 h

Procedure:
An aqueous solution of sodium nitrite (337 mg, 4.89 mmol) in water (2 mL) was added dropwise to a suspension of 1H-indazol-4-ylamine D (631 mg, 4.74 mmol) in 6M hydrochloric acid (7.2 mL) at below 0° C. After stirring for 30 minutes, sodium tetrafluoroborate (724 mg) was added to the reaction mixture. A viscous solution resulted, which was filtered and washed briefly with water to yield 1H-indazole-4-diazonium tetrafluoroborate salt E (218 mg, 20%) as a deep red solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][C@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([C:33]3[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC[C@H](O)C2)c(Br)c1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CCC[C@H](O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 118 using (S)-5-bromo-6-(3-hydroxypiperidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 124.1) and (6-methylpyridin-3-yl)boronic acid to afford a white solid. UPLC-MS (condition 1) tR=2.16 min, m/z=473.1 [M+H]+, m/z=471.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.39 (m, 2H) 1.53-1.62 (m, 1H) 1.78-1.86 (m, 1H) 2.55 (s, 3H) 2.55-2.62 (m, 1H) 2.69-2.78 (m, 1H) 3.42-3.51 (m, 2H) 3.55-3.63 (m, 1H) 4.37-5.01 (m, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.42 (d, J=8.07 Hz, 1H) 7.83-7.89 (m, 2H) 7.93-8.00 (m, 1H) 8.07 (d, J=2.20 Hz, 1H) 8.71 (d, J=1.22 Hz, 1H) 8.75 (d, J=2.20 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[C:21]([C:23]1[C@@H:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[N:27]2[N:37]=[C:38]([NH:40][C:41](=[O:50])[O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[N:39]=[C:26]2[N:25]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)[C:24]=1[CH3:61])#[N:22]>CN(C1C=CN=CC=1)C.ClCCl>[C:21]([C:23]1[C@@H:28]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[N:27]2[N:37]=[C:38]([N:40]([C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[C:41]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:50])[N:39]=[C:26]2[N:25]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=2)[C:24]=1[CH3:61])#[N:22]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(C(=O)OCc3ccccc3)C(=O)Oc3ccc([N+](=O)[O-])cc3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 5 h

Procedure:
Under an atmosphere of argon protective gas and at 0° C., 4-nitrophenyl chloroformate (27.2 mg, 135 μmol, 2.5 eq.), triethylamine (11.1 mg, 140 μmol, 2.6 eq.) and DMAP (0.7 mg, 5.4 μmol, 0.1 eq.) were added to a solution of benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (30 mg, 54 μmol; Example 38) in dry dichloromethane (2 ml), and the mixture was then stirred for 5 h. This reaction solution was used as such without further purification for subsequent reactions.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:28])[C:11]([OH:27])([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=3[CH:26]=2)[C:12]([F:15])([F:14])[F:13])=[C:6]([Cl:29])[CH:5]=1.[Li+].[OH-]>C1COCC1>[Cl:29][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH:10]([CH3:28])[C:11]([OH:27])([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)[C:12]([F:14])([F:13])[F:15])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)c1ccc(C(C)C(O)(c2ccc3oc(=O)n(C)c3c2)C(F)(F)F)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Yield: 46.2 %

Procedure:
In analogy to Example 230, 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-benzoic acid methyl ester (1.05 g) was saponified with LiOH solution (1M, 6.12 mL) in THF (15 mL) to give the title compound 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-benzoic acid as an off-white foam (0.47 g). MS (m/e, ISP neg. ion)=428.3 [M−H+].
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][S:38]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[O:31][CH3:30])(=[O:40])=[O:39])=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: COc1nccc2c(-c3cc(CN)ccc3Oc3ccc(F)cc3F)cn(C)c12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1S(=O)(=O)NCc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(OC)nccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
A solution of Example 106B (70 mg, 0.177 mmol) in dichloromethane (2.5 mL) was treated with 2-methoxybenzene-1-sulfonyl chloride (43.9 mg, 0.212 mmol) and triethylamine (0.049 mL, 0.354 mmol). The reaction mixture was stirred for 1 hour at ambient temperature and then partitioned between 50% aqueous saturated sodium chloride (50 mL) and ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (104 mg, 100% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]1=[O:24]>C(N(CC)CC)C>[CH3:17][N:18]1[C:22](=[O:23])[CH2:21][CH:20]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)[C:19]1=[O:24]
Reactant: CN1C(=O)C=CC1=O
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CN1C(=O)CC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 88 %

Procedure:
The procedure of Example 1 is repeated using 11.92 grams 2,6-di-tert-butyl-4-mercaptophenol, 5.55 grams N-methylmaleimide, and 0.5 grams triethylamine. The residue is recrystallized from toluene: heptane to give 15.47 grams (88% yield), m.p. 132°-132.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Cl:14]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:14][C:3]1[C:4]2=[N:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[C:9]2[NH:1][CH:2]=1
Reactant: COC(=O)c1cnc2cc[nH]c2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2c(Cl)c[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a 0° C. solution of methyl 1H-pyrrolo[3,2-b]pyridine-6-carboxylate (1.00 g, 5.68 mmol) in N,N-dimethylformamide (15 mL) was added N-chlorosuccinimide (895 mg, 5.96 mmol). The reaction was allowed to gradually warm to room temperature and stir overnight. The reaction was diluted with water (125 mL) and stirred for 20 minutes. The resulting solid was collected by filtration, washed with water, and dried under vacuum to give the title compound (1.11 g, 93%) as an orange powder. +ESI (M+H) 211.0; 1H NMR (400 MHz, DMSO-d6, δ): 11.99 (br. s., 1 H), 8.92 (d, J=2.0 Hz, 1 H), 8.31 (d, J=1.8 Hz, 1 H), 8.08 (d, J=3.1 Hz, 1 H), 3.88 (s, 3 H).