Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:32])=[C:7]([CH:15]([C:17]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=2[OH:31])Br)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)(=O)C>C(O)C>[C:1]([C:5]1[C:6](=[O:32])[C:7](=[CH:15][C:17]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=2[OH:31])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C(Br)c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)C1=CC(=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)C(=O)C(C(C)(C)C)=C1
Reaction time: 0.33 h

Procedure:
Three tenths of a part of the di-(3,5-di-tert-butyl-2-hydroxyphenyl) bromomethane produced above is dissolved in 20 parts of ethanol and placed in the reaction vessel just above described. One part of 5 percent aqueous sodium hydroxide solution is added and a slow current of nitrogen is passed through the solution for 20 minutes. The reaction mixture is poured into a vessel containing crushed ice, neutralized with acetic acid and extracted with ether. The ether is evaporated and the residue crystallized twice from aqueous ethanol to yield (3,5-di-tert-butyl-2-oxo-3,5-cyclohexadien-1-ylidene)-(3,5-di-tert-butyl-2-hydroxyphenyl) methane.
Reaction SMILES: [Br-].[Li+].[CH3:3][C:4]1([O:7][CH2:6]1)[CH3:5].[CH2:8]([NH:15][CH2:16][C:17]([CH3:19])=[CH2:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([N:15]([CH2:16][C:17]([CH3:19])=[CH2:18])[CH2:6][C:4]([CH3:5])([OH:7])[CH3:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(C)CNCc1ccccc1
Reactant: CC1(C)CO1
Agent: [Br-]
Agent: [Li+]
Solvent: ClCCl
Product: C=C(C)CN(Cc1ccccc1)CC(C)(C)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 98.1 %

Procedure:
Add lithium bromide (955 mg, 11.0 mmol) to a mixture of isobutylene oxide (6.20 mL, 68.8 mmol) and benzyl-(2-methyl-allyl)-amine (9.51 g, 59.0 mmol). Stir the mixture for 3.5 h at room temperature then treat with additional epoxide (1.5 mL, 16.6 mmol) and heat at 60° C. for 1.7 h. Dilute the mixture with CH2Cl2 (200 mL) and wash with water (200 mL). Dry, filter and concentrate the organic solution. Dry the residue at 80° C. under vacuum to give the title compound (13.5 g, 98%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.2-7.4 (5H, m), 4.90 (1H, s), 4.83 (1H, s), 4.18 (1H, s), 3.59 (2H, s), 2.98 (2H, s), 2.27 (2H, s), 1.71 (3H, s), 1.05 (6H, s).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].C[C@H]1CCCCN1>>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:17]([F:19])([F:18])[F:20]
Reactant: C[C@@H]1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Agent: C[C@H]1CCCCN1
Product: C[C@H]1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F

Procedure:
The title compound was prepared following the procedure described in Intermediate 10 Steps 1 and 2, but starting from (S)-(+)-2-methylpiperidine. It was isolated as a beige powder. 1H NMR (DMSO-d6) δ 13.29 (s, 1H), 8.23-8.12 (m, 2H), 7.68 (d, J=8.4 Hz, 1H), 3.07 (m, 1H), 2.94-2.81 (m, 1H), 2.61-2.45 (m, 2H), 1.75 (m, 1H), 1.67-1.18 (m, 4H), 0.71 (d, J=6.1 Hz, 3H). HPLC (Method A), Rt 4.79 min (Purity: 99.9%). LC/MS (Method B): 286.2 (M−H)−, 288.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][O:20][CH3:21]>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(C(C)=O)c(O)c1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
To 1-(2,4-dihydroxyphenyl)ethanone (1.52 g, 10 mmol) in 12 mL acetone was added K2CO3 (1.38 g, 10 mmol) followed by slow addition of chloro(methoxy)methane (885 mg, 11 mmol) with stirring under Ar atmosphere at rt. The reaction mixture was stirred at rt for 4 h and filtered. Solid was washed with EtOAc (80 mL) and the combined filtrate was washed with NaH2PO4 (sat. 50 mL) and water (80 mL) and dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (hexane/EtOAc) to afford 1-(2-hydroxy-4-(methoxymethoxy)phenyl)ethanone as a off-white solid (1.2 g, 61%). MS (ESI) m/z 197 (M+H+).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=O)[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C:53]1[CH:54]=[C:55]([NH:60][C:61](=[O:72])[C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:71])([F:70])[F:69])[CH:63]=2)[CH:56]=[CH:57][C:58]=1[CH3:59]>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:52][C:53]3[CH:54]=[C:55]([NH:60][C:61](=[O:72])[C:62]4[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:69])([F:70])[F:71])[CH:63]=4)[CH:56]=[CH:57][C:58]=3[CH3:59])=[O:18])[C:10]=2[CH:9]=[CH:8][N:7]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: CC(C)(C)Nc1nccc2c(C(=O)O)cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Reaction time: 0.17 h
Yield: 18.5 %

Procedure:
1-(t-Butylamino)isoquinoline-5-carboxylic acid (0.33 g, 1.35 mmol) obtained in Step (6) of Preparation Example 1 was dissolved in dimethyl formamide (3 mL), added with HATU (0.62 g, 1.62 mmol) and DIPEA (0.47 mL, 2.70 mmol), and stirred for 10 minutes. The reaction mixture was added with N-(3-amino-4-methylphenyl)-3-(trifluoromethyl)benzamide (0.40 g, 1.35 mmol) obtained in Step (2) above, and stirred for 12 hours or more at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with a saturated sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography to obtain the title compound (0.13 g, 18%).
Reaction SMILES: [CH:1]1([N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]2=[O:15])[CH2:3][CH2:2]1.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[C:37]([O:41][C:42](=[O:61])[NH:43][CH2:44][C:45]1[CH:60]=[CH:59][C:48]2[N:49]([CH2:54][CH2:55][CH:56]([CH3:58])[CH3:57])[C:50]([CH2:52]Cl)=[N:51][C:47]=2[CH:46]=1)([CH3:40])([CH3:39])[CH3:38].Cl>CN(C=O)C>[C:37]([O:41][C:42](=[O:61])[NH:43][CH2:44][C:45]1[CH:60]=[CH:59][C:48]2[N:49]([CH2:54][CH2:55][CH:56]([CH3:57])[CH3:58])[C:50]([CH2:52][N:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:13](=[O:14])[N:4]([CH:1]4[CH2:3][CH2:2]4)[C:5]3=[O:15])=[N:51][C:47]=2[CH:46]=1)([CH3:38])([CH3:40])[CH3:39]
Reactant: O=c1[nH]c2ccccc2c(=O)n1C1CC1
Reactant: CC(C)CCn1c(CCl)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Reaction time: 0.33 h
Yield: 80 %

Procedure:
To a solution of the 3-cyclopropyl-1H-quinazoline-2,4-dione (148 mg, 0.73 mmol) in DMF (10 mL) was added BTPP (684 mg, 2.19 mmol). After stirring for 20 minutes, [2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester; HCl salt (294 mg, 0.73 mmol) was added and the resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue precipitated from water. The title compound was collected by filtration and extensively washed with water and dried in vacuo to yield [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester as an off-white solid (310 mg, 80%):
Reaction SMILES: C[O-].[Na+].CO.Cl[CH2:7][C:8]([NH:10][C:11]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=1[OH:13])=[O:9].O>CN(C)C=O>[OH:18][C:16]1[CH:15]=[CH:14][C:12]2[O:13][CH2:7][C:8](=[O:9])[NH:10][C:11]=2[CH:17]=1
Reactant: O=C(CCl)Nc1cc(O)ccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2ccc(O)cc2N1

Procedure:
30% sodium methoxide in methanol (18.4 g, 0.075 mole) was added under stirring to the 2-(α-chloroacetamido)-hydroquinone (13.4 g, 0.075 mole) in dimethylformamide (DMF 10 ml). The resulting solution was poured into water (150 ml) and the separated solid was Coupler (1) (9 g, 73%).
Reaction SMILES: [CH3:1][C:2]1[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6]1>C(O)C.[Pd]>[NH2:19][C:18]1[C:2]([CH3:1])=[C:3]([CH:15]=[CH:16][CH:17]=1)[CH2:4][C:5]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6]1
Reactant: Cc1c(CC2(C(=O)OC(C)(C)C)CC2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(N)cccc1CC1(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
765 mg (2.63 mmol) of tert-butyl 1-(2-methyl-3-nitrobenzyl)cyclopropanecarboxylate were dissolved in 5 ml of ethanol, and 139.7 mg (0.13 mmol) of palladium (10% on carbon) were added. At RT, the mixture was hydrogenated at atmospheric pressure for 2 h. The reaction mixture was filtered off with suction through kieselguhr, the residue was washed with THF and the filtrate was concentrated. This gave 680 mg (99.1% of theory) of the title compound.
Reaction SMILES: C1(OC)C=CC=CC=1.[F:9][C:10]1[CH:18]=[CH:17][C:16]2[N:15](CC3C=CC(OC)=CC=3)[C:14]3[CH:28]=[CH:29][N:30]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][C:38]=4[C:39]([F:42])([F:41])[F:40])[C:31](=[O:32])[C:13]=3[C:12]=2[CH:11]=1.C(OCC)(=O)C>C(O)(C(F)(F)F)=O.CCCCCC>[F:9][C:10]1[CH:18]=[CH:17][C:16]2[NH:15][C:14]3[CH:28]=[CH:29][N:30]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][C:38]=4[C:39]([F:41])([F:40])[F:42])[C:31](=[O:32])[C:13]=3[C:12]=2[CH:11]=1
Reactant: COc1ccc(Cn2c3ccc(F)cc3c3c(=O)n(-c4cnccc4C(F)(F)F)ccc32)cc1
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=c1c2c(ccn1-c1cnccc1C(F)(F)F)[nH]c1ccc(F)cc12
Temperature: 80 °C
Yield: 12.8 %

Procedure:
Anisole (0.25 mL) was added to a stirred solution of 8-fluoro-5-(4-methoxybenzyl)-2-(4-(trifluoromethyl)pyridin-3-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (I-64c: 95 mg, 0.203 mmol) in TFA (10 mL) under nitrogen atmosphere and the resulting reaction mass was refluxed at 80° C. overnight. The reaction was monitored by TLC (80% ethyl acetate in hexane). The reaction mass was cooled to room temperature, concentrated under reduced pressure, basified using NaHCO3 solution to pH 8 and extracted using ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (2% methanol in DCM), followed by preparative HPLC afforded 9 mg of the product (75% yield).
Reaction SMILES: CN(C(O[N:9]1[N:17]=[N:16][C:11]2[CH:12]=[CH:13]C=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:48]=[CH:47][C:46]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][N:50]=2)=[CH:45][C:27]=1[C:28]([NH:30][C:31]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:34]=[C:33]([C:42](O)=[O:43])[CH:32]=1)=[O:29].CCN(C(C)C)C(C)C.CC1C(N)=CNN=1>CN(C=O)C.CCOC(C)=O>[Cl:25][C:26]1[CH:48]=[CH:47][C:46]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][N:50]=2)=[CH:45][C:27]=1[C:28]([NH:30][C:31]1[N:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:34]=[C:33]([C:42]([NH:16][C:11]2[C:12]([CH3:13])=[N:17][NH:9][CH:10]=2)=[O:43])[CH:32]=1)=[O:29]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1n[nH]cc1N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1n[nH]cc1NC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To a solution of HATU (0.3 mmol, 113 mg) and 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105, 0.23 mmol, 100 mg) in DMF (0.9 mL) was added DIPEA (1.10 mmol, 0.191 mL). The solution was stirred at room temperature for 15 minutes. 3-methyl-1H-pyrazol-4-amine (0.23 mmol, 100 mg) was added and the reaction stirred at room temperature for 18 hours. The reaction was diluted with EtOAc (20 mL), washed with NaHCO3 (20 mL), 10% aqueous citric acid solution (20 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo. The residue was purified using reverse phase column chromatography to afford the title compound as a yellow solid (35 mg, 29%).
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([CH:13]=O)[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:20][C:21]1[S:25][C:24]2[C:26]3([O:32][CH2:33][C:34]([F:36])([F:35])[C:23]=2[CH:22]=1)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:20][C:21]1[S:25][C:24]2[C:26]3([O:32][CH2:33][C:34]([F:35])([F:36])[C:23]=2[CH:22]=1)[CH2:27][CH2:28][N:29]([CH2:13][C:11]1[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:9][N:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:12]=1)[CH2:30][CH2:31]3
Reactant: FC1(F)COC2(CCNCC2)c2sc(Cl)cc21
Reactant: CCOC(=O)c1nn(-c2ncccc2F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)c1nn(-c2ncccc2F)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
To a solution of ethyl 1-(3-fluoro-2-pyridyl)-4-formyl-pyrazole-3-carboxylate (342.5 mg) in 1,2-dichloroethane (6.7 mL), 2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (280 mg, 1 mmol) is added. The mixture is stirred for 10 min. Then, sodium triacetoxyborohydride (442 mg) is added and the mixture is stirred overnight at room temperature. Sodium bicarbonate (saturated aqueous solution) is added and the organic phase extracted with dichloromethane, dried over magnesium sulfate and solvent evaporated in vacuo. Crude is purified by normal phase Isco chromatography using as eluent ethyl acetate and hexane to give 450 mg of ethyl 4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-1-(3-fluoro-2-pyridyl)pyrazole-3-carboxylate. MS (m/z): 527 (M+1).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:21][C:22]([CH3:52])([CH2:48][CH2:49][CH2:50][CH3:51])[C:23]([NH:25][CH2:26][C@@H:27]1[O:31][C:30]([CH3:33])([CH3:32])[N:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@H:28]1[CH2:41][C@H:42]([CH:46]=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:24].[NH4+].[Cl-]>C1COCC1>[CH3:52][C:22]([CH3:21])([CH2:48][CH2:49][CH2:50][CH3:51])[C:23]([NH:25][CH2:26][C@@H:27]1[O:31][C:30]([CH3:32])([CH3:33])[N:29]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C@H:28]1[CH2:41][C@H:42]([CH:46]([OH:47])[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][CH:3]=1)[CH:43]([CH3:44])[CH3:45])=[O:24]
Reactant: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](C=O)C(C)C
Reactant: COCCCn1ncc2ccc(I)cc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C(C)C)C(O)c1ccc2cnn(CCCOC)c2c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
To a solution of 6-iodo-1-(3-methoxypropyl)-1H-indazole (1.1 g, 3.48 mmol) in anhydrous THF (15 mL) at −78° C. under N2 was added dropwise n-BuLi (2.5 M in hexanes, 1.4 mL, 3.5 mmol). After stirring at −78° C. for 2 h, the reaction mixture was added through a cannula to a solution of (4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-formyl-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (160 mg, 0.35 mmol) in anhydrous THF (10 mL) at −78° C. The mixture was stirred at this temperature for 2 h, allowed to warm to rt and stirred overnight. Satd aq NH4Cl (25 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel to give (4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-(hydroxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (45 mg, 20% yield). MS: 645 (M++1)
Reaction SMILES: BrC1CN(C(CC)C(N)=O)C(=O)C1C#C.Br[C:17](Br)=[CH:18][CH:19]1[CH2:23][N:22]([CH:24]([CH2:28][CH3:29])[C:25]([NH2:27])=[O:26])[C:21](=[O:30])[CH2:20]1.CC(C)([O-])C.[K+]>C1COCC1>[C:18]([CH:19]1[CH2:23][N:22]([CH:24]([CH2:28][CH3:29])[C:25]([NH2:27])=[O:26])[C:21](=[O:30])[CH2:20]1)#[CH:17]
Reactant: CCC(C(N)=O)N1CC(C=C(Br)Br)CC1=O
Agent: C#CC1C(=O)N(C(CC)C(N)=O)CC1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#CC1CC(=O)N(C(CC)C(N)=O)C1

Procedure:
Alternatively, 2-(4-bromo-ethynyl-2-oxo-1-pyrrolidinyl)butanamide 267 is obtained by reacting 2-[4-(2,2-dibromovinyl)-2-oxo-1-pyrrolidinyl]butanamide 47 with two equivalent of potassium tertbutoxide in THF at low temperature (−50° C. to 0° C.).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:17]O>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Agent: Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1Cl

Procedure:
100 g (0.4 mol) of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid were dissolved in 1 l of methanol and hydrogen chloride gas was passed in for 5 hours at reflux temperature. The mixture was subsequently concentrated. This gave 88.5 g (84% of theory) of methyl 2-chloro-3-methyl-4-methylsulfonylbenzoate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[O:19][CH3:20]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]([C:16]1[CH:15]=[CH:14][C:13]([O:19][CH3:20])=[C:12]([CH3:11])[C:17]=1[CH3:18])=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: COc1cccc(C)c1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCl)c(C)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Chloropropionyl chloride (12.70 g, 100 mmol) is slowly added to a suspension of AlCl3 (16.0 g, 120 mmol) in CH2Cl2 (200 mL) at 0° C. under N2. Next, 2,3-dimethylanisole (13.62 g, 100 mmol) is slowly added at 0° C. The resulting yellow solution is stirred at 0° C. for 30 min, and then quenched by the addition of ice-cold 1.0 N HCl (200 mL) (the first several mL are added very slowly). The resulting mixture is stirred at room temperature for 20 min and then extracted with CH2Cl2. The extract is washed again with water (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo to a yield white solid. 1H NMR (CDCl3, 400 MHz): 7.50 (d, J=8.6 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 3.90 (t, J=6.8 Hz, 2H), 3.87 (s, 3H), 3.34 (t, J=6.8 Hz, 2H), 2.41 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:2]1.Cl[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=2)[O:18][C:17](=[O:26])[CH:16]=1.N12CCCN=C1CCCCC2>C1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[O:18][C:17](=[O:26])[CH:16]=2)=[O:11])[S:2]1
Reactant: O=c1cc(CCl)c2ccc(O)cc2o1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: O=C(CCCC[C@@H]1CCSS1)OCc1cc(=O)oc2cc(O)ccc12
Temperature: 80 °C
Yield: 24.9 %

Procedure:
To a room temperature solution of (R)-(+)-1,2-dithiolane-3-pentanoic acid (2.66 g, 12.9 mmol) and 4-Chloromethyl-7-hydroxy-2H-chromen-2-one (1) (2.40 g, 11.4 mmol) in anhydrous benzene (160 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.8 mL, 25 mmol) in one portion. The reaction mixture was heated to 80° C. (oil bath temperature) for 1 h, cooled to room temperature, then quenched with aqueous 15% citric acid (200 mL). The resulting suspension was filtered, and the collected insoluble material was suspended in acetone (100 mL), sonicated for 60 s, then filtered onto a bed of silica gel (˜10 g). The suspension-sonication-filtration step was repeated a second time. Concentration of the filtrate under reduced pressure followed by flash column chromatography (1% MeOH in CH2Cl2) provided the desired product as a pale yellow powder (1.08 g, 25%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](=[O:35])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][NH:26][C:25]([C:10]2[C:9]3[C:13](=[CH:14][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=3)[N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]=2[CH:22]([CH3:23])[CH3:24])=[O:35])=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)cc3)c(C(C)C)n(Cc3ccccn3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1c(C(=O)NCc2ccc(F)cc2)c2ccc(C(=O)O)cc2n1Cc1ccccn1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Following General Procedure F, ethyl3-(4-fluorobenzylcarbamoyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 50, 90 mg, 0.18 mmol) in EtOH (6 ml) was added NaOH (39 mg, 0.90 mmol) and H2O (1 ml). The reaction was stirred at 55° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[N:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18].C(OCC)(=O)C>O1CCCC1>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[N:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cncc(C(C)=O)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(C(=O)C=CN(C)C)c1

Procedure:
The mixture of methyl 5-acetyl-3-pyridinecarboxylate (3.0 g) and N,N-dimethylformamide dimethyl acetal (6.7 ml) in tetrahydrofuran (30 ml) was heated under reflux for 6 hours. To the mixture was added a mixture of ethyl acetate and tetrahydrofuran, and the mixture was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration and the residue was triturated with diisopropyl ether to give methyl 5-(3-dimethylamino-1-oxo-2-propenyl)-3-pyridinecarboxylate (1.88 g).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[S:18])SC)([OH:3])=[O:2].[N-:19]=[N+:20]=[N-:21].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15]([SH:18])=[N:21][N:20]=[N:19]1)([OH:3])=[O:2]
Reactant: CSC(=S)NCCCCCCCCCCC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: O=C(O)CCCCCCCCCCn1nnnc1S

Procedure:
Methyl 10-carboxydecyldithiocarbamate (28 g., 0.096 mol.) was reacted with 6.5 g. (0.1 mol.) of sodium azide according to the procedure described in Example 7. Acidification upon work-up gave 1-(10-carboxydecyl)tetrazole-5-thiol as a white precipitate, m.p. 95°-98°.