Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH2:16]([NH2:19])[CH2:17][CH3:18].Cl>CS(C)=O>[F:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]2[C:2]=1[N:19]([CH2:16][CH2:17][CH3:18])[C:13](=[O:15])[CH2:12]2
Reactant: CCCN
Reactant: O=C(O)Cc1cc([N+](=O)[O-])cc(F)c1F
Agent: Cl
Solvent: CS(C)=O
Product: CCCN1C(=O)Cc2cc([N+](=O)[O-])cc(F)c21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Crude (2,3-difluoro-5-nitrophenyl) acetic acid (2.00 g, 9.2 mmol) and n-propylamine (6 eq., 4.54 ml, 0.0553 mol) are mixed in DMSO (10 ml) and stirred at 50° C. for 2 hours. 2N Hydrochloric acid (40 ml) is added in one portion and the mixture stirred at room temperature for 2 hours. The resulting light yellow precipitate is filtered, washed with water and dried under vacuum. The residue is purified by flash column chromatography (20% Ethylacetate/hexane) to give the title compound as a yellow solid. HPLC r.t. 5.40 min; MS for C11H11FN2O3 m/z 239.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[C:21]1([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 90 %

Procedure:
To a stirred solution of ethyl 4-aminophenylacetate (6.43 g, 35.9 mmol) and Et3N (5.50 ml, 39.5 mmol) in THF (70 ml) was added phenyl isocyanate (3.90 ml, 35.9 mmol), and the reaction mixture was stirred at room temperature for 4 days. Resulting precipitate was collected under a reduced pressure and the filtrate was washed with n-hexane to give ethyl 4-(N′-phenylureido)phenylacetate (9.64 g, 90%) as a white crystalline powder. mp 153-155° C.; 1H-NMR (CDCl3) δ1.26 (t, J=7.1 Hz, 3 H), 3.52 (s, 2 H), 4.15 (q, J=7.1 Hz, 2 H), 6.98-7.04 (m, 1 H), 7.07-7.11 (m, 4 H), 7.18-7.25 (m, 5 H), 7.42 (s, 1 H); MS (FAB) m/z 299 (M++1); Anal. Calcd. for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39. Found: C, 68.22; H, 6.10; N, 9.36.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.C(N(CC)CC)C.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>O1CCCC1.O>[CH:35]1([C:38]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[N:24]([CH3:25])[N:23]=[C:22]([CH3:26])[CH:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:27]=2)=[O:39])[CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n(C)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c2)n(C)n1
Yield: 59.6 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (270 mg, 0.745 mmol) and triethylamine (310 μL, 2.24 mmol) in tetrahydrofuran (5 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (88.0 μL, 0.969 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/50→0/100) and recrystallized from ethyl acetate-hexane to give the title compound (191 mg, 60%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N+:9]([O-])[CH:8]=[CH:7]2.CC(OC(C)=O)=[O:15]>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:15])[NH:9][CH:8]=[CH:7]2
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc2cc[n+]([O-])cc12
Product: Cc1cccc2cc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 10 h
Yield: 71 %

Procedure:
A solution of 8-methylisoquinoline 2-oxide (1.4 g, 8.8 mmol) in Ac2O (20 mL) was refluxed for 3 hours. The mixture was concentrated under vacuum and the residue was dissolved in MeOH (20 mL). To the reaction mixture was added aq. NaOH (20 mL, 1M). The mixture was refluxed for 1 hour and stirred at room temperature for 10 hours. The mixture was concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 3:1) to give 8-methylisoquinolin-1(2H)-one (76a, 1 g, 71%) as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C[Al](C)C.C(O[C:17]([C@@H:19]1[CH2:21][C@H:20]1[C:22]1[CH:27]=[C:26]([N:28]2[C:32]([CH3:33])=[N:31][C:30]([CH3:34])=[N:29]2)[N:25]=[C:24]([S:35][CH3:36])[N:23]=1)=O)C>C1(C)C=CC=CC=1>[CH3:34][C:30]1[N:31]=[C:32]([CH3:33])[N:28]([C:26]2[N:25]=[C:24]([S:35][CH3:36])[N:23]=[C:22]([C@@H:20]3[CH2:21][C@H:19]3[C:17]3[N:2]([CH3:1])[C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[N:9]=3)[CH:27]=2)[N:29]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(SC)n1
Reactant: CNc1ccccc1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CSc1nc([C@@H]2C[C@H]2c2nc3ccccc3n2C)cc(-n2nc(C)nc2C)n1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
To N1-methylbenzene-1,2-diamine (2.01 g, 16.5 mmol, 1.1 eq.) dissolved in toluene (20 mL) was added trimethylaluminium solution (2.0 M in toluene, 22.5 mL, 44.98 mmol, 3.0 eq.) under nitrogen at 0° C. dropwise. The reaction was stirred at a temperature between 10° C. to 20° C. for 30 minutes followed by the addition of ethyl-trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropanecarboxylate (1-4) (5.00 g, 14.99 mmol, 1.0 eq.) in toluene (80 mL) and the reaction was heated to 130° C. for 12 hours. The reaction was cooled to room temperature and quenched with saturated sodium bicarbonate (100 mL) then extracted with ethyl acetate (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrate to dryness. The crude product was purified by silica gel column chromatography (0-30% acetone in dichloromethane) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-(methylthio)pyrimidin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (1-5) as a pale pink solid. 1H NMR (400 MHz, CDCl3) δ 7.72-7.67 (m, 1H), 7.56 (s, 1H), 7.31-7.22 (m, 3H), 3.81 (s, 3H), 2.90 (s, 3H), 2.86-2.76 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.06-1.97 (m, 2H). LRMS m/z (M+H) 392 found, 392 required. m.p. 157-159° C.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>O.CO.C1COCC1>[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:18])=[O:2])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 24 h
Yield: 90.7 %

Procedure:
Sodium periodate (1.23 g, 5.76 mmol) in water (2.0 mL) was added to a solution of the above thioether (1.08 g, 4.80 mmol) in methanol/THF (2:1, 15 mL). The mixture was stirred at 50° C. for 24 h, then the solvent was concentrated in vacuo. The residue was diluted with diethyl ether and washed with water and saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification of the crude product by silica-gel chromatography (methylene chloride—50% ethyl acetate in methylene chloride) provided 4-tert-butyl-1-methanesulfinyl-2-nitro-benzene (1.05 g, 91%) as a white solid.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]1[CH:16]=[CH:15][C:11](C(Cl)=O)=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18].NC1C=CC=CC=1.Cl>O1CCCC1>[N+:17]([C:9]1[CH:10]=[CH:11][CH:15]=[CH:16][CH:8]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: O=[N+]([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
0.87 mL (10.8 mmole) of pyridine and 956 mg (4.35 mmoles) of 4-chloro-3-nitrobenzoylchloride were added to a 30 mL tetrahydrofuran solution of 1.0 g (3.6 mmoles) of aniline compound (1B-18) and the mixture was stirred for one hour at room temperature. To the reaction solution was added 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was slurry washed with ethyl acetate-hexane, yielding 1.41 g (a yield of 85 percent) of nitrobenzene compound (1B-19).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([Cl:23])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[Cl:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(Cl)c(Cl)c1
Temperature: 4 °C
Yield: 52.7 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 3,4-dichlorobenzoic acid (15.3 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product obtained by precipitation in water (17.6 g; m.p. 228° C.) is dissolved in boiling ethanol (900 cc). After cooling for 2 hours at 4° C., the crystallized solid is separated by filtration, washed with isopropyl ether (2×30 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3,4-dichlorobenzamide (9.2 g), m.p. 230° C., is obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][N:8]1[CH2:31][CH2:30][C:11]2[N:12]([CH2:20][C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=O)[C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=3[C:10]=2[CH2:9]1>C1COCC1>[CH3:7][N:8]1[CH2:31][CH2:30][C:11]2[N:12]([CH2:20][CH2:21][N:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)[C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][C:18]=3[C:10]=2[CH2:9]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCN(C)CC2)CCN(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CCN2CCN(C)CC2)CCN(C)C1
Yield: 22.9 %

Procedure:
LAH (0.022 g, 0.58 mmol) was charged in dry THF (3 mL) and cooled to 0 deg C., 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-methylpiperazin-1-yl)ethanone (0.05 g, 0.147 mmol) was added to it portion wise. The reaction mixture was refluxed for 4 h. The reaction mixture was cooled to 0 deg C. and quenched with sat. Na2SO4. The solid formed was filtered through celite, washed with THF, dried over Na2SO4 and concentrated under reduced pressure to obtain 11 mg of 2,8-dimethyl-5-(2-(4-methylpiperazin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:23]([O:24][C@@H:25]2[O:33][C@H:32]([CH2:34][OH:35])[C@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[C@@H:22]([OH:36])[C@@H:21]([CH2:37][OH:38])[O:20][C@@H:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](OC)=[O:17])(=[O:3])[CH3:2].O.[NH2:40][NH2:41]>>[C:1]([NH:4][C@@H:5]1[C@@H:23]([O:24][C@@H:25]2[O:33][C@H:32]([CH2:34][OH:35])[C@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[C@@H:22]([OH:36])[C@@H:21]([CH2:37][OH:38])[O:20][C@@H:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:40][NH2:41])=[O:17])(=[O:3])[CH3:2]
Reactant: COC(=O)CCCCCCCCO[C@H]1O[C@H](CO)[C@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H]1NC(C)=O
Reactant: NN
Solvent: O
Product: CC(=O)N[C@H]1[C@@H](OCCCCCCCCC(=O)NN)O[C@H](CO)[C@H](O)[C@@H]1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
Compound (6) was dissolved in hydrazine hydrate and left to stand for 2 h. At that time, the solvent was removed by co-evaporation with butanol-water 1:1 (v/v) 3×5 mL) to provide the hydrazide (7) used in preparing artificial antigens and immunoadsorbents as described below.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:32])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)=[CH:17][C:16]=2[CH2:28][NH:29][CH2:30][CH3:31])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3].[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH2:2]([O:4][C:5](=[O:32])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)=[CH:17][C:16]=2[CH2:28][N:29]([C:36]([CH:33]2[CH2:35][CH2:34]2)=[O:37])[CH2:30][CH3:31])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH3:3]
Reactant: CCNCc1cc(-c2ccc(F)cn2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc(F)cn3)cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: [2′-ethylaminomethyl-4′-(5-fluoro-pyridin-2-yl)-6-methoxy-biphenyl-3-yl]-acetic acid ethyl ester, hydrochloride and cyclopropanecarbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:24]C(=O)C(C)(C)C)=[C:6]([C:22]=1[CH3:23])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[O:20][CH3:21])=[O:8].C(=O)([O-])[O-].[Na+].[Na+].CO>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C:22]=1[CH3:23])[C:7]([C:9]1[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[O:20][CH3:21])=[O:8]
Reactant: COc1cc(C)c(C(=O)c2c(OC(=O)C(C)(C)C)ccc(Br)c2C)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C)c(C(=O)c2c(O)ccc(Br)c2C)c(OC)c1OC
Reaction time: 1 h

Procedure:
A mixture of 50B (5.1 g, 10.6 mmol), sodium carbonate (3.65 g), methanol (100 ml) and water (30 ml) is heated to reflux with stirring for 1 hour. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase is separated and concentrated. The residue is recrystallized from petrol ethers/ethyl acetate (95:5 v/v) The pure product is obtained as yellowish crystals, 3.70 g (88.3%), mp. 119-120° C.
Reaction SMILES: Cl.[C:2]1([N:8]2[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[N:11][N:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[C:2]1([N:8]2[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:11][N:10]=[N:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCc1nnnn1-c1ccccc1
Agent: Cl
Solvent: O
Product: O=C(O)CCCCc1nnnn1-c1ccccc1
Yield: 93.2 %

Procedure:
20% aqueous Hydrochloric acid (100 ml) is added to methyl 5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valerate (9.3 g) and the mixture is refluxed for 4 hours. After cooling, water is added and the mixture is extracted with chloroform. The chloroform solution is extracted with aqueous saturated sodium bicarbonate solution. The aqueous layer is acidified with concentrated hydrochloric acid and again extracted with chloroform. The latter chloroform extract is washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off to give 5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeric acid (8.2 g), pale yollow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8]([C:31]([F:34])([F:33])[F:32])([O:26][Si](C)(C)C)[C:9]=1[N:10]2S(C1C=CC(C)=CC=1)(=O)=O.[OH-].[K+].CCO>C1COCC1.O>[Cl:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][C:8]([C:31]([F:32])([F:33])[F:34])([OH:26])[C:9]=1[NH:10]2
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(F)ccc42)CCCC3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1ccc(F)c(Cl)c21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
To a solution of 5-chloro-6-fluoro-9-tosyl-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.08 g, 0.15 mmol) in THF (5 mL), cooled to 0° C., KOH (0.042 g, 0.7 mmol) in H2O (1 mL) was added and the resulting mixture was stirred for 30 min. EtOH (4 mL) was added to the reaction mixture and heated to 60° C. for 3 h, diluted with water (10 mL) and extracted with EtOAc (4×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude compound which was purified by column chromatography [EtOAc-hexane (3:17) as eluant] to give the title compound (0.025 g, 55%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.22 (s, 1H), 7.34 (dd, J=9.0, 4.5 Hz, 1H), 7.14 (t, J=9.0 Hz, 1H), 6.70 (s, 1H), 3.09 (t, J=11.0 Hz, 1H), 2.94-2.89 (m, 1H), 2.10 (t, 6.5 Hz, 1H), 2.00-1.92 (m, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:10][C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=[O:25])[CH3:24]>C1COCC1.[Cl-].[Na+].O>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([C:9]2[S:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:18][CH2:19]1)(=[O:25])[CH3:24]
Reactant: CCOC(=O)c1sc(C2CCNCC2)nc1-c1ccccc1
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1sc(C2CCN(C(C)=O)CC2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To prepare compound 90, the procedure was followed as outlined in Scheme 10, Step 2 replacing compounds 77 and 78 with compounds tent-butyl 4-carbamothioylpiperidine-1-carboxylate and ethyl 2-bromo-3-oxo-3-phenylpropanoate to afford compound 90 (0.790 g, 21% yield) as a white solid. To a stirring solution of ethyl 4-phenyl-2-(piperidin-4-yl)thiazole-5-carboxylate 90 (0.235 g, 0.743 mmol) in THF (8 mL) was added acetyl chloride (1.11 mL, 0.891 mmol) and the reaction was stirred at room temperature for 2 h. The solution was diluted with brine and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to afford ethyl 2-(1-acetylpiperidin-4-yl)-4-phenylthiazole-5-carboxylate 91 as a light yellow oil (0.196 g, 74% yield) after purification by flash chromatography (0 to 10% MeOH in ethyl acetate). LRMS (ESI): (calc) 358.45 (found) 359.3 (MH)+
Reaction SMILES: C[O:2][C:3](=[O:47])[C@H:4]([C:23](=[O:46])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:26][CH:25]=1)[CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH-].[Na+]>CO>[C:39]([N:31]([CH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:23]([C@H:4]([CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[C:3]([OH:47])=[O:2])=[O:46])=[CH:25][CH:26]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40]
Reactant: COC(=O)[C@@H](CCCN(Cc1ccccn1)C(=O)OC(C)(C)C)C(=O)c1ccc(CN(Cc2ccccn2)C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCC[C@H](C(=O)O)C(=O)c1ccc(CN(Cc2ccccn2)C(=O)OC(C)(C)C)cc1)Cc1ccccn1
Reaction time: 24 h
Yield: 91.7 %

Procedure:
The compound obtained in Example 66-3 (8.96 g) was dissolved in methanol (134.4 ml) and 1 N aqueous solution of sodium hydroxide (134.4 ml) was added. The mixture was stirred for 1 day. After confirming completion of the reaction with TLC, the reaction solution was concentrated under reduced pressure. The residue was dissolved in 1N aqueous solution of sodium hydroxide and washed with diisopropyl ether. 1 N hydrochloric acid aqueous solution was added to the resulting water layer to adjust the pH to 2-3. The solution was extracted with ethyl acetate and the organic layer separated was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain the title compound (8.04 g) as a light brown solid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[CH3:40][N:41]1[C:45]([CH3:46])=[C:44](B(O)O)[CH:43]=[N:42]1>>[NH2:32][C:4]1[S:3][C:2]([C:44]2[CH:43]=[N:42][N:41]([CH3:40])[C:45]=2[CH3:46])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cc1c(B(O)O)cnn1C
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cc1c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)c(N)s2)cnn1C

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid gave 257. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.80 (s, 1H), 7.72 (s, 1H), 7.25 (s, 2H), 4.79 (dd, J=10.7, 3.6 Hz, 1H), 4.41 (ddd, J=49.5, 4.9, 2.7 Hz, 1H), 4.26-3.94 (m, 2H), 3.76 (d, J=5.4 Hz, 6H), 3.30-3.16 (m, 1H), 2.52 (s, 3H), 2.04 (dq, J=11.8, 4.1 Hz, 1H), 1.81 (dd, J=13.6, 10.0 Hz, 1H), 1.73-1.64 (m, 2H). LCMS (ES+) m/z 449 (M+1).
Reaction SMILES: C([O:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)C=C.[CH:16]1[CH:21]=CC=C[CH:17]=1>>[CH3:15][CH:6]([CH:7]([C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=1)[C:16]([CH3:21])=[CH2:17])[CH:5]=[O:4]
Reactant: C=CCOC/C(C)=C/c1ccc(C)cc1
Reactant: c1ccccc1
Product: C=C(C)C(c1ccc(C)cc1)C(C)C=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
The 1-[(1E)-3-(Allyloxy)-2-methyl-1-propenyl]-4-methylbenzene (72.7 g, 0.359 mol), [RuCl2(PPh3)3] (1.1 g), BHT (50 mg) and benzene (250 ml) were heated together in an autoclave placed in an oil bath at 165-170° C. for 24 hours. After cooling to room temperature, the benzene was evaporated under vacuum and the residue chromatographed on silica gel (eluent: heptanes/ethyl acetate 25:1 to 4:1), then distilled under vacuum through a 20-cm Widmer column. 21.3 g of the desired product were obtained (yield=29%) as a 40:60 mixture of diastereoisomers. B.P.=95° C./0.001 mbar
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=[C:9]2[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].[O-:19]Cl=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[C:1]([Si:5]([CH3:18])([CH3:17])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]([OH:19])=[O:16])[CH:14]=[C:9]2[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(C=O)cnc21
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(C(=O)O)cnc21
Yield: 16.4 %

Procedure:
To a stirred and cooled (0° C.) solution of aldehyde 16 (115 mg, 0.44 mmol) in tert-butanol (3.1 mL) and 2-methyl-2-butene (0.77 mL) was added a solution of NaClO2 (194 mg, 2.1 mmol) and NaH2PO4.H2O (244 mg, 1.8 mmol) in water (2.31 mL) dropwise. When 16 was consumed (TLC) the mixture was partitioned between AcOEt and water. The organic layer was washed with saturated brine (1×), dried (MgSO4), filtered and concentrated to afford acid 11 (20 mg, 16%) as an off-white solid. 1H NMR (400 MHz; CDCl3) δ 0.66 (s, 6H), 0.94 (s, 9H), 6.65 (s, 1H), 7.32 (s, 1H), 8.61 (s, 1H) and 9.03 (s, 1H).