Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[N:26](CC4C=CC(OC)=CC=4)[N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:40][CH2:41][CH3:42])[C:5]=1[OH:43])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:40][CH2:41][CH3:42])[C:5]=1[OH:43])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2cccc(NC(=O)c3nnnn3Cc3ccc(OC)cc3)c2C#N)ccc(C(C)=O)c1O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1c(OCCCOc2cccc(NC(=O)c3nnn[nH]3)c2C#N)ccc(C(C)=O)c1O

Procedure:
A solution of 7.05 g (12.06 mmol) of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-cyanophenyl}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 150 ml of trifluoroacetic acid and 15 ml of anisole is heated under reflux for 30 minutes. The reaction mixture is concentrated under reduced pressure, approximately 200 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. The resulting N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]- 2-cyanophenyl}-1H-tetrazole-5-carboxamide having a melting point of 206°-208° is dissolved in 50 ml of acetone while hot, and the calculated amount of triethanolamine in 30 ml of acetone is added thereto. After the addition of ether, crystallisation begins. The triethanolammonium salt of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-cyanophenyl}-1H-tetrazole-5-carboxamide having a melting point of 81° (decomposition) is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15](O)=[O:16])=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH:28]=1>>[C:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[O:16])=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2]
Reactant: NCCCCc1cccnc1
Reactant: CCCc1c(OCCOc2cccc(C(=O)O)c2)ccc(C(C)=O)c1O
Product: CCCc1c(OCCOc2cccc(C(=O)NCCCCc3cccnc3)c2)ccc(C(C)=O)c1O
Yield: 83 %

Procedure:
The reaction of 1.06 g of 3-[2-(4-acetyl-3hydroxy-2propylphenoxy)ethoxy]benzoic acid with 0.49 g of 3-pyridine butanamine according to Example 40 gave 1.20 g, mp 90°, (83% yield) of 3-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)ethoxy]-N-[4-(3-pyridinyl)butyl]benzamide, the title compound.
Reaction SMILES: FC1C=C(C=CC=1)C=NO.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:22]3[C:23](=[O:27])[CH2:24][CH2:25][CH2:26][C:21]=3[O:20][N:19]=2)[CH:15]=[CH:16][CH:17]=1.C([N-]C(C)C)(C)C.[Li+].[Cl:36][CH2:37][CH2:38][CH2:39]I>C1COCC1.CCOCC.O>[Cl:36][CH2:37][CH2:38][CH2:39][CH:24]1[C:23](=[O:27])[C:22]2[C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([F:11])[CH:13]=3)=[N:19][O:20][C:21]=2[CH2:26][CH2:25]1
Reactant: O=C1CCCc2onc(-c3cccc(F)c3)c21
Reactant: ClCCCI
Agent: CC(C)[N-]C(C)C
Agent: ON=Cc1cccc(F)c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=C1c2c(-c3cccc(F)c3)noc2CCC1CCCCl
Temperature: -78 °C

Procedure:
In a similar manner to that of Examples 7a-d starting with 3-fluorobenzaldehyde oxime, the starting ketone is prepared. In 200 ml anhydrous THF was dissolved 11.4 g 6,7-dihydro-3-(3-fluorophenyl)-1,2-benzisoxazol-4(5H)-one under nitrogen atmosphere with stirring. The solution was cooled to -78° C. and 49.4 ml lithium diisopropylamide (1.5 molar in cyclohexane) was added dropwise. The resulting solution was stirred for ten minutes at -78° C. and 6.4 ml 1-chloro-3-iodopropane was added. Upon warming to room temperature, the reaction mixture was poured into water and ether. The layers were separated and the aqueous phase was extracted twice with dichloromethane and once with ether. The combined organic layers were washed with brine and dried (MgSO4). Filtration and concentration gave the crude product. Column chromatography on silica gel (start with 10% dichloromethane in hexane and gradually increase polarity to 100% dichloromethane) gave 4.5 g of 5-(3-chloropropyl)-6,7-dihydro-3-(3-fluorophenyl)-1,2-benzisoxazol- 4(5H)-one.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)#[N:3]>>[ClH:1].[NH:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][N:8]=2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cn2)CC1
Agent: Cl
Product: N#Cc1ccc(C2CCNCC2)nc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
6N HCl (1.0 mL) was added to tert-butyl 4-(5-cyanopyridin-2-yl)piperidine-1-carboxylate (150 mg, 0.52 mmol) and the reaction mixture was stirred at 90° C. for 30 min, cooled to room temperature, and concentrated under reduced pressure. The crude residue was triturated with ether to afford 6-(piperidin-4-yl)nicotinonitrile hydrochloride (90 mg, crude). 1H NMR (300 MHz, D2O) δ 8.90 (d, J=0.7 Hz, 1H), 8.30 (dd, J=8.2 Hz, 1.9 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 3.60-3.55 (m, 2H), 3.27-3.13 (m, 3H), 2.20 (m, 2H), 2.07-1.97 (m, 2H). MS (ESI) m/z: Calculated for C11H13N3: 187.11. found: 188.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH:3]([CH:8]([S:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[CH3:1][O:2][CH:3]([CH:8]([S:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:4]([OH:6])=[O:5]
Reactant: COC(=O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(OC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(C(=O)O)C(SCCC(=O)O)c1ccccc1CCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
A solution of methyl 2-methoxy-3-(2-carbomethoxyethylthio)-3-[2-(8-phenyloctyl)phenyl]propanoate (0.5807 g, 1.2 mmoles) in methanol (5 ml) under argon was cooled to 0° C., after which 10% sodium hydroxide (1.5 ml, 3.5 mmoles) was added. The mixture was permitted to warm to room temperature and stirred for 2 hours. The methanol was evaporated and the mixture diluted with water. The pH of the aqueous layer was adjusted to 2 with dilute hydrochloric acid and extracted with ether. The organic phase was dried over magnesium sulfate, filtered and evaporated. The diastereomeric mixture of products was separated on a silica column using 23% ethyl acetate in hexane plus 0.5% formic acid. Five runs were made and the fractions analyzed on an analytical column. The separation provided both diastereomers in greater than 99% purity. The erythro isomer was obtained in 28% yield and the threo isomer in 22%. Erythro isomer: Analysis for C27H36SO5 1/8H2O:
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].[Br:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:16][CH2:17][CH2:18][CH2:19][C:20]([O:1][CH2:2][CH:3]([NH:8][C:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:15])[CH2:4][CH:5]([CH3:7])[CH3:6])=[O:21]
Reactant: O=C(O)CCCBr
Reactant: CC(C)CC(CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)CC(COC(=O)CCCBr)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
tert-Butyl 1-hydroxy-4-methylpentan-2-ylcarbamate (2.00 g, 9.20 mmol) and 4-bromo-butyric acid (2.57 g, 15.38 mmol) were dissolved in CH2Cl2 (40 ml) and the mixture was cooled to 0° C. EDC (4.20 g, 21.90 mmol) and DMAP (0.27 g, 2.21 mmol) were added and the reaction was slowly warmed to room temperature and stirred overnight. Then the reaction was treated with a solution of 5% aqueous NaH2PO4 (100 ml). The organic layer was washed with a solution of 10% aqueous Na2CO3 (100 ml) and brine, dried over Na2SO4, filtered and concentrated. The obtained crude clear oil corresponding to the title compound (3.30 g) was used without any further purification.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][NH:14][C@H:15]([CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:16](OC)=[O:17])=O)C1C=CC=CC=1.C(OC(C)C)(C)C.O.C(Cl)Cl.C(O)(C)C>CO>[C:22]([O:21][CH2:20][C@H:15]1[NH:14][CH2:13][CH2:12][NH:11][C:16]1=[O:17])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@@H](COC(C)(C)C)NCCNC(=O)OCc1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC[C@H]1NCCNC1=O
Reaction time: 3 h
Yield: 46.5 %

Procedure:
39.5 kg of (R)-methyl 2-(2-(benzyloxycarbonylamino)ethylamino)-3-t-butoxypropanoate was dissolved in 276 L of methanol in a reactor; purged with nitrogen; 5.9 kg of palladium/carbon (10% water mixture) was added and stirred for 3 hours while the hydrogen pressure was maintained at 10 bar. The reaction solution was filtered, concentrated under reduced pressure, and then again azeotroped by adding 30 L of isopropylether. 158 L (115 kg) of isopropylether, 39 L (35 kg) of ethyl acetate, and 36.4 kg of silica gel were added to a concentrated solution, stirred for 1 hour, decompression-filtered, and then concentrated under reduced pressure. A concentrated residue was azeotroped by adding 30 L of methanol, and then a concentrated solution and 221 L of methanol were added to a reactor. After purging with nitrogen, 11.85 kg of palladium/carbon (10% water mixture) was added, and then stirred for 6 hours while hydrogen pressure was maintained at 15 bar. The reaction solution was filtered, and then concentrated under reduced pressure. An aqueous layer was isolated in twice by adding 80 L of isopropylether and 80 L of purified water to the concentrated solution. An organic layer was isolated after adding methylene chloride/isopropanol=5:1 (126 L) to the aqueous layer and then stirring in 5 times. The organic layer was dehydration-filtered with 50 kg of sodium sulfate to obtain 9.7 kg of a title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][CH:32]=1)[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH3:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:30]=[CH:31][CH:32]=1)[CH2:14][C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:21](=[O:23])[CH:22]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(CCC(=O)O)(Cc1cccc(Cl)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(Cc1cccc(Cl)c1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of 4-(m-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.8 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.) and extracted with ether to remove the excess p-chlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (10 ml.), and the white solid which precipitates is collected and air-dried to yield 5.05 g., m.p. 65°-130°C. Several recrystallizations from n-butyl chloride and petroleum ether (30°-60°C.) give a material with m.p. 137°-139°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-])=O)=[CH:13][CH:14]=2)[CH:9]1[CH3:21])=[O:5])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:18][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:9]2[CH3:21])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCN1CCc2ccc(N)cc2C1C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
0.90 g of 2-[2-(ethoxycarbonyl)ethyl]-1-methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline was dissolved in 10 ml of ethanol, and 2.78 g of tin chloride dihydrate was added to the solution. The solution was heated under reflux with stirring for 2 hours. The resulting solution was neutralized with aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. After washing with water and saturated aqueous solution of sodium chloride, the solution was dried with anhydrous sodium sulfate. The desiccant was separated by filtration, and the solvent was distilled off to obtain 0.69 g of 7-amino-2-[2-(ethoxycarbonyl)ethyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline, which was an oily product. This product with no further purification was dissolved in 10 ml of DMF, and to this solution were added 0.92 g of separately synthesized 1-(benzyloxycarbonyl)-4-(carboxymethoxy)piperidine and 0.75 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The solution was stirred overnight at room temperature, and the resulting solution was extracted with ethyl acetate, washed with water, saturated aqueous solution of sodium bicarbonate, and saturated aqueous solution of sodium chloride, and dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the filtrate was purified by silica gel column chromatography to obtain 1.00 g of 7-[1-(benzyloxycarbonyl)piperidine-4-yloxyacetylamino]-2-[2-(ethoxycarbonyl)ethyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline, which was an oily product (yield: 71%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].[Cl:8][C:9]1[C:10](F)=[N:11][C:12]([F:23])=[N:13][C:14]=1[N:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][CH:17]([CH3:22])[CH2:16]1.[Cl-].[NH4+]>O1CCCC1>[Cl:8][C:9]1[C:10]([O:7][CH2:3][C:4]#[C:5][CH3:6])=[N:11][C:12]([F:23])=[N:13][C:14]=1[N:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][CH:17]([CH3:22])[CH2:16]1
Reactant: CC#CCO
Reactant: CC1CC(C)CN(c2nc(F)nc(F)c2Cl)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1nc(F)nc(N2CC(C)CC(C)C2)c1Cl
Reaction time: 0.17 h
Yield: 42 %

Procedure:
0.09 g of sodium hydride (60% oil suspention) was suspended in 2 ml of tetrahydrofuran. 0.3 ml of tetrahydrofuran solution of 0.13 g of 2-butyn-1-ol was added dropwise at room temperature therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 0.3 ml of tetrahydrofuran solution of 0.4 g of 5-chloro-2,4-difluoro-6-(3,5-dimethylpiperidino) pyrimidine at 0° C., and stirred for 30 minutes at same temperature. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.20 g of 5-chloro-4-(2-butynyloxy)-2-fluoro-6-(3,5-dimethyl piperidino)pyrimidine (hereinafter, referred to as Compound (52)). Compound (52) had the cis/trans diastereomer originated two methyls on the pyperidine ring. The ratio of the cis/trans diastereomer was about 5/1.
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([C:15](O)=[O:16])=[CH:13][C:12]([Cl:18])=[N:11][CH:10]=1)=O)(C)(C)C.[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:29])=[C:24]([C:26](=O)[CH3:27])[CH:25]=1>>[Cl:18][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][N:11]=1)[NH:8][C:26]([C:24]1[CH:25]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=1[CH3:29])=[CH:27][C:15]2=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Reactant: CC(=O)c1cc(F)ccc1C
Product: Cc1ccc(F)cc1-c1cc(=O)c2cc(Cl)ncc2[nH]1
Yield: 24 %

Procedure:
The title compound was prepared following a procedure similar to example 121 using 5-(tert-butoxycarbonylamino)-2-chloroisonicotinic acid (505 mg, 1.85 mmol) and 5′-fluoro-2′-methylacetophenone (566 mg, 3.72 mmol) to afford the impure title compound as a beige solid (128 mg), used without further purification. LCMS: M+H+=289 & 291.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([OH:19])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:20](I)([CH3:22])[CH3:21].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH:20]([CH3:22])[CH3:21])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)I
Reactant: Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reaction time: 0.25 h

Procedure:
0.23 g (7.8 mmol) of an 80% suspension of sodium hydride in mineral oil was washed with anhydrous pentane to remove the mineral oil and then suspended in 50 ml of anhydrous dimethylformamide. A solution of 2.0 g (6.5 mmol) of 3-chloro-2-(4-chloro-3-hydroxyphenyl)5-trifluoromethylpyridine in 50 ml of anhydrous dimethylformamide was added dropwise to this suspension at 0° C. After the addition is complete, the mixture was stirred for 15 minutes and then 1.3 g (7.8 mmol) of isopropyl iodide were slowly added dropwise. The mixture was then stirred at 20°-25° C. for about 15 h and subsequently poured into 400 ml of water and extracted three times with methyl tert-butyl ether. The combined organic phases were washed with water, dried over sodium sulfate and evaporated under reduced pressure. Yield: 1.9 g (83%) of a colorless oil.
Reaction SMILES: P(Br)(Br)(Br)(Br)[Br:2].O[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1>O>[Br:2][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1
Reactant: BrP(Br)(Br)(Br)Br
Reactant: O=C(O)c1ccc(O)nc1
Solvent: O
Product: O=C(O)c1ccc(Br)nc1

Procedure:
Phosphorus pentabromide (18 g.) was added carefully to 6-hydroxynicotinic acid (4.17 g) and the resulting mixture was heated with stirring for about 1/4 hour at 70°-80° and then 1 hour at 120°. During the heating, the resulting dark red liquid solidified to a yellow mass. After cooling, the mass was added to iced water, and the resulting white precipitate of 6-bromonicotinic acid was filtered off, washed with water, and recrystallized from aqueous ethanol (yield 4g, m.p. 190°-195°). The compound was used directly in the next stage.
Reaction SMILES: [CH2:1]([O:8][C@@:9]1([C:36]([F:39])([F:38])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][NH2:35])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH2:1]([O:8][C@@:9]1([C:36]([F:38])([F:39])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][NH:35][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Solvent: ClCCl
Product: CS(=O)(=O)NC[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude ((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methan amine (34, R1=4-Fluorophenyl, R3=Trifluoromethyl, R4═H, R3=Benzyl) (0.135 mmol) was dissolved in DCM (3 mL) and methanesulfonyl chloride (0.026 mL, 0.334 mmol) and TEA (0.023 mL, 0.167 mmol) were added at rt. The reaction was stirred at rt for about 30 min, then diluted with DCM (10 mL) and concentrated with silica gel (3 g). The residue was purified on silica gel using a gradient of 0-10% EtOAc in DCM. Product fractions were combined and concentrated to yield N-(((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)methanesulfonamide (35, R1=4-Fluorophenyl, R3=Trifluoromethyl, R4=Methanesulfonyl, R3=Benzyl) (40 mg, 39%) as a clear glass; LC/MS, method 3, Rt=2.95 min, MS m/z 616 (M+H)+.) The residue was used in step #4 without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH2:33][C:34]1[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=1.[C:40]([OH:48])(=[S:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)(O)[O-].[K+]>C1COCC1.C(OCC)(=O)C.O>[C:40]([S:47][CH2:33][C:34]1[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=1)(=[O:48])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: Cn1cc(CO)cn1
Reactant: OC(=S)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(CSC(=O)c2ccccc2)cn1

Procedure:
Under nitrogen atmosphere, 78.7 g of triphenylphosphine (300 m mol) and 47.2 ml of diethyl azodicarboxylate (300 m mol) were added to a stirred solution of 22.4 g of 4-hydroxymethyl-1-methylpyrazole (200 m mol) in THF (250 ml) at 5° C. After stirring for 1 hour at the same temperature, 42.3 ml of thiobenzoic acid (360 m mol) was added slowly to the mixture. The mixture was poured into a mixture of water and ethyl acetate, while Ph was adjusted to 9.5 with 30% potassium bicarbonate. Aqueous layer was separated, the organic layer was washed with brine, dried over magnesium sulfate. After filtration of the mixture, the filtrate was concentrated in vacuo, and the residue was purified on silica gel (eluent: n-hexane-ethyl acetate) to afford 4-(benzoylthiomethyl)-1-methylpyrazole (18.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]1)=[O:7]>CO.[Pd]>[NH2:18][C:17]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10]2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)N[C@@H]2CCN(C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)NC2CCN(C)C2)ccc1N
Yield: 99 %

Procedure:
A solution of 3-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-4-nitro-benzamide (Intermediate 188; 227 mg, 0.81 mmol) in methanol (25 mL) was hydrogenated using 10% Pd/C catalyst. Catalyst was filtered off and solvent evaporated to yield the title compound as a yellow gum (200 mg, 100%).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:6]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11]C)=O)[CH:7]=1)=O.CO.[CH3:27][NH2:28].[BH4-].[Na+].[ClH:31].C(=O)([O-])O.[Na+]>CO>[ClH:31].[ClH:31].[CH3:27][NH:28][CH2:1][C:3]1[N:4]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:6]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][OH:11])[CH:7]=1
Reactant: CN
Reactant: COC(=O)C(c1ccccc1)n1cc(C=O)nc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cn(C(CO)c2ccccc2)c(-c2ccccc2)n1
Reaction time: 0.25 h
Yield: 27 %

Procedure:
To a solution of methyl (4-formyl-2-phenyl-1H-imidazol-1-yl)(phenyl)acetate (200 mg) in methanol (10 mL) was added 40% methylamine methanol solution (243 mg) and the mixture was stirred for 15 min. Sodium borohydride (71 mg) was added and the mixture was stirred for 30 min. 1 mol/L Hydrochloric acid was added to the reaction mixture and the mixture was stirred for 5 min. The mixture was neutralized with saturated sodium hydrogen carbonate solution, and extracted with ethyl acetate-tetrahydrofuran (1:1). The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:ethyl acetate-methanol=1:0→3:2) and dissolved in methanol (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and insoluble materials were collected by filtration to give the title compound as a colorless powder (yield 63 mg, yield 27%).