Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:16])([CH3:15])[CH2:11][OH:14])[C:13]=1[OH:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc2c1OC(=O)C2(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)c1cccc(C(C)(C)CO)c1O
Temperature: 25 °C

Procedure:
A solution of 45 (235 mg, 1.077 mmol) in ether (5 ml) was dropwise added, with stirring and ice-cooling, to a suspension of LiAlH4 (49 mg, 1.29 mmol) in ether (5 ml). After washing a container of the solution with ether (5 ml), the washing was added to the mixture, which was warmed to room temperature and stirred for 45 minutes. The reaction mixture was added with ethyl acetate (1 ml) and 3 ml of a mixture of water and saturated ammonium chloride (1:1), and stirred for 30 minutes. Resultant slurry was removed by filtration through celite, and the filtrate was concentrated to obtain 253 mg (quant) of 46. 1H NMR (CDCl3) δ: 1.42 (9H, s, tBu), 1.44 (6H, s, 2×CH3), 3.81 (2H, s, CH2), 6.75-7.23 (3H, m, 3×Ar—H), 9.20 (1H, br s, phonemic-OH).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1F)[C:22]#[N:23]>CN(C=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[S:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2)[C:22]#[N:23]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: Sc1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Sc2cccc3cnccc23)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
According to the method in Example 10, 5-isoquinolinethiol 1.00 g (6.2 mmol), DMF 30 ml, potassium carbonate 1.60 g (11.6 mmol) and 3-chloro-4-fluorobenzonitrile 0.90 g (5.8 mmol) were stirred at 100° C. for 30 minutes, and 3-chloro-4-(5-isoquinolylsulfanyl)benzonitrile 1.55 g (90.3%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH:4]=1.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:4]=1
Reactant: COC(=O)CCc1cc(OC)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccnc(CCC(=O)O)c1
Temperature: 25 °C

Procedure:
41.95 g of methyl 3-(4-methoxypyridin-2-yl)propionate (starting material C1) are dissolved in 700 ml of tetrahydrofuran, and 217 ml of 1N sodium hydroxide solution are added. The mixture is stirred at RT until no more starting material is detectable (TLC). The mixture is neutralized using 217 ml of 1N hydrochloric acid solution, evaporated to dryness and dried under high vacuum. The colorless residue is ground and extracted four times with dichloromethane/methanol (9:1). The combined extracts are evaporated to dryness. This gives 33.2 g of the title compound as a colorless powder of m.p. 131-132° C. The mass spectrum shows the molecular peak MH+ at 182 Da.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:7][C:8]=1[CH2:9][OH:10])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(=O)([O-])O.[Na+].ClCCl>[CH:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[O:7][C:8]=1[CH:9]=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1C=O

Procedure:
[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol (0.46 g, 1.612 mmol), Dess-Martin periodinane (1.36 g, 3.22 mmol) and dichloromethane (25 mL) are stirred 1 hr at room temperature. The mixture is diluted with aqueous saturated sodium hydrogen carbonate (100 mL) and dichloromethane (100 mL). The layers are separated, the aqueous layer is washed with dichloromethane (100 mL). The organic washes are combined, washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The product is purified over silica eluting with 3:1 hexanes:ethyl acetate to afford 4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carbaldehyde as a white solid, 0.41 g, 90%. %. MS (M++1) 284.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[S:24]([NH2:34])(=[O:33])([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)=[O:25]>>[NH2:34][S:24]([C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[CH:30][CH:31]=1)(=[O:25])=[O:33]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(S(N)(=O)=O)cc3)(CC1)CC2
Yield: 24.6 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and sulfanilamide (59.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-aminosulfonylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (18.2 mg).
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C@@H:10]([N:25]2[CH2:30][C@@H:29]([CH3:31])[N:28]([CH2:32][CH:33]=[CH2:34])[CH2:27][C@@H:26]2[CH3:35])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][Si](C(C)(C)C)(C)C)[CH:12]=2)[CH:5]=1.[OH-].[Na+].Cl>C1COCC1>[CH2:32]([N:28]1[C@H:29]([CH3:31])[CH2:30][N:25]([C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:36])=[O:2])[C@@H:26]([CH3:35])[CH2:27]1)[CH:33]=[CH2:34]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)OC)c2)C[C@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)O)c2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A mixture of 3-{(R)-((2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl)[3-(tert-butyl-dimethylsilanyloxy)phenyl]methyl}benzoic acid methyl ester (7.4 g, 14.5 mmol) and 18.2 mL of 2.0 N aqueous sodium hydroxide (36.4 mmol, 2.5 eq) in THF (30 mL) was stirred overnight at room temperature. Hydrochloric acid (18.2 mL of 2 N aqueous solution) was added, and the THF was removed under vacuum. The aqueous residue was filtered to collect precipitated solid, which was washed with dichloromethane to remove organic impurities. The aqueous filtrate was concentrated to dryness to give additional solid material. The recovered solids were combined, washed with water to remove sodium chloride, and dried to give 5.5 g (99.4%) of crude 3-[(R)-((2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]benzoic acid (Acid A).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[N:12]1[CH2:23][CH2:22][C:15]2([C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1.Cl[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28](S(C2C=CC(C)=CC=2)(=O)=O)[CH:27]=1.[NH4+].[Cl-]>C1COCC1>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([CH2:25][N:19]2[CH2:18][CH2:17][CH2:16][C:15]3([CH2:22][CH2:23][N:12]([C:4]4[O:3][C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[N:5]=4)[CH2:13][CH2:14]3)[C:20]2=[O:21])=[CH:27]1
Reactant: O=C1NCCCC12CCN(c1nc3ccccc3o1)CC2
Reactant: Cc1ccc(S(=O)(=O)n2cc(CCl)c3ccccc32)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1N(Cc2c[nH]c3ccccc23)CCCC12CCN(c1nc3ccccc3o1)CC2
Temperature: 25 °C

Procedure:
NaH (28 mg, 1.16 mmol) was added to a stirred solution of 9-(benzo[d]oxazol-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (150 mg, 0.53 mmol) in THF (5 mL) and the resulting mixture was heated under reflux for 30 min. The reaction mixture was allowed to warm to rt. Then, 3-(chloromethyl)-1-tosyl-1H-indole [471294-27-6] (201 mg, 0.63 mmol) was added and the mixture was heated at 60° C. for 18 h. The mixture was cooled to rt and saturated aqueous NH4Cl solution was added and the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to yield a pale brown solid. This product was directly taken for the next step for detosylation to furnish the title compound as follows:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[OH:14])[C:9]#[N:10]>OS(O)(=O)=O>[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+:1]([O-:4])=[O:2])[C:13]=1[OH:14])[C:9]#[N:10]
Reactant: N#Cc1ccc(O)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: N#Cc1cc(F)c(O)c([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Fuming HNO3 (1.8 mL; 44 mmol) was added dropwise to a solution of 3-fluoro-4-hydroxybenzonitrile (4.0 g; 29 mmol) in conc. H2SO4 (10 mL) at −10° C. The mixture was stirred at −10° C. for 1 h and thereafter slowly poured into ice. The precipitate was filtered off and the filtrate was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was combined with the precipitate and crystallized from EtOAc/PE to give the sub-title compound.
Reaction SMILES: [C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C@@H:8]([NH:32]C(=O)OC(C)(C)C)[CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]3[N:22]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:21]4[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=4[N:19]=3)[CH2:13]2)=[O:11])[CH:2]=1.C(Cl)Cl.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>CO.CC#N.O>[NH2:32][C@H:8]([CH2:7][C:3]1[CH:2]=[C:1]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][CH:4]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]2[N:22]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[C:21]3[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=3[N:19]=2)[CH2:13]1)=[O:11].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]
Reactant: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3cccc(-c4ccccc4)c3)NC(=O)OC(C)(C)C)C2)nc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3cccc(-c4ccccc4)c3)C2)nc2ccccc21

Procedure:
tert-Butyl(R)-1-(biphenyl-3-yl)-4-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-4-oxobutan-2-ylcarbamate (52A) (0.05 mmol, 0.030 g) was weighed into a 20 mL round-bottomed flask equipped for stirring under nitrogen. CH2Cl2 (1 mL) and trifluoroacetic acid (1 mL) were then added and the solution was stirred at room temperature for 2 hrs. The solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in methanol (3 mL), filtered, and then purified by preparative LC/MS (20-55% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford (R)-3-amino-4-(biphenyl-3-yl)-1-((R)-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)butan-1-one (122) as its trifluoroacetic acid salt and as a white flocculent solid (0.021 mmol, 0.013 g, 42% yield). 1H NMR (400 MHz, DMSO-d5) δ ppm 1.39-1.58 (m, 1H) 1.73-2.15 (m, 5H) 2.60-2.88 (m, 4H) 2.90-3.13 (m, 4H) 3.15-3.25 (m, 3H) 3.30-3.51 (m, 3H) 4.07-4.32 (m, 2H) 4.34-4.68 (m, 3H) 7.23-7.32 (m, 1H) 7.33-7.52 (m, 6H) 7.54-7.61 (m, 2H) 7.62-7.80 (m, 4H). ESI-MS: m/z 511.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:15]([O:19][C:20](=[O:23])[CH2:21][NH2:22])([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:19][C:20](=[O:23])[CH2:21][NH:22][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
4-Nitrobenzenesulfonyl chloride (46.3 g) was added to a solution of glycine t-butyl ester hydrochloride (35 g) in pyridine (200 ml). The mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated. The precipitated crystals was washed with water and then a mixture of hexane and ethyl acetate (9:1) and dried to give the title compound (61.4 g) having the following physical data.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][S:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[NH2:20][C:21]1[CH:22]=[CH:23][C:24](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:52])[C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:43][CH:42]=3)=[CH:35][C:34]=2[S:53]([OH:56])(=[O:55])=[O:54])=[C:25]([S:27]([OH:30])(=[O:29])=[O:28])[CH:26]=1.C(N(CC)CC)C>CN(C=O)C.ClCCl.O>[CH3:51][O:50][CH2:49][CH2:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([C:40]([NH:39][C:36]2[CH:37]=[CH:38][C:33](/[CH:32]=[CH:31]/[C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:15](=[O:17])[C:14]4[CH:13]=[CH:12][C:11]([S:8]([CH3:7])(=[O:9])=[O:10])=[CH:19][CH:18]=4)=[CH:26][C:25]=3[S:27]([OH:30])(=[O:29])=[O:28])=[C:34]([S:53]([OH:56])(=[O:55])=[O:54])[CH:35]=2)=[O:52])=[CH:46][CH:45]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COCCOc1ccc(C(=O)Nc2ccc(/C=C/c3ccc(N)cc3S(=O)(=O)O)c(S(=O)(=O)O)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1ccc(C(=O)Nc2ccc(/C=C/c3ccc(NC(=O)c4ccc(S(C)(=O)=O)cc4)cc3S(=O)(=O)O)c(S(=O)(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.6 %

Procedure:
Oxalyl chloride (0.5 mL) and DMF (1 drop) were added to a 0° C., stirred solution of commercially available 4-(methylsulfonyl)-benzoic acid (97 mg, 0.5 mmol) dichloromethane (10 mL). Concentration in vacuum afforded an off white powder. A solution of this powder in dichloromethane (5 mL) was added to a 0° C., stirred solution of bis(tetra-N-butyl)ammonium salt of 5-amino-2-[(E)-2-(4-{[4-(2-methoxyethoxy)benzoyl]amino}-2-sulfophenyl)ethenyl]-benzenesulfonic acid (Example 39a, 0.50 g, 0.5 mmol) and triethylamine (0.14 g, 1.0 mmol) indichloromethane (25 mL). The resulting yellow mixture was allowed to warm to room temperature and was stirred for 20 hours. Water (15 mL) was added and the layers were separated. The organic phase was dried (MgSO4) and concentrated to provide a yellow powder that was chromatographed (gradient elution MeOH:CH2Cl2) to afford bis(tetra-N-butyl)ammonium salt of the title compound as a yellow foam (280 mg). A solution of this yellow foam in water:methanol/90:10 (300 mL) was passed through a sodium ion exchange resin (300 g, Toyopearl SP-650 resin). The fractions were combined and concentrated to about 20 mL. This concentrate was subjected to freeze drying which afforded the bis(sodium) salt of the title compound as a yellow powder (146 mg, 43% yield): 1HNMR (DMSO-d6) δ3.35 (s, 3H), 3.39 (s, 3H), 3.70 (t, J=5 Hz, 2H), 4.20 (t, J=5 Hz, 2H), 7.05 (d, J=14 Hz, 2H), 7.60 (t, 9 Hz, 2H), 7.88 (dt, J=17, 2 Hz, 2H), 7.98 (d, J=18 Hz, 2H), 8.04 (dd, J=1 Hz, 2H), 8.04 (d, J=11 Hz, 2H), 8.19 (dd, 10, 2 Hz, 2H), 8.21 (d, 15 Hz, 2H), 10.26 (s, 1H), 10.68 (s, 1H): MS (ESI) [M−H]− at m/z 729.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7].[CH2:17]([CH:19]1[O:21][CH2:20]1)[Br:18].[OH-].[K+]>ClCCl.O>[C:6]([CH:10]1[CH2:11][CH2:12][C:13]2([O:21][CH:19]([CH2:17][Br:18])[CH2:20][O:16]2)[CH2:14][CH2:15]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: BrCC1CO1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C1CCC2(CC1)OCC(CBr)O2
Temperature: 20 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
30.15 g (120 mmol) of tin(IV) chloride were added dropwise to 115.5 g (750 mmol) of 4-tert-butylcyclohexanone in 700 ml of absolute dichloromethane at 5° C., followed by the dropwise addition of 205.5 g (1.5 mol) of epibromohydrin ##STR9## in 370 ml of absolute dichloromethane in the course of 5 hours. The mixture was stirred overnight at room temperature (20° C.), hydrolyzed with a solution of 42 g of KOH in 180 ml of water while cooling, and worked up in a conventional manner. Distillation of the crude product (279 g) under reduced pressure gave 169 g (77.5%) of 8-tert-butyl-2-bromomethyl-1,4-dioxaspiro[4,5]decane of boiling point 110° C./0.2 mbar.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7](OCC)=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1N
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nn(-c2ccccc2)cc1CO
Yield: 71.2 %

Procedure:
A solution (70 mL) of ethyl 3-amino-1-phenyl-1H-pyrazole-4-carboxylate (17.2 g) in tetrahydrofuran was added dropwise to a mixture of lithium aluminum hydride (3.39 g) and tetrahydrofuran (130 mL) on an ice bath. The reaction mixture was heated under reflux for 2 hrs. To this reaction mixture was added sodium sulfate decahydrate by small portions with stirring until foams disappeared on an ice bath, and tetrahydrofuran (50 mL) was further added. After further stirring for 2 hrs., the reaction mixture was filtered, and the filtrate was concentrated. Recrystallization of the residue from tetrahydrofuran-hexane gave (3-amino-1-phenyl-1H-pyrazol-4-yl)methanol as pale-yellow crystals (10.02 g, yield 82%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 127-128° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[C:10]1[N:11]([CH2:23][CH2:24][OH:25])[CH:12]=[C:13]([C:15]2[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=2)[N:14]=1.[H-].[Na+]>CN(C=O)C>[CH:20]([N:16]1[C:15]([C:13]2[N:14]=[C:10]3[N:11]([CH2:23][CH2:24][O:25][C:2]4[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=43)[CH:12]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: COc1cc(Cl)c(-c2nc(-c3ncnn3C(C)C)cn2CCO)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
A solution of 2-[2-(4-chloro-6-methoxy-pyridin-3-yl)-4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol (7.52 g, 20.7 mmol) in DMF (100 mL) was cooled to 0° C. and treated with sodium hydride (804 mg, 20.1 mmol), the reaction mixture stirred at 0° C. for 10 min then allowed to warm to RT and stirred for 72 h. Further sodium hydride (150 mg) was added and stirring continued until no starting material remained before removal of solvent in vacuo. The residue was dissolved in ethyl acetate and the resultant solution washed three times with saturated brine then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated in pentane/diethyl ether (5:1) to give the title compound as a brown solid (5.38 g, 79%). LCMS RT=2.86, [M+H]+=327. 1H NMR 400 MHz (CDCl3) δ: 9.35 (1H, s), 7.87 (1H, s), 7.63 (1H, s), 6.37 (1H, s), 6.03-6.02 (1H, m), 4.54-4.53 (2H, m), 4.53-4.33 (2H, m), 3.99 (3H, s), 1.57 (6H, d, J=6.63 Hz).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([C:15]([F:18])([F:17])[F:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[C:15]([F:18])([F:16])[F:17]
Reactant: OC1CCN(Cc2ccccc2)CC1C(F)(F)F
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: OC1CCNCC1C(F)(F)F

Procedure:
A mixture of 1-benzyl-4-hydroxy-3-trifluoromethylpiperidine (1.8 g, 6.94 mmole and 20% palladium hydroxide (0.5 g) in methanol (25 ml) was stirred in hydrogen atmosphere (1.atm.) for 17 hr at 50° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3-trifluoromethylpiperidine as oil. Yield 0.7 g (60%), C6H10F3NO, m/z 170 (M+1).
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20]([Cl:27])=[CH:21][NH:22]2>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:27][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[CH:26][C:18]=2[N:17]=[C:8]=[S:9])[NH:22][CH:21]=1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Nc1cccc2[nH]cc(Cl)c12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: S=C=Nc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
4-Dimethylaminopyridine (0.031 g, 0.256 mmol) and di-2-pyridyl thionocarbonate (0.983 g, 4.23 mmol) are added to a solution of 4-amino-3-chloroindole (0.655 g, 2.82 mmol) in methylene chloride. The resulting mixture is stirred at room temperature for 1 hour. The volatile organics are removed by rotary evaporation and the crude residue is purified via silica gel column chromatography using 20% ethyl acetate/hexanes as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 0.511 g of 3-chloro-4-isothiocyanatoindole as a yellow solid (96%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]([F:8])([F:7])[CH2:4][C@@H:3]1[NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.Br[C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:7][C:5]1([F:8])[CH2:4][C@H:3]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)[C@@H:2]([NH:1][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:34])[F:33])=[CH:26][N:25]=2)[CH2:6]1
Reactant: N[C@H]1CC(F)(F)C[C@@H]1NC(=O)c1ccccc1-n1nccn1
Reactant: FC(F)(F)Oc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(N[C@H]1CC(F)(F)C[C@@H]1Nc1ccc(OC(F)(F)F)cn1)c1ccccc1-n1nccn1
Temperature: 120 °C

Procedure:
To a solution of N-[(1S,2S)-2-amino-4,4-difluorocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 46; 50 mg, 0.16 mmol) in dry toluene (1.6 ml) was added 2-bromo-5-(trifluoromethoxy)pyridine (CAS number 888327-36-4; 40 mg, 0.17 mmol), BINAP (10 mg, 0.016 mmol), tris(dibenzylideneacetone)dipalladium(0) (8 mg, 8.74 μmol) and sodium tert-butoxide (22 mg, 0.23 mmol). The reaction was placed under an atmosphere of nitrogen, sealed and heated at 120° C. for 17 hours then partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (silica, 10-70% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Br:9])=[C:6]([OH:8])[CH:7]=1.[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][C:5]1[C:6]([O:8][CH2:11][CH3:12])=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: Nc1cc(O)c(Br)cc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cc(N)c(F)cc1Br
Yield: 67.8 %

Procedure:
5-Amino-2-bromo-4-fluorophenol (10.30 g), ethyl iodide (9.36 g) and potassium carbonate (7.59 g) were suspended in acetonitrile (100 ml), and the mixture was heated under refluxing for about 6 hours. After the reaction, the precipitates were filtered, the solvent was distilled off, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off, and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3 v/v) to obtain the objective 4-bromo-5-ethoxy-2-fluoroaniline (7.93 g).