Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][C:11]1[CH:16]=[C:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:14]=[CH:13][C:12]=1[CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C(O)C>[Si:3]([O:10][C:11]1[CH:16]=[C:15]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19])[CH:14]=[CH:13][C:12]=1[C@@H:25]1[CH2:26][CH2:27][C@H:28]([OH:31])[CH2:29][CH2:30]1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 18 h

Procedure:
Sodium borohydride (164 mg) was added to a stirred solution of 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (1.57 g) in ethanol (50 ml) at 0° C. After 18 hr at room temperature, the mixture was partitioned between 2M HCl (20 ml), water (40 ml) and ethyl acetate (50 ml) and the aqueous layer was re-extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (40 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 3:17 v/v) to give the trans-title compound as a white solid (546 mg, 35%), and the cis-title compound as a white solid (83 mg, 5%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C)C=O>[Si:18]([O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: O=C(O)C=Cc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(/C=C/C(=O)O)cc1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
4-hydroxy-cinnamic acid (4.21 g, 25.67 mmol) and imidazole (5.24 g, 77.01 mmol) were charged in a 250 mL round-bottom flask and dissolved in 25 mL of dimethylformamide. Tert-butyldimethylsilyl chloride (8.12 g, 83.90 mmol) was added thereto at 0° C., followed by stirring for 30 minutes. The reaction liquid was concentrated by distillation under reduced pressure and dichloromethane (50 mL) was added thereto, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate, concentrated and dissolved in tetrahydrofuran (114 mL)/methanol (322 mL), and a 0.00035M potassium carbonate aqueous solution (120 mL) was added thereto, followed by stirring for 1 hour. After being concentrated by distillation under reduced pressure, the resulting solid was filtered, washed with water, and dried under vacuum to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][CH:24]([F:36])[O:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH:24]([F:23])[F:36])[CH:27]=3)(=[O:34])=[O:33])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Reactant: COc1ccc(N)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.5 %

Procedure:
0.745 g of 4-(5-Amino-2-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.423 mmol) were dissolved in 35 ml of pyridine. 0.588 g of 3-(difluoromethoxy)-benzene-sulfonylchloride were added dropwise and the reaction mixture was stirred for 72 h at room temperature. The solvent was evaporated, the residue was dissolved in 40 ml dichloromethane and the organic phase was washed twice with 30 ml aqueous saturated ammonium chloride. The organic phase was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified three times via silica gel chromatography using dichloromethane-methanol, and dichloromethane-ethyl acetate as eluent. 0.94 g of the title compound were isolated.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:20])=[CH:12][C:13]=1[C:14]#[C:15][C:16]([CH3:19])([CH3:18])[CH3:17])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:16]([C:15]1[NH:7][C:8]2=[CH:9][N:10]=[C:11]([Cl:20])[CH:12]=[C:13]2[CH:14]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C#Cc1cc(Cl)ncc1NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2cc(Cl)ncc2[nH]1
Temperature: 0 °C
Yield: 86.4 %

Procedure:
A mixture of [6-chloro-4-(3,3-dimethyl-but-1-ynyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (15.8 g, 51 mmol) and TBAF (26.6 g, 0.1 mol) in THF (200 mL) was heated at reflux for 24 hours. After cooling, the mixture was poured into ice water and extracted with CH2Cl2 (300 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a residue, which was purified by column chromatography (petroleum ether/ethyl acetate=10/1) to give 2-tert-butyl-5-chloro-1H-pyrrolo[2,3-c]pyridine (9.2 g, 87%). 1H NMR (300 MHz, CDCl3) δ 9.15 (br s, 1H), 8.43 (s, 1H), 7.44 (s, 1H), 6.25 (dd, J=0.6, 2.1 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH2:4][CH2:3]1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[NH4+]>C(O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8](=[N:18][OH:19])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[CH2:4][CH2:3]1
Reactant: NO
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CN1CCC(C(=NO)c2ccccc2F)CC1
Yield: 54 %

Procedure:
A mixture of 5.2 g of 1-methyl-4-(2-fluorobenzoyl)piperidine, 2.5 g of hydroxylamine hydrochloride, 5.4 g of ammonium acetate and 50+15 ml of ethanol-water was heated under reflux for 22 hrs. Most of the ethanol was removed under reduced pressure. The aqueous mixture was made basic with aqueous sodium hydroxide and the mixture was extracted with chloroform. The chloroform extract was dried over anhydrous magnesium sulfate and the chloroform was evaporated in vacuo to give a solid. The solid was triturated with ether. Recrystallization from ethanol-water gave 3.0 g (52.6%) of product, mp, 136°-139°.
Reaction SMILES: [CH2:1]([C:4](=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[O:6])[CH2:2][CH3:3]>[Pd].[C]>[CH2:1]([CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[O:6])[CH2:2][CH3:3]
Reactant: CCCCC=C(C=O)CCC
Agent: [Pd]
Product: CCCCCC(C=O)CCC
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
An autoclave was charged with 420 g of 2-propyl-2-heptenal and 4 g of a 5% Pd carbon powder (water content: 56%, manufactured by N.E. Chemcat Corporation), and the mixture was stirred at 75° C. for 1.5 hours under a hydrogen pressure of 1.5 MPa. The reaction product was filtered through a membrane filter (PTFE, 0.5 μm) to obtain 416 g of 2-propylheptanal.
Reaction SMILES: Br[CH2:2][CH:3]([CH3:23])[O:4][C:5]1[C:6](=[O:22])[O:7][C:8]([CH3:21])([CH3:20])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.CC(C)([O-])C.[K+]>C1COCC1>[C:3]([O:4][C:5]1[C:6](=[O:22])[O:7][C:8]([CH3:21])([CH3:20])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1)([CH3:23])=[CH2:2]
Reactant: CC(CBr)OC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)OC1=C(c2ccc(S(C)(=O)=O)cc2)C(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
To the bromide of Example 6 (300 mg, 0.746 mmol) in THF (10 mL) was added 1.5 mL of a 1M THF solution of potassium tert-butoxide. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then partitioned between 25% NH4OAc and EtOAc. The organic phase was dried over Na2SO4, filtered and evaporated. After flash chromatography, 100 mg of the title compound was obtained.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][CH2:4][C:5](=O)[OH:6].C(N1CCOCC1)C.ClC(OCC(C)C)=O.[BH4-].[Na+].Cl>C1COCC1.CO>[CH2:11]([O:10][C:8](=[O:9])[C@@H:2]([NH:1][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:3][CH2:4][CH2:5][OH:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.0 g Boc-Glu-OBn in 100 ml THF were added dropwise under Argon at −10° C. 2.9 ml N-ethylmorpholine and 3.0 ml isobutyl chloroformate. The reaction mixture was stirred for 10 minutes before 2.4 g sodium borohydride were added. Methanol (400 ml) was added slowly over a period of 70 minutes at this temperature. It was stirred for additional 30 minutes at RT before being neutralized with 1 N HCl. The mixture was concentrated, dissolved in ethyl acetate and washed with 1 N HCl and brine. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 5.3 g.
Reaction SMILES: I[CH2:2][CH3:3].[CH3:4][C@@:5]12[C@@H:13]([OH:14])[CH2:12][CH2:11][C@H:10]1[C@@H:9]1[CH2:15][CH2:16][C:17]3[C@@:23]([CH3:24])([C@H:8]1[CH2:7][CH2:6]2)[CH2:22][CH2:21][C:19](=[O:20])[CH:18]=3.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[OH:14][C@H:13]1[CH2:12][CH2:11][C@H:10]2[C@H:9]3[C@H:8]([CH2:7][CH2:6][C@:5]12[CH3:4])[C@:23]1([CH3:24])[C:17](=[C:18]([CH2:2][CH3:3])[C:19](=[O:20])[CH2:21][CH2:22]1)[CH2:16][CH2:15]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Reactant: CCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCC1=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.7 %

Procedure:
Iodoethane (1.60 g) in dry tert-butanol (150 ml) was added dropwise under N2, over 6 h to a vigorously stirred solution heated to reflux, of testosterone (3.00 g) and potassium tert-butoxide (1.75 g) in dry tert-butanol (100 ml). The mixture was refluxed for further 3 h. After cooling to RT, the mixture was quenched by addition of a saturated aqueous NH4Cl solution (170 ml). After stirring for 10 minutes, tert-butanol was evaporated and the mixture was extracted with toluene. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The mixture was purified by flash chromatography (SiO2, n-hexane/EtOAc 70/30) to give 17β-hydroxy-4-ethylandrost-4-ene-3-one (1.68 g, 51%).
Reaction SMILES: [CH:1](/[C@:11]1([CH3:22])[C@H:18]2[CH2:19][C@H:14]([C@@H:15]([CH3:21])[C:16](=[O:20])[CH2:17]2)[O:13][O:12]1)=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H]>C(OCC)(=O)C.[Pt]>[CH2:1]([C@@:11]1([CH3:22])[C@H:18]2[CH2:19][C@H:14]([C@@H:15]([CH3:21])[C:16](=[O:20])[CH2:17]2)[O:13][O:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCC/C=C/[C@@]1(C)OO[C@@H]2C[C@H]1CC(=O)[C@@H]2C
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCCCCCCCCC[C@]1(C)OO[C@@H]2C[C@H]1CC(=O)[C@@H]2C

Procedure:
3.59 g of (1R,4S,5S,8R)-4-[(E)-1-decenyl]-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]nonan-7-one [obtained in accordance with Example 2(e)] dissolved in 180 ml of ethyl acetate are hydrogenated for about 1.25 hours with hydrogen over 360 mg of 5 percent platinum/charcoal at 1.013·105Pa. The end point of the reaction is determined by gas-chromatographic analysis. The catalyst is then removed by filtration through diatomaceous earth and the filtrate is evaporated. The residue is purified by column chromatography on silica gel while eluting with hexane/ethyl acetate (3:1). There is obtained (1R,4S,5S,8R)-4-decyl-4,8-dimethyl-2,3-dioxabicyclo[3.3.1]-nonan-7-one as a colourless oil, which crystallizes from hexane [m.p. 57°].
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.Cl.[NH2:28][NH:29][C:30]([NH2:32])=[O:31].[OH-].[Na+].NNC(N)=O.[NH4+].[Cl-]>C(Cl)Cl.O.O1CCOCC1>[CH2:1]([O:8][CH2:9][C:10]([C:11]1[NH:32][C:30](=[O:31])[NH:29][N:28]=1)([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(N)=O
Reactant: CC(C)(COCc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(COCc1ccccc1)c1n[nH]c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
3-(Benzyloxy)-2,2-dimethylpropanoic acid (1.00 g, 4.80 mmol) was dissolved in DCM (10 mL) at RT. Oxalyl chloride (0.70 mL, 8.00 mmol) and DMF (0.10 mL, 1.29 mmol) were added sequentially and the reaction mixture was stirred at RT for 2 h. In a separate flask, semicarbazide hydrochloride (0.8 g, 7.24 mmol) and NaOH (0.80 g, 20.0 mmol) were dissolved in a solution of dioxane (2.0 mL) and water (10.0 mL). The solution of the acid chloride was added in one portion to the solution of the semicarbazide and the reaction mixture was stirred at RT for 12 h. 2 M NaOH (aq.) (28.0 mL, 56.0 mmol) was then added and the reaction mixture was stirred at 100° C. for 2 h, allowed to cool to RT, and neutralized by the addition of ¾ sat. NH4Cl (aq.) (75 mL). The resultant homogenous solution was sonicated for 12 h and the resultant precipitated solids were collected by filtration and dried in vacuo to afford 3-(1-(benzyloxy)-2-methylpropan-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.57 g, 48.0%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 11.09 (s, 1H), 7.34-7.23 (m, 5H), 4.44 (s, 2H), 3.39 (s, 2H), 1.16 (s, 5H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[CH3:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[O:33]>C1COCC1.CCCCCC>[CH3:25][O:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([OH:33])[C:14]1([CH3:13])[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24]
Reactant: CC1CCc2ccccc2C1=O
Reactant: COC(=O)CCCCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)CCCCC(O)C1(C)CCc2ccccc2C1=O
Reaction time: 0.17 h
Yield: 25.8 %

Procedure:
To 1.55 mL diisopropylamine in 40 mL THF is added a solution of 4.36 mL n-butyllithium (2.5M) in hexane at −78° C. After 10 min, 1.63 g 2-methyl-1-tetralone in 5 mL THF is added, and the solution is stirred for 50 min. Then, 1.60 g 6-oxo-hexanoic acid methyl ester in 5 mL THF is added dropwise, and stirring is continued for 15 min. After that, the cooling bath is removed and the mixture allowed to reach rt. Conc. ammoniachloride sol is added, and extracted with ethylacetate. After evaporation the residue is purified by column chromatography yielding 0.8 g 6-hydroxy-6-(2-methyl-1-oxo-1,2,3,4-tetrahydro-naphtalen-2-yl)-hexanoic acid methyl ester (7a). 2.5 g of this alcohol 8a is dissolved in 50 mL dichloromethane and 2.27 mL triethylamine is added. After cooling to 0° C., 2.86 g methanesulfonic acid anhydride in 20 mL dichloromethane is added dropwise. After complete addition, the cooling bath is removed and stirring continued over night. The solution is washed with 2N HCl and water, separated, dried and evaporated. The crude product and 1.6 g 1,8-diazabicyclo[5.4.0]undecen-7-en (DBU) is dissolved in 60 mL toluene an heated to reflux for 24 h. The mixture is poured on 2N HCl and extracted with dichloromethane. After evaporaton and column chromatography 0.6 g 6-(2-methyl-1-oxo-1,2,3,4-tetrahydro-naphtalen-2-yl)-hex-5-enoic acid methyl ester (7b) is obtained. 7b is converted to 7c in an analogous manner to that described for the conversion of 1c to 1d in example 1. 7c was obtained as an oil, MS (APCI): 286.1 (M−1).
Reaction SMILES: C([C@:3]1([C:16]([O-])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[OH:17][CH2:16][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC[C@]1(C(=O)[O-])CCCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Reaction time: 1 h
Yield: 98 %

Procedure:
(S)-1-tert-butyl 3-ethylpiperidine-1,3-dicarboxylate (4.27 g, 16.59 mmol) was dissolved in THF (100 ml), and then LiAlH4 (1.26 g, 33.19 mmol) was added at 0° C. The mixture was stirred for 1 hour, and then again at room temperature for 2 hours. When the reaction was completed, H2O (1.26 ml) was slowly added, and NaOH (15%, 1.26 ml) was slowly added. After that, H2O (4 ml) was added, followed by stirring at room temperature for 1 hour. The mixture was filtered through celite, and dried over MgSO4, followed by filtration and then concentration under reduced pressure, to give (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (3.5 g, 99%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=2)[C:42]#[N:43])O1>>[C:42]([C:41]1[CH:44]=[C:37]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:38]=[N:39][CH:40]=1)#[N:43]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford an off-white solid. UPLC-MS (condition 1) tR=2.38 min, m/z=484.0 [M+H]+, m/z=482.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.67 (m, 1H) 1.78-1.91 (m, 1H) 2.16-2.30 (m, 1H) 2.96 (dd, J=11.00, 6.85 Hz, 1H) 3.12-3.19 (m, 2H) 3.19-3.26 (m, 1H) 3.25-3.31 (m, 1H) 3.33-3.39 (m, 1H) 4.62 (t, J=5.26 Hz, 1H) 7.35 (d, J=8.56 Hz, 2H) 7.85 (d, J=9.29 Hz, 2H) 8.08 (d, J=2.45 Hz, 1H) 8.40 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.91 (d, J=2.20 Hz, 1H) 9.02 (d, J=1.96 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: C([O-])(=O)C.C([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH:17]=[C:18]2[N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=[CH:29]2)[CH2:10]1)(=O)C.[OH-].[K+]>CO>[OH:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH:17]=[C:18]2[N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[N:30]=[CH:29]2)[CH2:10]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4cnc5ccccc54)=CC[C@@H]32)C1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3cnc4ccccc43)=CC[C@@H]12

Procedure:
Compound 5 prepared by following general method C, treating acetate solution of 15 (1 g 3.02 mmol) in methanol (15 mL) with 10% methanolic KOH (5 mL) for 1.5 h. Purification by FCC over short column provided pure 5 with identical spectral and analytical data as we previously reported.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]([Cl:12])([Cl:11])[CH:5]([OH:10])[C:6]([Cl:9])([Cl:8])[Cl:7].O.S(OC)(O[CH3:18])(=O)=O>>[CH:5]([O:10][CH3:18])([C:6]([Cl:9])([Cl:8])[Cl:7])[C:4]([Cl:12])([Cl:11])[Cl:3]
Reactant: COS(=O)(=O)OC
Reactant: OC(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A 50% NaOH solution, 9.9 g (0.12 mole), was added to a mixture of 33.0 g (0.12 mole) of 1,1,1,3,3,3-hexachloro-2-propanol and 44.5 g (2.47 moles) of water at 0°-10° C. over 30 minutes. This cold mixture was warmed to room temperature and 15.6 g (0.12 mole) of dimethyl sulfate was added slowly at 20°-25° C. over 30 minutes. The reaction mixture was stirred for another 2 hours at room temperature. The crude product was washed with dilute NaOH solution, water and saturated NaCl solution to yield 29.5 g of a colorless liquid. Fractional distillation of the liquid at 93°-93.5° C. and 5 mm Hg gave 26.2 g of the methyl ether at 98.7% purity by GC analysis. This represents a 74.5% yield. The product was purified further by a second distillation to afford greater than 99.6% of purity. Elemental analysis: C4H4Cl6O Calculated C 17.11%, H 1.43%, Cl 75.75%. Found C 17.03%, H 1.43%, Cl 75.31%. ηD20 1.5195.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[CH:19]=[C:18]([C:29]([O:31][CH3:32])=[O:30])[C:14]=3[NH:15][C:16]=2[CH:17]=1)C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[CH:19]=[C:18]([C:29]([O:31][CH3:32])=[O:30])[C:14]3[NH:15][C:16]4[CH:17]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=4[C:13]=3[N:21]=2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1[nH]c1cc(OCc3ccccc3)ccc12
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)nc2c1[nH]c1cc(O)ccc12

Procedure:
An solution of methyl 7-(benzyloxy)-2-(4-chlorophenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (709 mg, 1.60 mmol) in trifluoroacetic acid (15 mL) was heated at 70° C. for 30 min. The solvent was removed and the residue was suspended in a mixture of EtOAc (25 mL) and hexane (50 mL). The suspended solid was collected by filtration and washed with the EtOAc/hexane mixture. This gave impure methyl 2-(4-chlorophenyl)-7-hydroxy-5H-pyrido[3,2-b]indole-4-carboxylate (573 mg). MS (ESI) m/z 353.0 (M+H).
Reaction SMILES: CNC(C1C2C=C(C3C(Cl)=CN=C(NCCCN4CCNC[C@H]4C)N=3)SC=2C=CC=1)=O.[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([CH3:51])=[CH:49][N:48]=[C:47](Cl)[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35].C(OC([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68][NH2:69])[CH2:62][C@@H:61]1[CH3:70])=O)(C)(C)C>>[CH3:32][NH:33][C:34]([C:36]1[C:44]2[CH:43]=[C:42]([C:45]3[C:50]([CH3:51])=[CH:49][N:48]=[C:47]([NH:69][CH2:68][CH2:67][CH2:66][N:63]4[CH2:64][CH2:65][NH:60][C@@H:61]([CH3:70])[CH2:62]4)[N:46]=3)[S:41][C:40]=2[CH:39]=[CH:38][CH:37]=1)=[O:35]
Reactant: C[C@H]1CN(CCCN)CCN1C(=O)OC(C)(C)C
Reactant: CNC(=O)c1cccc2sc(-c3nc(Cl)ncc3C)cc12
Agent: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCNC[C@H]4C)ncc3Cl)cc12
Product: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN[C@@H](C)C4)ncc3C)cc12

Procedure:
Using the method of (R)-2-{5-chloro-2-[3-(2-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide, the title compound is synthesized from 2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid methylamide and (S)-4-(3-aminopropyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester and isolated as a yellow solid. ES+(m/z) 439 [M+H].