Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19]>C1C=CC=CC=1.C(O)(C)C>[F:1][C:2]1[C:7]([C:8]([C:8]([C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])([OH:9])[C:10]2[C:15]([F:1])=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=2[F:19])=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19]
Reactant: O=C(c1ccccc1)c1c(F)c(F)c(F)c(F)c1F
Solvent: c1ccccc1
Solvent: CC(C)O
Product: OC(c1ccccc1)(c1ccccc1)C(O)(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F

Procedure:
Pentafluorobenzophenone (10.4 g) was dissolved in 250 ml of benzene/isopropanol (3.5:1). The solution was purged with nitrogen and irradiated for 6 hours with a Hanovia 450-watt Hg-arc lamp. The solvent was removed using a vacuum evaporator at a temperature less than 40° C. The crystallized product was washed twice with 25 ml of n-pentane. The slurry was centrifuged and n-pentane was decanted. The product was spread on a watch glass and air dried. Recovery of 2,3,4,5,6,2',3',4',5',6'-decafluorobenzopinacol was 9.1 g or 87.5%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]2[C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[S:15][C:16]=2[CH2:17][OH:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CS(Cl)(=O)=O>[CH3:1][S:2]([O:18][CH2:17][C:16]1[S:15][C:14]2[CH:19]=[CH:20][CH:21]=[CH:22][C:13]=2[C:12]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1sc2ccccc2c1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.6 %

Procedure:
Methanesulfonyl chloride (127 μL, 1.63 mmol) was added dropwise to a solution of (3-phenylbenzo[b]thiophen-2-yl)methanol (356 mg, 1.48 mmol) and DIPEA (322 μL, 1.85 mmol) in anhydrous DCM (10 mL) at 0° C. Stirring at 0° C. was continued for 15 min, then the mixture was slowly warmed to RT. After 2.5 h stirring at RT, additional methanesulfonyl chloride (1 drop) was added and stirring was continued for 1 h. The reaction mixture was diluted with DCM and the organic layer was washed with water, then dried (Na2SO4) and concentrated in vacuo affording (3-phenylbenzo[b]thiophen-2-yl)methyl methanesulfonate as a yellow oil (408 mg, 87%). 1H NMR (DMSO, 400 MHz): δ 8.07-8.02 (1H, m), 7.62-7.56 (2H, m), 7.55-7.37 (6H, m), 4.96 (2H, s), 3.33 (3H, s).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH:24]=[N:23][C:22]([NH2:30])=[CH:21]2>ClCCl.C(OCC)(=O)C.CCCCCC>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[CH:24]=[N:23][C:22]([N:30]=[C:1]=[S:2])=[CH:21]2
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc2cnc(N)cc2cc1Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc2cnc(N=C=S)cc2cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a stirring solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (142 mg, 0.611 mmol) in dichloromethane (5 mL) was added a suspension of 6-chloro-7-methoxyisoquinolin-3-amine (110 mg, 0.527 mmol) in dichloromethane (5.00 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was applied directly to a silica gel column in 10% ethyl acetate/hexane to yield 106 mg (80%) 6-Chloro-3-isothiocyanato-7-methoxyisoquinoline. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.90 (1H, s), 7.99 (1H, s), 7.36 (1H, s), 7.08 (1H, s), 4.05 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]([NH2:24])=O)[C:4]=2[N:3]=1.O=P(Cl)(Cl)Cl>ClCCl.CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=[C:21]([C:22]#[N:24])[C:4]=2[N:3]=1
Reactant: Cc1nc2c(C(N)=O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To the mixture of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carboxamide, prepared as described in Example 33 (0.4 g, 0.999 mmol) in Dichloromethane (DCM) (50 mL) was added in POCl3 (0.931 mL, 9.99 mmol) and followed by the addition of ten drops of DMF. The reaction was stirred at rt for 1 h. The mixture was quenched with aqueous sodium bicarbonate solution. The aqueous phase was extracted with DCM (100 mL). The combined organic phase was washed with Brine then dried (MgSO4), filtered and the solvent removed in-vacuo. The crude was purified on silica (20˜50% EtOAc/Hexane) to give the product (0.246 g, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H), 2.96-3.15 (m, 4H), 3.62-3.72 (m, 4H), 6.05 (s, 2H), 6.32 (d, J=7.07 Hz, 1H), 7.29-7.44 (m, 3H), 7.57-7.74 (m, 2H), 7.86 (d, J=8.08 Hz, 1H), 8.02 (d, J=7.83 Hz, 1H) 8.22 (d, 1H), MS (ES+) m/z 383.2 [M+H]+.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH:5]([CH3:7])[CH3:6].[Cl:8][C:9]1[C:14]2[S:15][CH:16]=[C:17]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.O>CN(C=O)C.C(OCC)(=O)C>[ClH:8].[Cl:8][C:9]1[C:14]2[S:15][CH:16]=[C:17]([N:18]([CH2:4][CH:5]([CH3:7])[CH3:6])[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)CBr
Reactant: Clc1cccc2c(Nc3ccncc3)csc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CN(c1ccncc1)c1csc2c(Cl)cccc12
Product: Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 157.7 %

Procedure:
To a suspension of NaH (463 mg, 11.57 mmole, washed with pentane) in dry DMF (15 mL) was added 1-bromo-2-methylpropane (1.26 mL, 11.57 mmole), and thereafter a solution of 7-chloro-3-[(4-pyridinyl)amino]benzo[b]thiophene (2.87 g, 11.02 mmole) in warm DMF (20 mL) was added so that the reaction mixture was warm to the touch. After the addition, the reaction mixture was stirred for one hour and then heated to 60° C. An additional 232 mg of NaH and 0.63 mL of 1-bromo-2-methylpropane were added twice to drive the reaction to completion. The reaction mixture was then distributed between water and ethyl acetate, and the organic phase was washed with water, dried (MgSO4) and concentrated to obtain 3.07 g of a dark brown oil. This was flash chromatographed twice (silica, 5% MeOH/EtOAc then 10% MeOH/EtOAc; alumina, Et2O then EtOAc) to yield 2.02 g of product. The hydrochloride salt was formed in methanol with ethereal hydrogen chloride, concentrated to a solid and recrystallized from methanol and diethyl ether. The resulting white solid was dried for four hours under high vacuum over P2O5 and refluxing toluene to yield 1.61 g, mp 264° C. (dec.).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].C(OC(=O)C)(=[O:30])C.[Cr]([O-])(OC(C)(C)C)(=O)=O.C(O)(=O)C(O)=O>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[O:30])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)O[Cr](=O)(=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 12 h
Yield: 61.66 %

Procedure:
A solution of 5-androstene-3β,17β-diol diacetate (5 g, 13.35 mmol) in a mixture of dry carbon tetrachloride (30 Ml), acetic anhydride (4.5 Ml) and glacial acetic acid (1.25 Ml) was treated while stirring with t-butyl chromate solution (35 Ml). The brown reaction mixture was brought to reflux temperature and further stirred for 12 h. The mixture was then cooled in an ice bath and treated in small portions with 10% oxalic acid solution (75 Ml). After adding a further quantity of solid oxalic acid (5.5 g), the reaction mixture was stirred for 2 h at room temperature. The organic phase was removed and the aqueous phase was extracted with carbon tetrachloride (4×50 Ml). The combined carbon tetrachloride extract was successively washed with 5% sodium carbonate solution (2×25 Ml), water and dried. Removal of solvent under reduced pressure gave a pale yellow solid, which was crystallized from methanol to afford the product 7-oxo-5-androstene-3β,17β-diol diacetate (3.2 g, 61.66%), mp 220-221° C. (lit 216-219° C.) [Singh. H., et al Indian J. Chem. 1969, 7, 1084-1087].
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][O:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[CH3:15]C(C)([O-])C.[K+].C(I)I.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][O:11][N:10]([CH3:15])[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)NC1CONC1=O
Agent: [K+]
Solvent: ICI
Solvent: CN(C)C=O
Solvent: O
Product: CN1OC[C@@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
(3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (1.01 g, prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002, 50(4) 554-557) was dissolved in dimethylformamide (5 ml), the solution was cooled to 0° C. and 616 mg of potassium t-butoxide was added portionwise. The reaction mixture was stirred at 0° C. for 1 hour then 710 mg methylene iodide was added and the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with diethyl ether. The organic phase was then washed several times with water, dried over sodium sulphate and the solvent removed in vacuo. Crude ((R)-2-methyl-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (140 mg) was obtained as a white solid. LCMS (method A) 1.11 min, MH+ 217; 1H-NMR (CDCl3, 400 MHz): 5.20 (m, 1H), 4.70 (m, 1H), 4.55 (m, 1H), 4.00 (dd, 1H), 3.20 (s, 3H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[CH:4]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(O)c(Cc2ccc(F)cc2)c1

Procedure:
Alkylation of 4-methoxyphenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-methoxy-2-(4'-fluorobenzyl)phenol. This material was converted to compound 69 and compound 70 by the procedure similar to that in Example 18 method B.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([N:15]2[CH:21]3[CH2:22][CH2:23][N:18]([CH2:19][CH2:20]3)[CH2:17][CH2:16]2)=[CH:11][C:3]=1[C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>C(O)C.C(O)(=O)C.CO.[O-2].[O-2].[Mn+4]>[N:18]12[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19]1)[N:15]([C:12]1[CH:11]=[C:3]3[C:2](=[CH:14][CH:13]=1)[N:1]=[C:28]([C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([Cl:24])[CH:26]=1)[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:4]3=[O:5])[CH2:16][CH2:17]2
Reactant: Nc1ccc(N2CCN3CCC2CC3)cc1C(=O)NCC(=O)O
Reactant: O=Cc1cccc(Cl)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCO
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCN4CCC3CC4)cc2c1=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
2-(2-Amino-5-(1,4-diazabicyclo[3.2.2]nonan-4-yl)benzamido)acetic acid (85.3 mg, 0.27 mmol) (Intermediate 9A) was dissolved in ethanol (3 mL). 3-Chlorobenzaldehyde (56.5 mg, 0.046 mL, 0.40 mmol) was added followed by 2 drops of acetic acid. The reaction mixture was refluxed at 85° C. overnight. The reaction mixture was diluted with methanol and purified directly using a 1 g SCX cartridge. The crude material was concentrated to dryness before re-dissolving in dichloromethane and manganese dioxide (18.8 mg, 0.32 mmol) added. The solution was then stirred overnight before filtering and concentrated under reduced pressure to give 2-(6-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-4-oxoquinazolin-3(4H)-yl)acetic acid (54 mg, 0.12 mmol).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=C/C(O)=O)=[CH:18][CH:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[CH3:2].[C:33](Cl)(=[O:37])[C:34](Cl)=O.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl>[CH2:1]([C:3]1[C:4]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:34]/[C:33]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)=[O:37])=[CH:18][CH:17]=2)[C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1CCNCC1
Reactant: CCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Solvent: ClCCl
Product: CCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)N3CCN(C)CC3)cc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of (2E)-3-(4-{[3-Ethyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)-2-propenoic acid (60) (0.10 g, 0.24 mmol) in CH2Cl2 (3 mL) at room temperature was added oxalyl chloride (63 μL, 0.71 mmol). The mixture was stirred at room temperature overnight. CH2Cl2 and excess of oxalyl chloride were removed under vacuum. The residue was dissolved in CH2Cl2 (4 mL), cooled in an ice bath, 1-methyl piperazine (40 μL, 0.35 mmol) was added. The resulting mixture was allowed to stir at room temperature overnight. Diluted with CH2Cl2 (50 mL), the mixture was washed with saturated aqueous NaHCO3, 0.5 N NaOH and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by flash chromatography over SiO2 with CHCl3:MeOH (75:1 to 50:1) to give 84 mg (70%) of compound 62 as a white foam. 1H NMR (400 MHz, CH3OH-d4): δ 1.09 (t, J=7.5 Hz, 3H), 2.32 (s, 3H), 2.47 (br s, 4H), 2.58 (q, J=7.5 Hz, 2H), 3.71 (br s, 4H), 3.92 (s, 3H), 6.54 (d, J=8.7 Hz, 2H), 6.91 (d, J=15.4 Hz, 1H), 7.02 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.10-7.16 (m, 2H), 7.18-7.28 (m, 3H), 7.30 (d, J=2.4 Hz, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.44 (d, J=15.4 Hz, 1H), 7.63 (d, J=9.3 Hz, 1H), 7.66 (s, 1H). LCMS (APCI): m/z 507 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=1)[C:11]([NH:13][C:14]1[S:15][C:16]2[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=2[C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)=[O:20])=[O:12])[CH2:4][CH3:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:61][N:62]([CH2:72][CH:73]=O)[C:63](=[O:71])[CH2:64][CH2:65][C:66]([O:68][CH2:69][CH3:70])=[O:67].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:69]([O:68][C:66](=[O:67])[CH2:65][CH2:64][C:63]([N:62]([CH3:61])[CH2:72][CH2:73][N:6]([CH2:7][C:8]1[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=1)[C:11]([NH:13][C:14]1[S:15][C:16]2[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=2[C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)=[CH:24][CH:23]=1)=[O:20])=[O:12])[CH:3]([CH2:2][CH3:1])[CH2:4][CH3:5])=[O:71])[CH3:70]
Reactant: CCC(CC)NCc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reactant: CCOC(=O)CCC(=O)N(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCC(=O)N(C)CCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C(CC)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a mixture of 1.00 g of methyl 4-{2-[4-({[2-({3-[(pentan-3-ylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate, 1.00 g of sodium triacetoxyborohydride, 0.50 mL of acetic acid and 20 mL of methylene chloride was added 473 mg of ethyl 4-[methyl(2-oxoethyl)amino]-4-oxobutanoate, followed by stirring for 1 hour at room temperature. 498 mg of sodium triacetoxyborohydride and 237 mg of ethyl 4-[methyl(2-oxoethyl)amino]-4-oxobutanoate were further added to the reaction mixture, followed by stirring for 2 hours at room temperature. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate), thereby obtaining 1.19 g of methyl 4-(2-{4-[({2-[(3-{[{2-[(4-ethoxy-4-oxobutanoyl)(methyl)amino]ethyl}(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[C:26]([O:32][CH3:33])=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=1>>[Br:31][C:29]1[CH:30]=[C:25]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]34[CH2:15][CH:6]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=53)[C:5]3[C:14]4=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19]2)[C:26]([O:32][CH3:33])=[N:27][CH:28]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ncc(Br)cc1Br
Product: COc1ncc(Br)cc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 63 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3,5-dibromo-2-methoxypyridine (literature preparation: J. M. Barger, J. K. Dulworth, M. T. Kenny, R. Massao, J. K. Daniel, T. Wilson, R. T. Sargent J. Med. Chem. 1986, 29, 1590), the title compound was formed in 63% yield as an off-white solid, mp 250°-251° C. (dec). free base: 1H NMR (CDCl3, 300 MHz) 8.08 (d, J=2.3 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.21 (m, 4H), 6.90 (m, 4H), 4.26 (s, 1H), 3.97 (s, 3 H), 3.56 (s, 1H), 3.47 (s, 2H), 2.86 (m, 2H), 2.77 (dt, J=2.6, 11.4 Hz, 2H), 2.60 (d, J=1.4 Hz, 2H), 1.96 (m, 4H) MS CI, CH4) m/z 491 (M+1,100), 483 (89), 492 (37), 494 (26), 521 (M+29, 13), 473 (28) hydrochloride salt:
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:6]=1[OH:15])([CH2:3][CH3:4])[CH3:2].[CH2:16]1[O:18][CH2:17]1>[OH-].[Na+]>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[C:6]=1[O:15][CH2:16][CH2:17][OH:18])([CH2:13][CH3:14])[CH3:12]
Reactant: C1CO1
Reactant: CCC(C)c1cccc(C(C)CC)c1O
Agent: [Na+]
Agent: [OH-]
Product: CCC(C)c1cccc(C(C)CC)c1OCCO

Procedure:
2,6-di-sec-butylphenol (103 parts) is ethoxylated with ethylene oxide (29 parts) using sodium hydroxide (0.5 part) as catalyst at 150° C. in a method similar to that used in Example 12 to give 2-(2,6-di-sec-butylphenoxy)-ethanol (70 parts) b.p. 132°-136° C./0.9 mm.
Reaction SMILES: C(O[C:5]([CH3:9])([CH3:8])[CH2:6]Br)(=O)C.Cl.[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:15].C(N(C(C)C)CC)(C)C.CCCCCC.[C:36](OCC)(=[O:38])[CH3:37]>C(#N)C>[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]([C:36](=[O:38])[CH3:37])[C:5]([CH3:9])([CH3:8])[CH3:6]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)(C)CBr
Agent: Cl
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N(C(C)=O)C(C)(C)C
Temperature: 60 °C

Procedure:
A solution of bromo-tert-butyl acetate (44.4 mL, 0.275 mol), (S)-leucine methyl ester hydrochloride (50 g, 0.275 mol) and diisopropylethyl amine (191 mL, 1.1 mol) in acetonitrile (400 mL) was stirred at room temperature for 16 hrs and heated at 60° C. for 4 hrs. After completion of the reaction (TLC, hexane-ethyl acetate, 9:1) a small aliquot (5 mL) was taken out and acetonitrile was removed under reduced pressure. Ethyl acetate (100 mL) was added and the solution was washed with water (2×100 mL), 10% aqueous citric acid (100 mL) and water (100 mL). The ethyl acetate extract was dried over sodium sulfate, evaporated under reduced pressure and chromatographed over silica gel column. Elution with 5% ethyl acetate in hexane gave pure N-tert-butyl acetyl-(S)-leucine methyl ester (2) as an oil, [α]D25 -17.2 (c, 2.9, MeOH); 1H NMR (CDCl3): 0.88 (3H, d, J=6.6 Hz), 0.89 (3H, d, J=6.6 Hz), 1.42 (9H, s), 1.48 (2H, m), 1.70 (1H, apparent hept, J=6.6 Hz), 3.24 (2H, ABq, J=18 Hz), 3.29 (1H, t, J=7.2 Hz), 3.68 (3H, s); 13C NMR (CDCl3): 22.34 (CH3), 22.65 (CH3), 24.81 (CH), 28.06 (C(CH3)3), 42.44 (CH2), 49.86 (CH2), 51.74 (OCH3), 59.22 (CH), 81.26 (C), 170.87 (CO), 175.43 (CO).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[N:5][S:6][C:7]=1[C:8]([OH:10])=[O:9])[CH3:2].[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>C(O)C>[CH2:1]([C:3]1[N:4]=[N:5][S:6][C:7]=1[C:8]([O-:10])=[O:9])[CH3:2].[C:11]([NH3+:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: CCc1nnsc1C(=O)O
Solvent: CCO
Product: CC(C)(C)[NH3+]
Product: CCc1nnsc1C(=O)[O-]
Reaction time: 24 h

Procedure:
In 3 ml of ethanol was dissolved 0.4 g of 4-ethyl-1,2,3-thiadiazole-5-carboxylic acid, after which 0.19 g of t-butylamine was added to the solution and the reaction was carried out at room temperature for 24 hours.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:17]([CH3:21])[CH2:18]SC)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.O[O:23][S:24]([O-:26])=O.[K+].[CH3:28]O>O>[CH3:1][C:2]1[N:3]([CH:17]([CH3:21])[CH2:18][S:24]([CH3:28])(=[O:26])=[O:23])[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:13])([F:12])[F:14])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: CO
Reactant: CSCC(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 2-methyl-1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 8) (0.045 g, 0.144 mmol) in MeOH (4 mL) was added a solution of Oxone (0.133 g, 0.216 mmol) in water (2 mL). After 1 h, additional Oxone (0.100 g, 0.163 mmol) was added, and the mixture was stirred at rt. After 30 min, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Phenomenex Luna column; gradient: 10-100% MeCN-water with 0.1% TFA). The fractions with product were basified with aq. saturated K2CO3 solution, and then concentrated down to the aqueous phase, which was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give 2-methyl-1-(1-(methylsulfonyl)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile: MS (ESI): m/z 345 (MH+).