Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[NH2:11][C:12]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.C(OCC)C>O1CCCC1.O>[CH2:14]([C:13]1[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:12]=1[NH2:11])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)c(N)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(Cc2ccccc2)c(N)c1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A solution of lithium aluminum hydride in tetrahydrofuran (1.0 M, 2.54 mL, 2.54 mmol) was added via syringe to a flask containing aluminum chloride (534 mg, 4.005 mmol) under a nitrogen atmosphere and cooled in a 0° bath. After letting the mixture cool for 5 minutes, a solution of 2-amino-4-methylbenzophenone (200 mg, 0.9467 mmol) in tetrahydrofuran (4 mL) was added slowly dropwise at 0°. The reaction was then heated at 50° for 30 minutes. The reaction was cooled to room temperature and moist ethyl ether (5 mL) was added. The reaction was carefully poured into water (20 mL) and extracted with ethyl ether (2×50 mL). The combined ethereal extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. Purification by silica gel flash chromatography using 40:60 hexanes/methylene chloride as eluent provided the title compound as an oil (94 mg, 50%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8]([O:15][CH3:16])(=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11]>CC(O)(C)C>[CH3:13][O:12][C:10]([CH:9]([C:8]([O:15][CH3:16])=[O:14])[C@@H:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)=[O:11]
Reactant: O=C1C=CCCC1
Reactant: COC(=O)CC(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=O)OC)[C@@H]1CCCC(=O)C1
Temperature: 30 °C
Reaction time: 72 h
Yield: 97 %

Procedure:
Under an atmosphere of argon, 11.0 mg (0.02 mmol, S/C=100) of Ru[(S,S)-Msdpen] (hexamethylbenzene), 194 μL (2.0 mmol) of 2-cyclohexenone, 228 μL (2.0 mmol) of dimethyl malonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 30° C. for 72 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 443 mg (97% yield) of the title compound. The optical rotation [α]D23 was +3.45 (c 2.44, CHCl3). The optical purity was measured by HPLC (CHIRALPAK AS manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=85:15, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 98% ee.
Reaction SMILES: Cl.CO.[CH:4]1([NH2:8])[CH2:7][CH2:6][CH2:5]1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[CH:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][CH:26]=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+]>CO>[CH:4]1([NH:8][CH2:26][CH2:25][CH:24]([C:18]2[CH:19]=[C:20]([Br:23])[CH:21]=[CH:22][C:17]=2[O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:7][CH2:6][CH2:5]1
Reactant: NC1CCC1
Reactant: O=CCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Brc1ccc(OCc2ccccc2)c(C(CCNC2CCC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 M HCl-methanol (3.50 mL, 17.71 mmol) was added to a solution of cyclobutylamine (4.50 mL, 53.15 mmol) in methanol (14 mL). The mixture was added to 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropanal (Example 20.1), (3.50 g, 8.86 mmol), followed by sodium cyanoborohydride (0.389 g, 6.20 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was chromatographed on silica (toluene-ethyl acetate-triethylamine 92:4:4). Yield 2.61 g (65%); 1H NMR (CDCl3) δ1.57 (m, 5H), 2.14 (m, 4H), 2.47 (t, 2H), 3.16 (m, 1H), 4.45 (t, 1H), 5.00 (s, 2H), 6.75 (d, 1H), 7.10-7.47 (m, 12H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=O)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1ccc(NC(=O)CCN2CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)c1ccc(NCCCN2CCOCC2)cc1

Procedure:
In a manner similar to Preparation 2 reaction N-[4-(1,1-dimethylethyl)phenyl]-4-morpholinepropanamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:17]=[C:16]4[C:31]([O:33]C)=[O:32])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].O>CO>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[CH:17]=[C:16]4[C:31]([OH:33])=[O:32])[CH:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cn(Cc2ccncc2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)O)c2c1
Temperature: 50 °C

Procedure:
To a mixture of the product of step ii) (0.7 g) in methanol (15 mL) was added a 5M aqueous solution of sodium hydroxide (1.8 mL) and the reaction heated at 50° C. for 6 hours. The reaction mixture was allowed to cool to room temperature and then treated with water (20 mL). The precipitate was collected by filtration, washed with water and dried to give the sub-title compound (0.52 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][CH:7]=1)=[O:5])C.Cl>[OH-].[Na+]>[Br:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc(Br)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
To a 100 mL 14/20 round bottom flask was charged 2.4 g (10.1 mmol) of 2-bromo-5-thiazolecarboxylic acid ethyl ester dissolved in 14 mL of 1N sodium hydroxide. The reaction was stirred at room temperature for 1.5 hours The yellow solution was acidified with SN hydrochloric acid to pH 2. The solid which formed was cooled in an ice bath, filtered, washed with water, and dried in a vacuum oven at 60° C. to give 1.9 g (90%) of 2-bromo-5-thiazolecarboxylic acid m.p. 185-186° C. (dec) as a white solid. Rf =0.12 (20% methanol/chloroform). 1H NMR (300 MHz, DMSO d6) δ 8.19(s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[CH2:12](C([Sn])=C(CCCC)CCCC)[CH2:13]CC>CN(C=O)C.C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[CH:3][C:2]([CH:12]=[CH2:13])=[CH:7][N:6]=1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 52.5 %

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-trifluoromethyl pyridine (2.0 g, 8.8 mmol) was dissolved in DMF:THF (3:1, 12 mL). Tributylvinyltin (3.0 g, 9.68 mmol) and Pd(PPh3)4 (0.135 g, 0.11 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 2 h. After completion of the reaction (TLC), the reaction mixture was cooled to RT and diluted with water (120 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator below 40° C. The crude was purified through column chromatography (2% ethylacetate:hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-(trifluoromethyl)-5-vinylpyridine as a light yellow oil (0.8 g, 52% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][N:26]([CH3:32])[CH2:27][CH2:28][CH2:29][NH:30][CH3:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]([CH2:29][CH2:28][CH2:27][N:26]([CH3:32])[CH3:25])[CH3:31])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNCCCN(C)C
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CCCN(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N1,N1,N3-trimethylpropane-1,3-diamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.98 (br. s., 2H) 2.43 (s, 3H) 2.68-2.95 (m, 7H) 3.00 (s, 3H) 3.13 (br. s., 1H) 3.23-3.61 (m, 2H) 7.60-7.89 (m, 3H) 7.99-8.82 (m, 4H) 9.53 (br. s., 1H) 12.69-13.62 (m, 1H). ESI-MS m/z [M+H]+ 419.3.
Reaction SMILES: C1(S([N:10]2[CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=[C:11]2[C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31](S(C3C=CC=CC=3)(=O)=O)[CH:30]=2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[NH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([C:11]2[NH:10][CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=2)=[CH:30]1
Reactant: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)n2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)c2c[nH]c(-c3c[nH]c4ccccc34)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17yaa) (1 mmol) in ethanol (40 mL) and water (4 mL) was added sodium hydroxide (10 equiv, 10 mmol) and stirred overnight under refluxing condition in darkness. The reaction mixture was diluted by 50 mL of water and extracted by ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 1:1) to give a yellow solid. Yield: 60%. NMR (500 MHz, CD3OD) δ 8.31 (d, J=6.5 Hz, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.48-7.52 (m, 3H), 7.24-7.28 (m, 2H), 4.00 (s, 6H), 3.93 (s, 3H). MS (ESI) calcd for C21H19N3O4 377.1. found 400.1 [M+Na]+. Mp 208-210° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[NH:10][C@H:11]([C:24]([NH:26][C:27]1[CH:28]=[N:29][N:30]([CH3:33])[C:31]=1[NH2:32])=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:49]1([C:55](Cl)([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]=[C:9]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[NH:10][C@H:11]([C:24]([NH:26][C:27]1[CH:28]=[N:29][N:30]([CH3:33])[C:31]=1[NH:32][C:55]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the crude product tert-butyl (5S)-5-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-6-oxohexylcarbamate and triethylamine (1.01 g) in chloroform (100 ml) was added triphenylmethyl chloride (2.78 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 3% methanol/chloroform to give tert-butyl (5S)-5-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-6-oxohexylcarbamate (5.60 g) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6][N:5]1CC1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1
Reactant: [H][H]
Reactant: COCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COCC1CNCCN1
Yield: 78.8 %

Procedure:
A mixture of 117 parts of 2-(methoxymethyl)-1,4-bis(phenylmethyl)piperazine and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was distilled, yielding 38.6 parts (78.8%) of 2-(methoxymethyl)piperazine; bp. 75°-80° C. (intermediate 31).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][CH2:15][C:16](=O)[NH2:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([O:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC(N)=O)CC1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OCC#N)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of trans (4-carbamoylmethoxy-cyclohexyl)-carbamic acid tert-butyl ester (500 mg, 1.80 mmol) and triethylamine (510 μL, 3.70 mmol) in DCM (9 mL) at 0° C. was treated dropwise with a solution of 2,2,2-trichloroacetyl chloride (310 μL, 2.80 mmol) in DCM (1 mL). After the addition the mixture was stirred at ambient temperature for 45 minutes. The reaction mixture was diluted with water and the phases separated. The aqueous phase was extracted with DCM (2×) and the combined organic phases washed with a 10% citric acid solution, a saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum. Purification by column chromatography on silica gel (gradient: 0-40% ethyl acetate in cyclohexane) to afford 280 mg (60%) of trans (4-cyanomethoxy-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. LCMS (Method Q, ESI): RT=3.53 min, m+H=255.0; 1H NMR (400 MHz, CDCl3) δ: 4.37 (s, 1H), 4.27 (s, 2H), 3.47 (m, 1H), 2.05 (d, 4H), 1.44 (s, 9H), 1.38 (m, 2H), 1.18 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[N:14])=O.[CH3:18][C:19]([S:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>O1CCCC1.CO.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]#[N:14])=[N:24][S:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)S(N)=O
Reactant: N#Cc1ccccc1C(=O)c1cccc(Br)c1
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1ccccc1C#N
Temperature: 50 °C
Reaction time: 0.03 h
Yield: 66.4 %

Procedure:
To a solution of titanium (IV) ethoxide (3.48 g, 15.3 mmol) in tetrahydrofuran (14.0 mL) was added 3-bromo-2′-cyanobenzophenone (2.00, 7.0 mmol). After stirring for two minutes, 2-methyl-2-propanesulfinamide (0.93 g, 7.68 mmol) was added. The mixture was refluxed for 13 hours and heated at 50° C. for 31 hours. After cooling to ambient temperature, the mixture was diluted with methanol (15 mL) and treated with saturated aqueous sodium bicarbonate solution (15 drops) to form a gelatinous precipitate. The material was further diluted with ethyl acetate and vacuum filtered through a pad of sodium sulfate to remove the precipitate. The filtrate was concentrated to a crude oil that was purified by flash chromatography on silica gel with 10% acetonitrile/dichloromethane and triturated with hexane/ethyl acetate to give the title compound as a yellow solid (1.81 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 7.98 (d, J=7.7 Hz, 1 H), 7.87-7.79 (m, 2 H), 7.72-7.66 (m, 2 H), 7.64-7.43 (m, 3 H), 1.27 (s, 9 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([C:7]1[C:16]([CH3:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:18][CH3:19])[C:8]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[OH:6])[CH3:2].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(OC(C)(C)C)(=O)C>[CH2:1]([O:3][C:4](=[O:27])[CH:5]([O:6][C:7]([CH3:16])([CH3:8])[CH3:5])[C:7]1[C:16]([CH3:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:18][CH3:19])[C:8]=1[C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)[CH3:2]
Reactant: CCOC(=O)C(O)c1c(C)cc2c(OC)cccc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(OC)cccc2c1-c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A solution of [1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-hydroxy-acetic acid ethyl ester (23 mg) and perchloric acid, 70% (3 μL) in tert-butyl acetate (1 mL) was stirred at room temperature for 2 h. After 2 h, the reaction had apparently stalled, so 3 μL additional perchloric acid was added. After 2 additional hours, no further conversion was observed (LCMS analysis). Saturated sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate (3×). The combined organic layer was dried (Na2SO4), and concentrated. The crude mixture was purified by flash column chromatography to give tert-butoxy-[1-(4-chloro-phenyl)-5-methoxy-3-methyl-naphthalen-2-yl]-acetic acid ethyl ester (9 mg) plus 7 mg of recovered starting material. The recovered starting material was re-subjected to similar reaction conditions to yield an additional 3 mg of desired. 1H-NMR: 400 MHz, (CDCl3) δ: 8.10 (s, 1H), 7.39-7.48 (m, 3H), 7.25 (s, 1H), 7.17 (app t, 1H), 6.78 (app t, 2H), 5.09 (s, 1H), 4.06-4.20 (m, 2H), 3.99 (s, 3H), 2.61 (s, 3H), 1.185 (t, 3H), 0.98 (s, 9H).
Reaction SMILES: P([O-])([O-])([O-])=O.[CH:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:15]C2OC(CO)C(O)C(O)C2O)=[CH:8][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+]>>[N+:12]([C:10]1[CH:11]=[CH:6][CH:7]=[CH:8][C:9]=1[OH:15])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1OC1OC(CO)C(O)C(O)C1O
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccccc1O

Procedure:
That is, 0.1 ml of the present enzyme solution is added to 2.4 ml of 0.1M phosphate buffer (pH 6.5) containing 1.50% o-nitrophenyl-β-D-galactopyranoside (hereinafter referred to as "ONPG") and reacted at 70° C. for 10 minutes. Thereafter, the reaction is discontinued by the addition of 2.5 ml of 10% Na2CO3 solution. The amount of o-nitrophenol formed is obtained from the absorbance at 420 nm, and the amount of enzyme liberating 1 μmol of o-nitrophenol per minute is taken as one unit.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:35][C:36]([F:49])([F:48])[C:37]1[CH:38]=[C:39]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[NH2:40]>>[CH3:1][O:2][C:3](=[O:34])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[C:25]([F:33])[CH:26]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:28]=2)[CH:12]=[C:13]([NH:40][C:39]2[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:37]([C:36]([F:35])([F:48])[F:49])[CH:38]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Yield: 97 %

Procedure:
The title compound was prepared in 97% yield from 2-(5′-fluoro-5-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 40, step (a)) and 3,5-bis-(trifluoromethyl)aniline under the conditions described in Example 37, step (b).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:15]([CH3:17])[CH3:16])([CH3:14])[C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-]>>[CH3:14][C:10]([N:15]([CH3:17])[CH3:16])([CH2:11][OH:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CN(C)C(C)(Cc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: [H-]
Product: CN(C)C(C)(CO)Cc1ccc(Cl)c(Cl)c1

Procedure:
--in esterifying an acid (III), then, when R1 and/or R2 are hydrogen, in methylating the amine with formaldehyde and formic acid to obtain a (+/-)3-(3,4-dichlorophenyl)-2-dimethyl-amino-2-methylpropionic acid ester(II) ##STR10## in which R is lower alkyl, then iv)--in reducing the ester (II) by a metal or organometal hydride to obtain (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropan-1-ol or cericlamine (INN) of formula (I) ##STR11## and in making the addition salt with hydrochloric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]=[C:8]([OH:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:5]=2[CH:4]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH2:7][C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11]=[CH:12][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C=Cc1ccccc1C(O)=C2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2c(c1)C=Cc1ccccc1C(=O)C2
Yield: 93.3 %

Procedure:
To a solution of 2-methoxy-6-hydroxy-dibenzo[a,e]cyclooctene (1.5 g) in dry dichloromethane (100 ml) was added pyridinium dichromate (4.5 g) and crushed 4A molecular sieves (2.3 g). After stirring at room temperature for 2h, diethyl ether (200 ml) was added and the reaction mixture was filtered through a plug of celite. The solvent was removed in vacuo and the residue purified by chromatography on flash silica with 5% ethyl acetate in hexane as eluent to give, as a colourless solid, the title compound (1.4 g), m.p. 104°-106° C. δ(360 MHz, CDCl3), 3.75 (3H, s, CH3O), 3.99 (2H, s, CH2 --CO), 6.73 (1H, d, J=2.7 Hz, CH=(OCH3)--CH), 6.86 (1H, dd, J=8.5 and 2.7 Hz, CH=C(OCH3)--CH), 7.01 (2H, s, Ar--CH=CH--Ar), 7.29-7.51 (4H, m, aromatics) and 8.24 (1H, dd, J=8.0 and 1.4 Hz, CH=C--CO). m/e 250 (M+). i.r. (νmax, nujol) 1665 cm-1 (CO). Found: C,81.5; H, 5.6. C17H14O2 requires: C, 81.0; H, 5.8%