Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][N:31]3[C:35](=[O:36])[C:34]4=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]4[C:32]3=[O:41])[CH2:24]2)=[CH:19][CH:18]=1>N1C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[C:32]1(=[O:41])[N:31]([CH2:30][CH2:29][CH2:28][CH2:27][N:23]2[CH2:22][CH2:21][C:20]3[C:25](=[CH:26][C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:18][CH:19]=3)[CH2:24]2)[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc(O)cc2C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
Trifluoromethanesulfonic anhydride (0.53 ml, 3.14 mmol) was added dropwise with stirring to an ice-cooled solution of 7-hydroxy-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (1 g, 2.86 mmol) in anhydrous pyridine (10 ml). After stirring at room temperature for 18 h the reaction mixture was added to 10% aqueous Copper (II) sulfate (100 ml) and extracted into ethyl acetate (200 ml). The organic layer was separated, washed with 10% aqueous copper (II) sulfate (2×50 ml), dried (Na2SO4) and evaporated in vacuo. Chromatography on silica gel using 10-100% ethyl acetate-hexane gradient elution gave the title compound as a green oil (0.45 g, 33%).
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].[CH3:5][N:6]1[C:14]2[CH:13]=[C:12]([N:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)=[CH:17][C:16]3=[O:31])[CH:11]=[CH:10][C:9]=2[C:8]2[CH2:32][NH:33][CH2:34][CH2:35][C:7]1=2.CCN(CC)CC.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:33]1[CH2:34][CH2:35][C:7]2[N:6]([CH3:5])[C:14]3[CH:13]=[C:12]([N:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][N:22]=5)=[CH:17][C:16]4=[O:31])[CH:11]=[CH:10][C:9]=3[C:8]=2[CH2:32]1)(=[O:2])[CH3:3]
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CNCC2
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCc2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.6 %

Procedure:
AcCl (0.03 mL, 0.4 mmol) was added to a solution of 1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (125 mg, 0.294 mmol), DMAP (7 mg, 0.06 mmol) and Et3N (0.08 mL, 0.6 mmol) in CH2Cl2 (10 mL) under N2, and the resulting solution was stirred at 25° C. for 17 h. H2O was added to the solution, and the phases were separated. The organic phase was washed with saturated NH4Cl solution, dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded the title compound (116 mg, 84%) as a mixture of rotomers as a white powder: mp 232-236° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.35 (d, J=8.3 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.59-7.54 (m, 2H), 7.28 (d, J=1.5 Hz, 1H), 7.08-7.03 (m, 2H), 4.70 (s, 0.8H), 4.68 (s, 1.2H), 3.88 (t, J=5.5 Hz, 0.8H), 3.83 (t, J=5.5 Hz, 1.2 H), 3.67 (s, 3H), 2.97-2.91 (m, 1.2H), 2.86-2.81 (m, 0.8H), 2.15 (s, 1.8H), 2.13 (s, 1.2H); ESI MS m/z 467 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][C:11]([CH3:13])=O>>[F:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[N:1]=[C:11]([CH3:13])[CH3:10]
Reactant: Nc1ccc(O)cc1F
Reactant: CC(C)=O
Product: CC(C)=Nc1ccc(O)cc1F

Procedure:
Using the procedure for Example 13, 4-amino-3-fluoro-phenol Compound 14a was refluxed with acetone to provide 3-fluoro-4-isopropylideneamino-phenol Compound 14b in quantitative yield. MS (ESI) m/z: 168 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][Cl:14]
Reactant: O=S(Cl)Cl
Reactant: OCc1c(F)ccc(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(F)c(CCl)c1F

Procedure:
To a solution of 2,3,6-trifluorobenzyl alcohol (41 g) in dichloromethane (100 ml) is added dropwise a solution of thionyl chloride (50 ml) in dichloromethane (80 ml) under ice cooling with stirring, and the mixture is stirred at room temperature overnight. To the mixture is added triethylamine (10 ml), and the solvent is distilled off under reduced pressure to give 2,3,6-trifluorobenzyl chloride (28.6 g), as colorless oil, b.p. 63° C. (13 mmHg).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH:16][C:17](=[NH:19])[CH3:18])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[CH:23]([NH:26]N)([CH3:25])[CH3:24]>C(O)(=O)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:26]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:17]([CH3:18])[N:16]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC(=N)NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)NN
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1

Procedure:
9-Bromo-N-(1-iminoethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide 29 was reacted with isopropylhydrazine hydrochloride 4 in acetic acid to give III.
Reaction SMILES: [C:1]([O:8][C:9]([C:12]([CH2:15][CH2:16]I)([F:14])[F:13])([F:11])[F:10])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2].CN1CCCC1=[O:24]>O>[C:1]([O:8][C:9]([C:12]([CH2:15][CH2:16][OH:24])([F:14])[F:13])([F:11])[F:10])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)(F)C(F)(F)OC(F)(F)C(F)(F)CCI
Reactant: CN1CCCC1=O
Solvent: O
Product: OCCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Yield: 52 %

Procedure:
The flask was charged with 130 g of C2F5OCF2CF2CH2CH2I, 643 mL of the methylpyrrolidinone and 48 mL of deionized (DI) water. The reaction mixture was heated to 132 C for 20 hours. DI water was added and the lower layer was separated. The lower layer was dissolved in ether, washed with saturated sodium sulfite, and dried over anhydrous sodium sulfate. After rotary vaporization, 48 g of C2F5OCF2CF2CH2CH2OH was obtained by distillation in 52% yield. The boiling point was 70˜72° C. at 60 mm Hg pressure (7980 Pa).
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.[CH2:10](N(CC)CC)C.IC>C(#N)C>[O:6]=[C:4]1[CH:1]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2][O:5]1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1(C(=O)O)CC1
Solvent: CI
Solvent: CC#N
Product: COC(=O)C1CCOC1=O
Temperature: 75 °C
Reaction time: 2 h

Procedure:
Cyclopropane-1,1-dicarboxylic acid (10 g) in acetonitrile(200 ml) was treated with triethylamine (43 ml) and iodomethane (19 ml) at room temperature. The solution was stirred for 2 h then heated at 75° C. for 16 h. The solvent was removed under reduced pressure, the residue dissolved in water, extracted with ethyl acetate, dried(MgSO4) and evaporated to a brown oil (6.70 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([I:18])=[C:7]([C:9]2[CH:14]=[C:13]([O:15]C)[CH:12]=[CH:11][C:10]=2[I:17])[CH:8]=1.B(Br)(Br)Br.C(Cl)Cl>C(=O)=O.CC(C)=O>[OH:15][C:13]1[CH:12]=[CH:11][C:10]([I:17])=[C:9]([C:7]2[CH:8]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=2[I:18])[CH:14]=1
Reactant: COc1ccc(I)c(-c2cc(OC)ccc2I)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Oc1ccc(I)c(-c2cc(O)ccc2I)c1
Reaction time: 18 h
Yield: 85 %

Procedure:
A flask containing 5,5'-dimethoxy-2,2'-diiodobiphenyl (10.0 g, 21 mmol) was cooled to -76° C. in dry ice/acetone. A 1.0 M solution of boron tribromide in methylene chloride (64 ml, 64 mmol) was added via syringe to the cold substrate. The ice bath was removed and the reaction allowed to reach room temperature. After 18 hours, the solution was added slowly to 1 L of water. The aqueous mixture was stirred for 2 hours, and the white solid which formed was filtered, washed with water, and dried to give I, which melted at 181°-182° C., in 85% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6](SC)[CH2:5]2.[OH:14][S:15]([O-:18])(=O)=O.[K+].[CH3:20]O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([S:15]([CH3:20])(=[O:18])=[O:14])[CH2:5]2
Reactant: CO
Reactant: CSC1Cc2cc(Cl)ccc2C1=O
Reactant: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)C1Cc2cc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.5 g (2.35 mmol) of 5-chloro-2-methylsulfanylindan-1-one is dissolved in 10 ml of methanol; at 0° C., a solution of 4.33 g (7.05 mmol) of 2KHSO5×KHSO4×K2SO4 in 10 ml of water is added dropwise. The mixture is stirred at room temperature for 5 h; the methanol is distilled off and the aqueous residue is extracted with dichloromethane. The organic phase is separated off, dried over MgSO4, filtered and concentrated under reduced pressure. This gives 0.5 g of 5-chloro-2-methanesulfonylindan-1-one of melting point 197° C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][S:7]([C:10]([C:13]1[CH:14]=[C:15]2[C:20](=[C:21]([C:23]3[CH:24]=[C:25]([CH2:29][CH:30]([C:37]4[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=4)[C:31](N(OC)C)=[O:32])[CH:26]=[CH:27][CH:28]=3)[CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)([CH3:12])[CH3:11])(=[O:9])=[O:8]>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[CH:1]1([C:31](=[O:32])[CH:30]([C:37]2[CH:38]=[CH:39][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:41][CH:42]=2)[CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:21]3[CH:22]=[C:13]([C:10]([S:7]([CH3:6])(=[O:9])=[O:8])([CH3:12])[CH3:11])[CH:14]=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH:24]=2)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CON(C)C(=O)C(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(c1cc(-c2cccc(CC(C(=O)C3CC3)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anhydrous CeCl3 (266 mg, 1.26 mmol) was heated 2 h at 130° C. under high vacuum, refluxed in THF (10 mL) for 1 h then cooled to 0° C. To the resulting white suspension at 0° C. was added freshly prepared cyclopropylmagnesium bromide (0.6M, THF, 2.11 mL, 1.25 mmol) and the resulting mixture stirred at 0° C. for 1 h then cooled to −78° C. The 3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-N-methoxy-N-methyl-propionamide from Step 1 (in THF, 150 mg, 0.25 mmol) was added and the mixture warmed to 0° C. for 1 h, diluted with ethyl acetate and saturated ammonium chloride solution. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 1:4) provided the 1-cyclopropyl-3-{3-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-2-(4-methanesulfonyl-phenyl)-propan-1-one compound as a white foam.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[CH2:9]([O:11][C:12](=[O:26])[C:13](=O)[C:14]1[C:22]2[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH3:10]>O.C(O)C>[CH2:9]([O:11][C:12](=[O:26])[C:13](=[N:7][OH:8])[C:14]1[C:22]2[C:17](=[C:18]([CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH3:10]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(CC)cccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NO)c1c[nH]c2c(CC)cccc12
Yield: 75.7 %

Procedure:
Solutions of sodium acetate (43.7 g, 0.53 mol) in water (100 mL) and hydroxylamine hydrochloride (37 g, 0.53 mol) in water (100 mL) were added to 7-ethyl-α-oxo-1H-indole-3-acetic acid ethyl ester 4 (17.4 g, 0.07 mol), in ethanol (250 mL) and the mixture was heated at reflux for 12 hours. The ethanol was removed by distillation and the resultant precipitate was filtered and recrystalized from hot ethanol to give the product (13.8 g, 75%), m.p. 167°-169° C. as a mixture of isomers.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=N[C:13](OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH:29]=[CH:30][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CN(C=O)C.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:30]1[CH:29]=[C:28]([CH2:32][CH:33]([CH3:13])[C:34]([OH:36])=[O:35])[CH:27]=[CH:26][CH:31]=1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: CCOC(=O)CCc1cccc(O)c1
Reactant: Cc1cccc(C)c1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C)c1COc1cccc(CC(C)C(=O)O)c1
Reaction time: 4 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (7.71 g, 56.7 mmol) and diisopropyl azodicarboxylate (DIAD, 11.36 g, 56.18 mmol) in THF (30 ml) and DMF (13 ml) was added drop wise to a solution of Ethyl 3-(3-hydroxyphenyl)propanoate (Step A, 10.0 g, 51.5 mmol) and triphenylphosphine (14.73 g, 56.18 mmol) in THF (100 ml) at 0° C. The reaction mixture was stirred at the same temperature for 4 hours, diluted with ether and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([S:12]([NH2:15])(=[O:14])=[O:13])[N:4]([CH3:16])[N:3]=1.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:21]([O:20][C:18]([NH:15][S:12]([C:5]1[N:4]([CH3:16])[N:3]=[C:2]([Cl:1])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:14])=[O:13])=[O:19])[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1c(Cl)nn(C)c1S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)NS(=O)(=O)c1c(C(=O)OCC)c(Cl)nn1C
Yield: 88.4 %

Procedure:
Into 30 ml of dry acetone, there were added 5.35 g of 3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide, 2.5 g of ethyl chloroformate and 4.14 g of anhydrous potassium carbonate and the mixture was refluxed for three hours. After cooling, acetone was evaporated and the residue was added into ice-water. After separation of a trace of water insolubles, the filtrate was made acidic with hydrochloric acid. The reaction mixture was extracted with diethyl ether and organic layer was dried and the solvent was evaporated under reduced pressure to give 6.0 g of N-(ethoxycarbonyl)-3-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide. m.p.: 82°-85° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:18][C:19]([NH2:21])=[S:20]>C(O)C.C(OCC)(=O)C>[NH2:21][C:19]1[S:20][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]3([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[N:18]=1
Reactant: COC(=O)C1(c2ccc(C(=O)CCl)cc2)CC1
Reactant: NC(N)=S
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C1(c2ccc(-c3csc(N)n3)cc2)CC1

Procedure:
A mixture of methyl 1-[4-(chloroacetyl)phenyl]cyclopropanecarboxylate (0.30 g, 1.2 mmol) and thiourea (0.18 g, 2.4 mmol) in ethanol (5.0 ml) was refluxed overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 and brine successively; then dried; and then concentrated. The residue was tritrurated with ether followed by filtration to afford the product. LC-MS: 275.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:22]=[CH:21][C:20](Cl)=[C:19](Cl)[CH:18]=3)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.[NH:41]1CCC[CH2:43][CH2:42]1.C(N1CC[C@H]([C@H]([OH:62])C)[C@@H](C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.N1C2C(=CC(O)=CC=2)C=C1.ClC(OC(Cl)=O)C.CCN(C(C)C)C(C)C>CO>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([N:30]2[CH2:31][CH2:32][CH:27]([C:25]([OH:26])=[O:62])[CH2:28][CH2:29]2)=[N:34][CH:35]=1)#[N:40].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C@@H:13]([C@@H:14]([O:16][C:17]3[CH:18]=[C:19]4[C:20](=[CH:21][CH:22]=3)[NH:41][CH:42]=[CH:43]4)[CH3:15])[CH2:12][CH2:11][N:10]([C:25]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)[CH2:31][CH2:32]3)=[O:26])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1ccc(Cl)c(Cl)c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Reactant: C1CCNCC1
Reactant: C[C@@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: Oc1ccc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H](Oc1ccc2[nH]ccc2c1)[C@H]1CCN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1

Procedure:
In analogy to the procedure described for the synthesis of 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(S)-1-(3,4-dichloro-phenoxy)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile (example 49) the respective piperidine derivative was prepared from (R)-1-[(3S,4S)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 1H-indol-5-ol via Mitsunobu reaction and subsequently the benzyl group was cleaved by treatment with 1-chloroethyl-chloroformate, DIPEA and methanol. Coupling with 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) yielded the title compound as viscous yellow oil. MS (m/e): 568.3 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=[CH2:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[N+]1([O-])CC[O:37]CC1.[OH2:41]>C1COCC1.C(O)(C)(C)C.CCOC(C)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].O=[Os](=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]([OH:37])[CH2:23][OH:41])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([O:31][CH3:32])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C[C@H](CC)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@@H](C(O)CO)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-pent-1-en-3-yl)piperidin-3-yl)acetate (Example 415, Step B, 85 mg, 0.18 mmol) in THF (1 mL), t-butanol (1 mL) and water (1.5 mL) was added 4-methylmorpholine 4-oxide (63.0 mg, 0.54 mmol) and OsO4 (1.1 mg, 4.5 μmol). The reaction was stirred at rt overnight. The reaction was diluted with EtOAc (40 mL) and Na2S2O3 (20 mL, saturated aqueous solution). The separated aqueous layer was extracted with EtOAc (20 mL) and the combined organic extracts were washed with brine (20 mL), dried over MgSO4, filtered and evaporated in vacuo to give the title compound as a 5:1 mixture of diastereomers.
Reaction SMILES: [Mg:1].[CH2:2]([OH:5])[CH2:3][CH3:4]>>[CH2:2]([O-:5])[CH2:3][CH3:4].[CH2:2]([O-:5])[CH2:3][CH3:4].[Mg+2:1]
Reactant: CCCO
Reactant: [Mg]
Product: CCC[O-]
Product: [Mg+2]

Procedure:
112 g of magnesium turnings and 3 000 g of propan-1-ol are initially introduced into a 10 l steel autoclave. Reaction is performed for a total of 5 hours at 188° C. and a pressure of 38 bar. Then n-propanol is removed by distillation at a temperature of 80° C. and a pressure of about 50 mbar. The alkoxide is then dried at 80° C. and a pressure of <1 mbar. The product still contains a proportion of metallic magnesium amounting to 0.04 wt. %.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[S:15][C:16](Cl)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[K+].CN(C=O)C>CCOC(C)=O.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[S:15][C:16]([O:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCC3)sc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCC3)sc1Oc1ccccc1
Temperature: 70 °C
Yield: 71.3 %

Procedure:
To ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-chlorothiazole-4-carboxylate (1J) (0.250 g, 0.69 mmol), phenol (0.129 g, 1.4 mmol), and KOH (0.284 g, 2.1 mmol) was added DMF (10 mL). The reaction mixture was allowed to heat to 70° C. for 72 hours. The reaction mixture was cooled to rt and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 80% EtOAc in hexanes to provide 0.208 g (72%) ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-phenoxythiazole-4-carboxylate (21A): LC/MS (APCI): m/z 424.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10](S(C)=O)SC)=[CH:5][CH:4]=1.C([OH:18])C.C([O-])([O-])OCC>S(=O)(=O)(O)O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(SC)S(C)=O)cc1
Reactant: CCO
Agent: CCOC([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(CC=O)cc1

Procedure:
764 mg. of methyl 2-(p-methoxyphenyl)-1-methylthioethyl sulfoxide was dissolved in 6 ml. of ethanol, and with the addition of 1.03 ml. of ethyl orthoformate and 5 drops of concentrated sulfuric acid, the solution was stirred for 27 hours at room temperature. 10 ml. of water was added, and the reaction mixture was extracted with methylene chloride. The product was dried with anhydrous sodium sulfate, and concentrated at reduced pressure to give a diethyl acetal of p-methoxyphenylacetaldehyde. 5 ml. of ether was added to the acetal, and 20 ml. of 0.25 N dilute sulfuric acid was further added. The mixture was stirred for 12 hours at room temperature. The stirred mixture was then extracted with ether, and the ether layer was dried with anhydrous sodium sulfate, followed by concentration at reduced pressure. The residue was subjected to column chromatography to give 386 mg of p-methoxyphenylacetaldehyde as a colorless liquid. Yield 82%.