Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:26][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:25][CH:24]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and [4-(trifluoromethyl)phenyl]methanol (111 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (125 mg, yield: 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:32]=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:32][C:28]4[S:27][CH:31]=[CH:30][N:29]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=Cc1nccs1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3nccs3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.070 mmol) was reacted with 2-thiazolecarboxaldehyde to provide 28 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:20]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:57][CH2:58]1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NC2CCOCC2)s1
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) in DMF (1.2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.00 mmol) and 4-aminotetrahydropyran (22 mg, 0.22 mmol). The resulting reaction mixture was stirred for 1 h and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 4:1 to 0:1) afforded the title compound (64 mg, 77%) as a white solid after recrystallization from ethyl acetate:heptane. MS: m/e=417.2 [M+H]+.
Reaction SMILES: CC(=C(C)C)C.[CH3:7][O:8][C:9]([CH:11]1[CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10].C([Li])CCC.[O:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][CH2:28][C:29]#[CH:30].II.[OH-].[Na+].OO>C1COCC1.C(OCC)(=O)C.CO>[CH3:7][O:8][C:9]([CH:11]1[CH2:15][CH2:14][CH:13]([C:30]#[C:29][CH2:28][O:27][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][O:21]2)[CH2:12]1)=[O:10]
Reactant: COC(=O)C1CC=CC1
Reactant: C#CCOC1CCCCO1
Agent: CC(C)=C(C)C
Agent: II
Agent: OO
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1CCC(C#CCOC2CCCCO2)C1
Temperature: -25 °C

Procedure:
To a solution of a borane-dimethylsulfide complex (1.98 ml, 20.2 mmol) in THF (18.3 ml), a 1M THF solution of 2,3-dimethyl-2-butene (20.2 ml, 20.2 mmol) was added at 0° C., and the mixture was stirred at the same temperature. Two hours later, the reaction solution was cooled to -25° C., and a solution of 3-cyclopentenecarboxylic acid methyl ester (2.55 g, 20.2 mmol) in THF (20 ml) was dropwise added thereto. The mixture was stirred at the same temperature for 1.5 hours. Then, methanol (1.64 ml) was dropwise added thereto. The reaction temperature was raised to 0° C., and the mixture was stirred for one hour. The reaction solution was concentrated under reduced pressure, dried and then dissolved in THF (20 ml). Separately, a n-butyllithium/1.5M hexane solution (1.37 ml, 20.6 mmol) was added at 0° C. to a solution of propargyl tetrahydropyranyl ether (2.83 g, 20.2 mmol) in THF (20 l), and the mixture was stirred for one hour. This solution was dropwise added at 0° C. to the above THF solution (10 ml). Then, the reaction solution was cooled to -78° C., and a solution of iodine (5.13 g, 20.2 mmol) in THF (10 ml) was dropwise added thereto, and the mixture was stirred at the same temperature for one hour and at room temperature for two hours. A 2N sodium hydroxide aqueous solution (12.1 ml) and a 30% hydrogen peroxide aqueous solution (2.83 ml) were dropwise added thereto, and the mixture was stirred for 5 minutes, then diluted with ethyl acetate (150 ml) and washed with a saturated sodium thiosulfate aqueous solution (150 ml) and a saturated sodium chloride aqueous solution (150 ml). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the above identified compound (2.56 g, 47.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:15])[CH:9]([CH:16]([OH:20])[C:17]([OH:19])=[O:18])[O:8][CH:7]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])[C:6]=2[CH:28]=1.O.[C:30]1(C)C=CC(S(O)(=O)=O)=C[CH:31]=1>C(O)C>[CH2:30]([O:18][C:17](=[O:19])[CH:16]([CH:9]1[O:8][CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:6]2[CH:28]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]([CH:12]([CH3:14])[CH3:13])[C:10]1=[O:15])[OH:20])[CH3:31]
Reactant: CC(C)N1C(=O)C(C(O)C(=O)O)OC(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(O)C1OC(c2ccccc2Cl)c2cc(Cl)ccc2N(C(C)C)C1=O
Yield: 841.1 %

Procedure:
A mixture of (3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid (0.15 g) obtained in Example 7, p-toluenesulfonic acid monohydrate (7 mg) and ethanol (20 ml) was heated for 24 hours under reflux. Ethanol was distilled off under reduced pressure. The residue was dissolved in a mixture of water (50 ml) and ethyl acetate (50 ml). The organic layer was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate, then the solvent was was distilled off under reduced pressure to leave (3RS,5RS,αRS)-7-chloro-5-(2-chlorophenyl)-1-isopropyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-glycolic acid ethyl ester (0.14 g) as prisms, m.p. 119°-120° C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Cl:14])=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH-].[K+].[CH3:17]N(C)C=O.CI>CO>[CH3:17][O:2][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Cl:14])=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)=[O:3]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc2c(Cl)ccnc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CO
Product: COC(=O)c1ccc2c(Cl)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
7-Carboxy-4-chloroquinoline (5 g, 24.0 mmol) was dissolved in a mixed solution of potassium hydroxide (1.49 g, 26.6 mmol) with methanol (150 ml) and stirred at room temperature overnight. The reactant was evaporated to dryness under reduced pressure. The residue was added with dimethylformamide (DMF; 60 ml) and methyl iodide (3.5 g, 24.6 mmol) in the order named and stirred at 80° C. for an hour. The reaction mixture was poured into ice water. The resulting precipitates were collected by filtration, dried over phosphorus pentoxide and recrystallized from ethanol (20 ml) to obtain 3.6 g (61%) of 7-methoxycarbonyl-4-chloroquinoline.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH2:51][NH2:52]>CN(C=O)C.CCOC(C)=O>[CH3:46][O:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][C:55]=1[O:56][CH3:57])[CH2:51][NH:52][C:3](=[O:5])[C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:1])[CH3:6]
Reactant: COc1ccc(CN)cc1OC
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)C(C)(C)c2ccccc2)cc1OC
Yield: 94.9 %

Procedure:
A solution of 2-methyl-2-phenylpropionic acid (3.28 g, 20 mmol) in DMF (50 ml) was treated sequentially with N,N-diisopropylethylamine (8.09 g, 80 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (7.60 g, 20 mmol) then 3,4-dimethoxybenzylamine (3.34 g, 20 mmol) and then stirred at room temperature, under argon for 24 h. The reaction mixture was diluted with EtOAc then washed with water (3×) then brine. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with diethyl ether/pentane to afford the title compound as a beige solid (5.95 g, 95%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[N:18][N:17]=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[F:23][C:20]([F:21])([F:22])[C:19]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[N:16]=[N:17][N:18]=1
Reactant: FC(F)(F)c1nnnn1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Oc1ccc(-n2nnnc2C(F)(F)F)cc1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of 1(4-benzyloxy-phenyl)-5-trifluoromethyl-1H-tetrazole (45.3 mmol) in ethanol (100 ml) and tetrahydrofuran (100 ml) was hydrogenated at room temperature and atmospheric pressure over 10% palladium-carbon catalyst (6 g). After 2 h, the mixture was filtered and the filtrate was evaporated to give the title compound (10.4 g) as a cream solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.C1(C)C=CC=CC=1.S(Cl)([Cl:31])=O>CN(C=O)C>[Cl:31][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCCC1
Yield: 82 %

Procedure:
A solution of 6methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (228 mg, 7.9 mmol) in thionyl chloride (5 ml) and DMF (0.2 ml) was heated at reflux for 1 hour. Toluene was added and the volatiles were removed by evaporation. The residue was dissolved in methylene chloride and cooled aqueous sodium hydrogen carbonate solution was added. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazoline (200 mg, 82%).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.[P:12]([O-:19])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[C:7]1([CH3:11])[CH:8]=[CH:9][CH:10]=[C:5]([PH:12](=[O:19])[C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)[CH:6]=1
Reactant: Cc1cccc(Br)c1
Reactant: CCOP([O-])OCC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc([PH](=O)c2cccc(C)c2)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
Under a nitrogen stream, a solution of magnesium (3.60 g, 3.50 equivalents) and a small amount of iodine and 1,27 dibromoethane-in THF (25 mL)solution was stirred at room temperature for 30 min. A solution of m-bromotoluene (25.36 g, 3.51 equivalents) in THF (130 mL) was added at 24° C., and the mixture was stirred at 40° C. for 30 min. Then, a solution of diethyl phosphite (5.84 g, 42.3 mmol) in THF (10 mL) was added at 25° C., and the mixture was stirred at 24° C. for 1.5 hrs. 6M-HCl (20 mL) was added at 4° C., and then water (20 mL) and toluene (60 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with 10% aqueous NaHCO3 solution (20 mL), water (20 mL) and 10% aqueous NaCl solution (20 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and further passed through a membrane filter (0.2 μm) under reduced pressure. The filtrate was concentrated under reduced pressure to give the title compound (9.09 g, colorless oil). yield 93.3%
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:47](Cl)[C:48]#[CH:49]>C(O)C>[C:1]([O:5][NH:6][C:7]([C@:9]1([CH3:38])[C@H:14]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]([CH2:49][C:48]#[CH:47])[CH2:10]1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCl
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCNC[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: C#CCN1CC[C@@H](NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)[C@@](C)(C(=O)NOC(C)(C)C)C1
Yield: 60 %

Procedure:
To 364 mg (0.673 mmol) of (3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)piperidine-3-carboxamide (Example 47, Step 8) was added ethanol (6 mL), catalytic sodium iodide, potassium carbonate (112 mg, 0.812 mmol), and propargyl chloride (52 μL) and the resulting mixture was heated to reflux overnight. The solvent was then concentrated and the residue was dissolved in ethyl acetate. The organics were washed with saturated aqueous Na2CO3 (3×), dried over Na2SO4, concentrated, and then purified via column chromatography on silica gel eluting with 50% ethyl acetate/hexanes to give (3S,4R)-N-tert-butoxy-3-methyl-4-(4-((2-methylquinolin-4-yl)methoxy)phenylsulfonamido)-1-(prop-2-ynyl)piperidine-3-carboxamide (235 mg, 0.406 mmol, 60%) as a colorless solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.92-0.96 (m, 3H) 1.23-1.30 (m, 11H) 1.60-1.71 (m, 1H) 1.89-1.97 (m, 1H) 2.05-2.12 (m, 1H) 2.27-2.36 (m, 2H) 2.74 (s, 3H) 2.84-2.91 (m, 1H) 3.00 (ddd, J=12.06, 7.52, 4.17 Hz, 1H) 3.14 (dd, J=10.74, 2.15 Hz, 1H) 3.16-3.20 (m, 1H) 3.34 (dd, J=16.67, 2.53 Hz, 1H) 5.54 (s, 2H) 6.16 (d, J=7.58 Hz, 1H) 7.07-7.12 (m, 2H) 7.41 (s, 1H) 7.52-7.57 (m, 1H) 7.71 (ddd, J=8.46, 6.95, 1.26 Hz, 1H) 7.81-7.86 (m, 2H) 7.90 (d, J=7.58 Hz, 1H) 8.08 (d, J=8.59 Hz, 1H) 10.71 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].C[O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1>C(=S)=S>[C:1]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:11]=1[OH:10])[NH:17][C:16](=[O:20])[CH2:15]2)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)NC(=O)C2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1cc2c(cc1O)NC(=O)C2
Reaction time: 0.04 h
Yield: 86.6 %

Procedure:
Acetyl chloride (4.09 mL, 0.0575 mol) was added to a slurry of aluminum trichloride (AlCl3) (35.36 g, 0.265 mol) in carbon disulfide (CS2) (250 mL). After 2-3 min, 6-methoxyoxindole (7.22 g, 0.0442 mol) was added. The resulting mixture was heated to reflux for 2.5 hours. (A black tar developed with time). Excess solvent was decanted and ice water was added carefully to the residue. The resulting mixture was stirred overnight. The pale yellow solid obtained was collected, washed with water and dried under high vacuum to give the title compound (7.32 g, 87%).
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Ca+2].[F:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][CH:21]2[CH2:25][CH2:24][CH:23](O[Si](C(C)(C)C)(C)C)[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[C:1]1([S:7]([CH:23]2[O:22][CH:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:35][CH:34]=3)[CH2:25][CH2:24]2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(COc2ccc(F)cc2)O1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)C1CCC(COc2ccc(F)cc2)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To benzenesulfinic acid sodium salt (10.0 g, 0.061 mol), 25% HCl was added dropwise with stirring until the solid dissolved. The reaction mixture was extracted (100 mL each, 3 times) with EtOAc, dried over Na2SO4 and concentrated to give benzenesulfonic acid (7.8 g, 90%). To a 100 mL round bottom with a magnetic stir bar, benzenesulfonic acid (4.61 g, 0.0324 mol), CaCl2(3.6 g, 0.0324 mol) and dry dichloromethane (30 mL) were added. The reaction mixture was cooled to 0° C. and (2S) (5RS)-2-(4-fluorophenoxymethyl)-5-hydroxy-tetrahydrofuran (4.6 g, 0.0216 mol) in dry CH2Cl2 (20 mL) was added. The reaction mixture was stirred for 3 h and monitored by TLC (EtOAc-light petroleum ether 1:4, Rf=0.25). The reaction mixture was filtered through celite and washed with CH2Cl2 (3 times). The combined organic layer was washed with saturated aqueous Na2CO3, water brine and dried over Na2SO4. Solvent was removed under reduced pressure to afford the crude (2S) (5RS)-5-benzenesulfonyl-2-(4-fluorophenoxymethyl)tetrahydrofuran 14 which was crystallized from chloroform-hexane to give pure white solid, yield 6.8 g (93%), m.p. 102° C.-104° C. 1H NMR (200 Mz CDCl3): δ1.90-3.0 (m, 4H), 3.85-5.0 (m, 4H), 6.70-7.05 (mn, 4H), 7.45-7.72(m, 3H), 7.77-8.0 (n,2H).
Reaction SMILES: C(S)CCCCCCCCCCC.[CH3:14][N:15]([CH2:17][CH:18]([C:27]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:19]1[CH:20]=[CH:21][C:22]([O:25]C)=[CH:23][CH:24]=1)[CH3:16].C([O-])C.[Na+]>>[CH3:14][N:15]([CH2:17][CH:18]([C:27]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[CH3:16]
Reactant: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
Agent: CCCCCCCCCCCCS
Agent: CC[O-]
Agent: [Na+]
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Temperature: 150 °C
Reaction time: 48 h

Procedure:
Dodecanethiol (69 g), venlafaxine (55 g), and an ethanolic solution of sodium ethanolate (21%, 82 g) are charged to a pressure vessel. The temperature is raised to 150° C. and the reaction mixture is stirred for 2 days. Then the temperature is lowered and the solution is filtered. The pH of the filtrate is adjusted to 9.5 with aqueous hydrogen chloride. The crystals are collected by suction filtration. The cake is washed with ethanol and dried in vacuo.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7](O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].OS([O-])(=O)=O.[K+].C(OC(=O)C)C.OS([O-])(=O)=O.[K+]>>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]=[CH:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(O)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCC1CC=CCC1
Temperature: 70 °C

Procedure:
19 g 4-propyl-1-cyclohexanol are mixed with 16 g KHSO4 and stirred for one week at 70° C. After the addition of ethylacetate KHSO4 is filtered off. Ethylacetate is evaporated and the product obtained by fractional distillation.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-])=O.[Cl-].[NH4+]>[Zn].CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH2:14]
Reactant: Cc1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cc1ccc(N2CCOCC2)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
To a methanol solution (10 ml) of 4-(4-methyl-3-nitro-phenyl)-morpholine (22 mg) obtained in Step A, zinc (65 mg) and ammonium chloride (16 mg) were added, followed by stirring at room temperature for 3 hours. After filtration through Celite, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=30/1), to obtain the desired compound as a colorless solid (17 mg, 90%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH2:11])=[O:5].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([C:13]([F:12])([F:22])[F:23])[CH:15]=1)=[O:5]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
(1R,2S)-2-Amino-cyclopentanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 11a, 130 mg, 0.91 mmol) was dissolved in methanol (5 mL). 3-Trifluoromethyl-benzaldehyde (160 mg, 0.91 mmol) was added, stir at 25° C. for 15 min, acetic acid (0.2 mL) added, followed with sodium cyanoborohydride (150 mg, 2.3 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product (1R,2S)-2-(3-trifluoromethyl-benzylamino)-cyclopentanecarboxylic acid methyl ester (200 mg, 0.664 mmol, 73%), as a clear oil. LC-MS (ESI) calcd for C15H18F3NO2 301.13, found 302.2 [M+H+].
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([OH:9])[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+]>C(O)(C(F)(F)F)=O.ClCCl.CO.ClCCl>[N:1]([C@@H:4]1[CH2:5][NH:6][CH2:7][C@H:8]1[OH:9])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1CNC[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(3R,4R)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (3.6 g, 16.0 mmol) was stirred in 10% TFA in dichloromethane (100 mL) for 2 hours. The mixture was concentrated under reduced pressure and the residue obtained dissolved in a 10% MeOH/dichloromethane solution (50 mL) and treated with potassium carbonate (20 g) and the suspension stirred at ambient temperature for 2 hours, then filtered through a pad of Celite and washed with 10% MeOH: dichloromethane. The filtrate was concentrated to afford (3R,4R)-4-azidopyrrolidin-3-ol in quantitative yield.