Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([OH:22])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([O:22][C:4]2[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: N#Cc1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2C#N)C1
Reaction time: 18 h
Yield: 79.3 %

Procedure:
To a solution of 4-bromo-2-fluoro-benzonitrile (1.0 g, 5.0 mmol) and 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (0.95 g, 5.5 mmol) in DMF (15 mL) at 0° C., was added NaH (60% in mineral oil, 130 mg, 5.5 mmol). After 18 h, H2O and EtOAc were added and the organic portion washed with brine (3×) and dried to provide the title compound (1.4 g, 79%). MS (ESI): mass calcd. for C15H17BrN2O3, 352.0. m/z found, 377.1 [M+Na]+. 1H NMR (CDCl3): 7.48 (d, J=8.2 Hz, 1H), 7.25 (dd, J=8.2, 1.7 Hz, 1H), 6.79 (d, J=1.6 Hz, 1H), 5.00-4.92 (m, 1H), 4.38 (ddd, J=9.9, 6.4, 1.1 Hz, 2H), 4.11 (dd, J=10.0, 3.8 Hz, 2H), 1.48 (s, 9H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].S(=O)(=O)(O)O>O>[C:20]([O:19][C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:9]2[CH:10]=[CH:11][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)=[CH:18][CH:17]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(Nc2ccn(-c3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 85.7 %

Procedure:
A mixture of 4-(1-phenyl-1H-pyrazol-3-yl)aminophenol (2.0 g), acetic anhydride (4 g) and sulphuric acid (0.2 g) was heated at 100° C. on the steam bath for 15 minutes, water was added and the product was collected by filtration and dried to give the sub-title compound (2.0 g) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[C:12]=1Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([SH:34])[CH2:32][CH3:33].CCOC(C)=O>C(#N)CCC>[C:1]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=2)[C:12]=1[S:34][CH2:31][CH2:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Cn2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCC#N
Product: CCCSc1c(C(=O)OC(C)(C)C)cnn1Cc1ccc(C(=O)OC)cc1
Temperature: 180 °C
Yield: 62.1 %

Procedure:
5-Chloro-1-(4-methoxycarbonyl-benzyl)-1H-pyrazole-4-carboxylic acid tert-butyl ester (Intermediate#48) (397 mg, 1.13 mmol) was dissolved in butyronitrile (8 mL), potassium carbonate (470 mg, 3.40 mmol) and propanethiol (128 ul, 1.41 mmol) were added and the mixture heated to reflux and stirred at this temperature over night. The reaction mixture was transferred to a microwave vial (using ˜5 ml extra Butyronitrile to ensure complete transfer), a further 3 eq of propane thiol was added and the reaction was heated at 180° C. for 4 hours. EtOAc (˜50 mL) was added and the mixture washed with water (3×˜20 mL) and brine (˜20 ml) then dried (MgSO4), filtered and evaporated to give a yellow oil. Oil purified by column chromatography (12 g Si, eluting with 10 to 50% EtOAc in IH) to yield the title compound as a yellow oil (274 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20](Cl)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[S:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1c(Cl)cccc1Cl
Yield: 40.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.70 mmol), 2,6-dichlorobenzenesulfonyl chloride (190 mg, 0.83 mmol) and DMAP (cat.) gave the title compound (100 mg, 41%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH2:1]([C@H:5]([CH2:8][C:9]#[N:10])[C:6]#[N:7])[CH:2]([CH3:4])[CH3:3].C1(C)C=CC=CC=1.N12CCCN=C1CCCCC2>O>[CH2:1]([CH:5]([CH2:8][C:9]#[N:10])[C:6]#[N:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[C@@H](C#N)CC#N
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(C)CC(C#N)CC#N
Yield: 84 %

Procedure:
The racemization of (R)-2-isobutyl-succinonitrile was carried out on material recovered from bioconversion of racemic 2-isobutyl-succinonitrile with NIT-102 C2. A mixture of (R)-2-isobutyl-succinonitrile (1.36 g, 10 mmol, 69% ee), toluene (5 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.076 g, 5 mmol) was refluxed for 2 h. Water (10 mL) was added to the reaction and the resulting mixture extracted with ethyl acetate (2×10 mL). The combined organic extracts were washed sequentially with 5% HCl (20 mL) and saturated aqueous sodium chloride (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give racemic 2-isobutyl-succinonitrile (1.14 g, 84%). Enantiomeric purity was determined by GC using a Chiraldex™ G-TA column (30 M×0.25 mm ID, 125 micron film thickness).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:31])=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[C:24]([Cl:30])[CH:23]=2)[CH:21]=1>>[Cl:30][C:24]1[CH:23]=[C:22]([C:20]2[CH:21]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:17]=[CH:18][C:19]=2[F:31])[CH:27]=[CH:26][C:25]=1[C:28]#[N:29]
Reactant: N#Cc1ccc(-c2cc(Br)ccc2F)cc1Cl
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(C#N)c(Cl)c4)c3)cnc2c1F
Yield: 7 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol and 5′-bromo-3-chloro-2′-fluorobiphenyl-4-carbonitrile were coupled in the same way as in Example 6 to give 3-chloro-2′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-4-carbonitrile as an off-white solid (20 mg, 7%): δH (400 MHz, d6-DMSO) 1.59 (6H, s), 7.33 (1H, t, J 7), 7.63 (1H, dd, J 11 and 9), 7.80-7.89 (2H, m), 7.96 (1H, dd, J 7 and 2), 8.03 (1H, s), 8.11-8.14 (2H, m), 8.53 (1H, d, J 7); m/z (ES+) 424 [MH+].
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[CH2:16](O)[CH2:17][OH:18].O>C1(C)C=CC=CC=1>[C:10]1([C:5]2([C:8]#[N:9])[CH2:4][CH2:3][C:2]3([O:18][CH2:17][CH2:16][O:1]3)[CH2:7][CH2:6]2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: OCCO
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC1(c2ccccc2)CCC2(CC1)OCCO2
Reaction time: 3 h

Procedure:
The title compound of step 2 (43.3 g, 217 mmol) and ethylene glycol (27.4 g, 435 mmol) were boiled in toluol (430 mL) with the addition of p-toluol sulphonic acid (1.87 g, 10.9 mmol) at a water separator for 3 h with reflux. After the reaction had ended, the mixture was cooled, washed with NaHCO3 solution and saturated NaCl solution, dried with Na2SO4 and concentrated to low volume in a vacuum.
Reaction SMILES: [C:1]([N:9]1[CH:14]=[CH:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CN(C)C(=O)C>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(c1ccccc1)N1C=CC(c2c[nH]c3cc(F)ccc23)C=C1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Temperature: 80 °C

Procedure:
A mixture of 95 parts of 1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-1,4-dihydropyridine and 540 parts of N,N-dimethylacetamide is hydrogenated in the Parr-apparatus with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over Hyflo and the filtrate is poured onto water while stirring: an oil is precipitated. The supernatant aqueous phase is decanted and the residual oil is washed with water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is washed successively with a mixture of petroleumether and 2,2'-oxybispropane, with a hydrochloric acid solution 2 N and with water, and dissolved in trichloromethane. The latter is washed with a sodium hydroxide solution 1 N and with water, dried, filtered and evaporated. The residue is heated in a small amount of N,N-dimethylacetamide at 80° C. and the mixture is allowed to stand over week-end. The solid product is filtered off, washed with a mixture of water and ethanol, and dried in vacuo at 80° C., yielding 25 parts of 1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-piperidine; mp. 220° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Mg]Cl)=[CH:4][CH:3]=1.[Br:11][C:12]1[C:13]([CH3:32])=[N:14][O:15][C:16]=1[NH:17][S:18]([C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26](N(C)OC)=[O:27])(=[O:20])=[O:19]>C1COCC1>[Br:11][C:12]1[C:13]([CH3:32])=[N:14][O:15][C:16]=1[NH:17][S:18]([C:21]1[CH:25]=[CH:24][S:23][C:22]=1[C:26](=[O:27])[CH2:6][C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:19])=[O:20]
Reactant: CON(C)C(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Br
Reactant: Cc1ccc(C[Mg]Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 78 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl)acetyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 93B by reacting 4-methylbenzylmagnesium chloride with N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-methoxy(methylaminocarbonyl)]thiophene-3-sulfonamide in THF (see Example 93A) at −78° C. to room temperature, resulting in 78% yield. m.p. 146-150° C. 8
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>CC(CC)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(F)c1

Procedure:
A mixture of 10.0 g (64 mmol) 2-fluoro-4-nitrophenol, 130.24 g (70 mmol) 3-fluorobenzyl bromide and 17.6 g (127 mmol) potassium carbonate in 200 ml methyl-ethylketone is heated overnight at 80°. Water is added and the product is extracted with ethyl acetate, dried and evaporated. Recrystallisation from diethyl ether/hexane yields 12.68 g (75%) of a slightly yellow solid. MS: m/e=265.1 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11]([N:17]2[C:22](=[O:23])[NH:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[S:18]2(=[O:29])=[O:28])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([F:42])[C:33]=1[CH2:34]Br.C([O-])([O-])=O.[K+].[K+].COC1C(C)=CC(N2C(=O)N(CC3C(F)=CC(F)=CC=3F)C3C=CC=CC=3S2(=O)=O)=CC=1C>CN(C=O)C>[F:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]([F:42])[C:33]=1[CH2:34][N:21]1[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[S:18](=[O:29])(=[O:28])[N:17]([C:11]2[N:10]=[C:9]([CH2:8][NH:7][C:6](=[O:30])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:14]([O:15][CH3:16])=[CH:13][CH:12]=2)[C:22]1=[O:23]
Reactant: COc1ccc(N2C(=O)Nc3ccccc3S2(=O)=O)nc1CNC(=O)OC(C)(C)C
Reactant: COc1cc(F)c(CBr)c(F)c1
Agent: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(CNC(=O)OC(C)(C)C)n3)S(=O)(=O)c3ccccc32)c(F)c1
Yield: 64.6 %

Procedure:
The title compound (301 mg, 0.51 mmol) was prepared from tert-butyl[6-(1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl)-3-methoxypyridin-2-yl]methylcarbamate (IntA31) (343 mg, 0.79 mmol), 2,6-difluoro-4-methoxybenzyl bromide (225 mg, 0.95 mmol) and K2CO3 (164 mg, 1.19 mmol) in DMF (4 mL) at rt using the methods of (115).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=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.[F:55][C:56]([F:60])([F:59])[CH2:57][NH2:58]>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:58][CH2:57][C:56]([F:60])([F:59])[F:55])=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC(F)(F)F
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(-c2ccccc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (228 mg, 0.71 mmol), N,N-diisopropyl ethyl amine (552 μL, 3.22 mmol) and 2,2,2-trifluoroethylamine 77 μL, 0.77 mmol). The resulting reaction mixture was stirred for 12 h at ambient temperature. After dilution with ethyl acetate (20 mL) it was washed with water (20 mL) and aqueous sodium carbonate (saturated, 40 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 20:80) afforded the title compound (213 mg, 84%) as a white solid. MS: m/e=392.2 [M+H]+.
Reaction SMILES: [Cl:1][CH:2](Cl)[C:3](=[O:5])[CH3:4].[C:7]([NH:10][C:11]([NH2:13])=[S:12])(=[NH:9])[NH2:8]>CC(C)=O>[ClH:1].[Cl:1][CH2:2][C:3]1([OH:5])[CH2:4][S:12][C:11]([N:10]=[C:7]([NH2:9])[NH2:8])=[N:13]1
Reactant: CC(=O)C(Cl)Cl
Reactant: N=C(N)NC(N)=S
Solvent: CC(C)=O
Product: Cl
Product: NC(N)=NC1=NC(O)(CCl)CS1
Reaction time: 120 h

Procedure:
60.0 kg of dichloroacetone is dissolved in 550 ml of acetone. After cooling the solution to -5°~7° C., 55.8 kg of (aminoiminomethyl)thiourea[amidinothiourea] is added to the solution under cooling portionwise at one hour intervals each time in a 10 kg amount of amidinothiourea. The mixture is stirred continuously for 5 days below 0° C. The resultant precipitates are collected by filtration, and washed with 50 l of acetone to provide 111.6 kg of the desired compound. This material can be used as the starting material for the next process.
Reaction SMILES: [CH3:1][O:2][C:3]([NH2:5])=N.Cl.C[O:8][C:9](=O)[CH2:10][C:11]#[N:12].[CH3:14][O-].[Na+]>CO>[CH3:1][O:2][CH:3]1[CH2:14][C:11](=[NH:12])[CH2:10][C:9](=[O:8])[NH:5]1
Reactant: COC(=O)CC#N
Reactant: COC(=N)N
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC1CC(=N)CC(=O)N1
Reaction time: 8 h
Yield: 76 %

Procedure:
Compound III is synthesized according to the procedure of Pfeiderer (Pfeilderer, W. (1957) Chem. Ber., 90:2272-2276) as follows. 12.2 g of o-methylisourea hydrochloride (110.6 mmol), 11.81 mL methylcyanoacetate (134 mmol), 12.45 g of sodium methoxide (230.5 mmol) and 80 mL of methanol are placed in a 250 mL round bottom flask. The suspension is stirred and refluxed for 5 hours at 68°-70° C. After cooling at room temperatute, the suspension is filtered through a sintered glass funnel (Pyrex, 40-60 ASTM, 60 mL), and the NaCl on the filter is washed with methanol. The filtrate is filtered by gravity through a Whatman™ no. 1 paper in a 500 mL round bottom flask, and the solvent is evaporated under reduced pressure with a rotary evaporator at 50° C. The residue is solubilized with warm distilled water, and the product is precipitatedd by acidification to pH 3-4 with glacial acetic acid. After 2 hours (or overnight) at room temperature, the suspension is filtered under vacuum through a sintered glass funnel (Pyrex, 40-60 ASTM, 60 mL). The product is washed with water, acetone, and dried. The product is recrystallized with water as the solvent and using charcoal for decolorizing (activated carbon, NoritrA<100 mesh, decolorizing). The yield is 76%.
Reaction SMILES: C(N1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](O)[CH:15]=2)C(O)C1)C1C=CC=CC=1.[Br:22][CH2:23]CCOC1CCCCO1.[C:33](=O)([O-])[O-].[K+].[K+].C(N1CCC(C2C=CC=C(OCCCOC3CCCCO3)C=2)C(O)C1)C1C=CC=CC=1>CC(C)=O.CCCCCC>[Br:22][CH2:23][C:13]1[CH:12]=[CH:11][C:14]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:33]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(C2CCN(Cc3ccccc3)CC2O)c1
Reactant: BrCCCOC1CCCCO1
Agent: OC1CN(Cc2ccccc2)CCC1c1cccc(OCCCOC2CCCCO2)c1
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: BrCc1ccc2ccccc2c1

Procedure:
In an analogous manner to that described in Example 14, by alkylating (3RS,4RS)-1-benzyl-4-(3-hydroxy-phenyl)-piperidin-3-ol with rac.-2-(3-bromo-propoxy)-tetrahydro-pyran in the presence of potassium carbonate there was obtained a mixture of the diastereomeric racemates of (3RS,4RS)-1-benzyl-4-{3-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-phenyl}-piperidin-3-ol as a colourless oil; Rf : 0.38 (hexane:acetone=1:1). Subsequent alkylation with 2-bromomethylnaphthalene analogously to Example 12(b) gave a mixture of the diastereomeric racemates of 1-benzyl-3-(naphthalen-2-ylmethoxy)-4-{3-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-phenyl}-piperidine as a colourless oil; MS: 566 (M+H)+. Subsequent reaction with 2,2,2-trichloroethyl (sic) chloroformate analogously to Example 12(c) yielded a mixture of the diastereomeric racemates of 2,2,2-trichloroethyl 3-(naphthalen-2-ylmethoxy)-4-{3-[3-(tetrahydro-pyran-2-yloxy)-propoxy]-phenyl}-piperidine-1-carboxylate which, without further purification and characterization, was reacted with p-toluenesulphonic acid analogously to Example 53(c) to give 2,2,2-trichloroethyl (3RS,4RS)-4-[3-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate. Finally, by reaction with pyridine-2-carbonyl azide in an analogous manner to that described in Example 24(m) there was obtained 2,2,2-trichloroethyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{3-[3-(pyridin-2-ylcarbamoyloxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a colourless oil; Rf : 0.55 (methylene chloride:ethyl acetate=1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([S:22][CH3:23])[C:4]=1[C:5]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:6].[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[CH:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[NH:7][C:5](=[O:6])[C:4]1[C:14]([S:22][CH3:23])=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:3]=1[O:2][CH3:1]
Reactant: CNC
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1=O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N(C)C

Procedure:
The title compound, brown gum, MS: m/e=377.3 [(M+H, was prepared in accordance with the general method of example 1 and 2 from 2-methoxy-6-methylsulfanyl-N-(2-oxo-cyclopentyl)-4-trifluoromethyl-benzamide (intermediate M) and dimethylamine. The cis- and trans-isomer could be separated by column chromatography.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]Cl)=[CH:16][CH:15]=1.C(Cl)(Cl)(Cl)[Cl:23]>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH:1]([S:3]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)(=[O:5])=[O:4])[CH2:2][Cl:23])=[CH:16][CH:15]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C=CS(=O)(=O)c1ccc(C)cc1
Reactant: ClSc1ccc(Br)cc1
Product: Cc1ccc(S(=O)(=O)C(CCl)Sc2ccc(Br)cc2)cc1
Reaction time: 72 h

Procedure:
A solution of 26.8 g (0.147 mole) of p-tolyl vinyl sulfone in 50 ml of carbon tetrachloride was treated with 32.8 g (0.146 mole) of p-bromobenzenesulfenyl chloride. There was an exotherm from 25° to 29° in one hour. The mixture was allowed to stand 72 hours. The solvent was removed at reduced pressure and the residue recrystallized from ethyl acetate-petroleum ether (1:1) to give colorless needles, m.p. 82.5°-84.0°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,4-dimethoxy-phenylboronic acid to give [1-(3,4-dimethoxy-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [N+]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[C-:17]#[N:18].[K+].[OH2:20]>CS(C)=O>[C:17]([C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:4]=1[OH:20])[C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9])#[N:18]
Reactant: [C-]#N
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1cccs1
Reactant: O
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(C(=O)c2cccs2)ccc1O

Procedure:
2-p-Nitrobenzoylthiophene (2.33 g.) was allowed to react with potassium cyanide (3.9 g., 6 mols) in dimethyl sulphoxide (40 ml.) at 100°C for 31/2 hours. The solution was poured into water and the cloudiness removed with charcoal. The clear filtrate gave a precipitate on acidification; this was collected and crystallised from aqueous ethanol to give 2-(3-cyano-4-hydroxybenzoyl)thiophene, m.p. 216°C.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[C:4](=[O:7])[O:3][C:2]2=[O:8].[CH3:9][OH:10]>C(N(CC)CC)C>[CH3:9][O:10][C:4]([CH:5]1[CH2:6][CH:1]1[C:2]([OH:8])=[O:3])=[O:7]
Reactant: CO
Reactant: O=C1OC(=O)C2CC12
Solvent: CCN(CC)CC
Product: COC(=O)C1CC1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Oxabicyclo[3.1.0]hexane-2,4-dione (766 mg) was added to methanol (10 mL) at 0° C. After addition of triethylamine (0.953 mL), the mixture was stirred at room temperature for 1 hr. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 1 N hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (460 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH:11]1([O:16][C:17]2[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([O:16][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Product: COc1ccc(-c2ccc(Cl)cc2)cc1OC1CCCC1
Yield: 92 %

Procedure:
Following the procedure of Example 1, 4-chloro-phenylboronic acid and 3-cyclopentyloxy-4-methoxybromobenzene yielded 92% of the title compound as white needles: mp 94°-95° C.