Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:20](O)=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31]>>[CH:1]1([C:4]2[CH:5]=[C:6]([C:20]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:21])[C:7]3[C:12]([CH3:13])=[N:11][N:10]([CH:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[C:8]=3[N:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C2CCOCC2)c2nc(C3CC3)cc(C(=O)O)c12
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C2CCOCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 6-cyclopropyl-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg, 0.498 mmol), and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (98 mg, 0.647 mmol). The product was collected as a solid, 0.170 g (78%). LCMS E-S (M+H)=436.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.14 (m, 4H), 1.79 (dd, J=12.63, 2.27 Hz, 2H), 2.05-2.18 (m, 5H), 2.19-2.27 (m, 4H), 2.36 (s, 3H), 3.53 (t, J=11.12 Hz, 2H), 3.98 (dd, J=11.49, 3.41 Hz, 2H), 4.33 (d, J=4.80 Hz, 2H), 4.87 (m, J=11.53, 11.53, 4.11, 3.92 Hz, 1H), 5.87 (s, 1H), 6.99 (s, 1H), 8.59 (t, J=4.93 Hz, 1H), 11.51 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8](Br)[CH:9](OC)OC)[N:3]=1.[Cl:15][C:16]1[C:17]([NH2:22])=[N:18][CH:19]=[CH:20][N:21]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC#N.O>[Br:1][C:2]1[N:3]=[C:4]([C:8]2[N:18]3[CH:19]=[CH:20][N:21]=[C:16]([Cl:15])[C:17]3=[N:22][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(Br)c1cccc(Br)n1
Reactant: Nc1nccnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: Clc1nccn2c(-c3cccc(Br)n3)cnc12
Temperature: 25 °C

Procedure:
A mixture of 2-bromo-6-(1-bromo-2,2-dimethoxy-ethyl)-pyridine (from Example 37 supra) (5.267 g, 16.2 mmol), 3-chloropyrazin-2-amine (2.1 g, 16.2 mmol), and pTsOH.H2O (2.1 g, 11 mmol) in CH3CN (900 mL) and water (90 mL) was stirred and heated at reflux overnight. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure. The crude product was purified by chromatography (CH2Cl2:CH3OH, 100:1) to give 3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine. (Yield 4.86 g, 52%). LC-MS: [M+H]+ 309.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:12]=2[O:16][CH2:17][CH2:18][CH3:19])[N:7]1[C:26](=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl>[C:26]([N:7]1[C:8]2[C:13](=[C:12]([O:16][CH2:17][CH2:18][CH3:19])[C:11]([CH:20]3[CH2:25][CH2:24][N:23]([C:1](=[O:3])[CH3:2])[CH2:22][CH2:21]3)=[CH:10][CH:9]=2)[CH2:14][CH2:15][C@@H:6]1[CH3:5])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1c(C2CCN(C(C)=O)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Acetyl chloride (6 μL, 0.08 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (26.1 mg, 0.07 mmol) and triethylamine (0.03 mL, 0.21 mmol) in dichloromethane (1.0 mL), and the reaction stirred at room temperature overnight. The reaction solution was purified directly via column chromatography on silica gel (Biotage 10 g column, gradient elution with 10-20% methanol in ethyl acetate) to afford (S)-1-(4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-1-yl)ethan-1-one (19 mg, 71%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.05 (m, 6H), 1.17-1.29 (m, 1H), 1.38-1.47 (m, 1H), 1.54-1.59 (m, 1H), 1.65-1.81 (m, 5H), 2.01 (s, 6H), 2.16-2.35 (m, 2H), 2.48-2.59 (m, 1H), 2.71-2.78 (m, 1H), 3.01-3.03 (m, 2H), 3.55-3.76 (m, 2H), 3.90 (br d, J=14.66 Hz, 1H), 4.52 (br d, J=13.20 Hz, 1H), 7.04 (br s, 2H). MS (ESI, pos. ion) m/z 373 [M+H]+.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=CO[CH:8]=2)=[CH:3][CH:2]=1.[CH2:18]([C@H:25]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[N:26]1[C:32](=[O:40])[CH2:33][N:34]1C=C(I)C=[N:35]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(C2C=CC=CC=2)C=CC(B(O)O)=CC=1>>[CH2:18]([C@H:25]1[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[N:26]1[C:32](=[O:40])[CH2:33][N:34]1[CH:8]=[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:6][CH:5]=2)[CH:11]=[N:35]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cn1cc(I)cn1
Reactant: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Agent: OB(O)c1ccc(-c2ccccc2)cc1
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cn1cc(-c2ccc(-c3ccccc3)cc2)cn1
Yield: 39 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, 1-(4(S)-benzyl-2,2-dimethyl-oxazolidinyl)-2-(4-iodopyrazol-1-yl)-ethanone was coupled to 4-biphenylboronic acid to provide in 39% yield 1-(4(S)-benzyl-2,2-dimethyl-oxazolidinyl)-2-(4-biphenyl-4-yl-pyrazol-1-yl)-ethanone as a white solid, mp 150-1° C. 1H NMR: δ 7.83 (s, 1H), 7.68 (s, 1H), 7.62-7.52 (m, 6H), 7.47-7.28 (m, 8H), 4.83, 4.38 (AB quartet, 2H, J=15.6 Hz), 4.22-4.18 (m, 1H), 3.94 (m, 2H), 3.09 (dd, 1H, J=6.4, 13.0 Hz), 2.97 (dd, 1H, J=8.5, 13.2 Hz), 1.79 (s, 3H), 1.55 (s, 3H). Anal. Calculated for C29H29N3O2: C, 77.14; H, 6.47; N, 9.31. Found: C, 77.04; H, 6.52; N, 9.37.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])([O-:33])=[O:32]>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:23])[CH2:21][NH:22][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc([N+](=O)[O-])c1)OCc1ccccc1
Yield: 100.1 %

Procedure:
To a mixture of O-benzylglycine p-toluenesulfonic acid salt (6.41 g) and triethylamine (4.04 g) in methylene chloride (100 ml) was added portionwise 3-nitrobenzoyl chloride (3.71 g) under cooling in an ice-bath and stirring. The resultant mixture was stirred for 1 hour under the same condition and for 1 hour further at ambient temperature. From the reaction mixture, methylene chloride was removed in vacuo and to the residue were added water and ethyl acetate with stirring. The separated organic layer was washed with diluted hydrochloric acid, aqueous sodium bicarbonate and water twice respectively. The extract was dried over magnesium sulfate and evaporated in vacuo to give N-(3-nitrobenzoyl)glycine benzyl ester (5.98 g). 1H-NMR (CDCl3, δ): 4.31 (2H, d, J=5.2 Hz), 5.24 (2H, s), 6.99 (1H, br, t, J=5.2 Hz), 7.38 (5H, s), 7.64 (1H, t, J=7.9 Hz), 8.15 (1H, d, t, J=7.9 Hz, 2.2 Hz), 8.35 (1H, d, t, J=7.9 Hz, 2.2 Hz), 8.64 (1H, t, J=2.2 Hz); APCI-MS (CHCl3) (m/z): 315 (M+ +1)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]([OH:18])[CH3:17])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cs].Br[CH2:21][C:22]1([CH3:26])[CH2:25][O:24][CH2:23]1>CN(C)C=O>[CH3:21][C:22]1([CH2:26][O:14][C:13](=[O:15])[CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:16]([OH:18])[CH3:17])[CH2:25][O:24][CH2:23]1
Reactant: CC(O)C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC1(CBr)COC1
Agent: [Cs]
Solvent: CN(C)C=O
Product: CC(O)C(NC(=O)OCc1ccccc1)C(=O)OCC1(C)COC1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a N,N-dimethylformamide (750 ml) solution 2-benzyloxycarbonylamino-3-hydroxy-butyric acid, cesium salt (123.9 g, 0.322 mol) at about 23° C. was added 3-bromomethyl-3-methyl-oxetane (60 ml, 0.420 mol). The reaction was stirred at about 23° C. for about 18 hours and was then concentrated in vacuo. The residue was diluted with ethyl acetate and extracted with saturated sodium bicarbonate, washed with saturated ammonium chloride and saturated sodium chloride, dried with sodium sulfate and concentrated to give 100 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](O)=[N:7][CH:6]=[C:5]2[O:13][CH3:14].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:6][N:7]=1
Reactant: COc1cnc(O)c2ccc(F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cnc(Cl)c2ccc(F)cc12
Yield: 69.3 %

Procedure:
A solution of 6-fluoro-4-methoxyisoquinolin-1-ol (2.9 g, 15.01 mmol) in POCl3 (10 ml, 107 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in Hexanes as eluent. The product fractions were collected and the solvent removed under vacuum to give 1-chloro-6-fluoro-4-methoxyisoquinoline (2.2 g, 67% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.29 (dd, J=9.2, 5.4 Hz, 1H), 7.84-7.79 (m, 2H), 7.45 (ddd, J=9.3, 8.2, 2.6 Hz, 1H), 4.06 (s, 3H); MS m/z 212.0 (M++1).
Reaction SMILES: C1(C(Cl)=O)CC1.[CH:7]1([C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH2:9][CH2:8]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[F:37].C1(C)C=CC=CC=1>C(O)C>[CH:7]1([C:10]([N:12]=[C:13]=[S:14])=[O:11])[CH2:9][CH2:8]1.[CH:7]1([C:10]([NH:12][C:13]([NH:34][C:33]2[CH:35]=[CH:36][C:30]([O:29][C:20]3[C:19]4[C:24](=[CH:25][C:26]([O:27][CH3:28])=[C:17]([O:16][CH3:15])[CH:18]=4)[N:23]=[CH:22][CH:21]=3)=[C:31]([F:37])[CH:32]=2)=[S:14])=[O:11])[CH2:9][CH2:8]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)C1CC1
Agent: O=C(N=C=S)C1CC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)C4CC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
1-Cyclopropanecarbonyl isothiocyanate was prepared using commercially available 1-cyclopropanecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 1-Cyclopropanecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 66%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1.C([Li])CCC.CCCCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:30]=[O:31])=[CH:3][C:4]=1[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCCCc1cc(Br)ccc1OC
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCCCCc1cc(C=O)ccc1OC
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-bromo-1-methoxy-2-(4-methoxy-butyl)-benzene (8.10 g, 29.7 mmol; described in EP0678 503 B1) in absolute THF (170 mL), cooled to −78° C., is added dropwise over 30 min and under an argon atmosphere a 1.6M solution of n-butyllithium in hexane (20.4 mL, 32.6 mmol). After stirring for 5 min, a mixture of DMF (5.03 mL, 65.2 mmol) in THF (20 mL) is added over 30 min at −78° C. Stirring is continued over 15 min at −78° C., and the reaction mixture is gradually warmed and stirred for an additional hour at room temperature before quenching with 1N HCl. The aqueous layer is extracted with diethyl ether (3×200 mL), the combined organics are dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (hexane/AcOEt 4:1) gives the title compound as yellowish oil. TLC, Rf (hexane/AcOEt 4:1)=0.27. MS: 223.2 [M+H]+. 1H-NMR (CDCl3): δ 1.6-1.74 (m, 4H) 2.70 (t, 2H), 3.37 (s, 3H), 3.43 (t, 2H), 3.96 (s, 3H), 6.99 (dd, 1H), 7.73 (d, 1H), 7.76 (dd, 1H), 9.70 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][C:3]=1[F:11].[F:12][C:13]([F:24])([F:23])[C:14]1[C:19]([C:20](O)=[O:21])=[CH:18][N:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([NH:10][C:20](=[O:21])[C:19]2[C:14]([C:13]([F:24])([F:12])[F:23])=[CH:15][CH:16]=[N:17][CH:18]=2)=[C:6]([NH:8][CH3:9])[CH:7]=1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: CNc1cc(Cl)c(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNc1cc(Cl)c(F)cc1NC(=O)c1cnccc1C(F)(F)F
Temperature: 80 °C

Procedure:
To the solution of compound 5-chloro-4-fluoro-N1-methylbenzene-1 2-diamine (0.3 g, 0.00172 mol) and 4-trifluoromethylnicotinic acid (0.36 g, 0.00189 mol) in DMF (5 ml) was added EDC-HCl (0.27 g, 0.00206 mol) followed by HOBt (0.39 g, 0.00206 mol) and Et3N (0.047 g, 0.00344 mol). Reaction mixture was heated at 80° C. for 12 h. Reaction mass was quenched with ice water and layers were separated. The aqueous layer was extracted with EtOAc (3×10 ml). The combined organic extracts were washed with sat NaHCO3 solution and brine dried over Na2SO4 and concentrated to get crude product which was purified by column chromatography to provide N-(4-chloro-5-fluoro-2-(methyl amino)phenyl)-4-(tri-fluoromethyl)nicotinamide as a brown colored solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.08 (s, 1H), 9.20 (s, 1H), 8.99-8.98 (d, J=4.8 Hz, 1H), 8.75-8.74 (d, J=4.8 Hz, 1H), 7.91-7.89 (d, J=5.2 Hz, 1H), 7.39-7.37 (d, J=10.4 Hz, 1H), 6.72-6.71 (d, J=7.2 Hz, 1H), 5.36 (bs, 1H), 2.74-2.73 (d, J=4.0 Hz, 3H). MS (M+1): 348.12.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])[CH2:2][CH3:3].N[C:26]1C=C(C2CCN(C(OC(C)(C)C)=O)CC2)C=CC=1.C1(C(Cl)=O)CC1>>[CH:2]1([C:1]([NH:5][C:6]2[CH:7]=[C:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:14][CH2:13]3)[CH:9]=[CH:10][CH:11]=2)=[O:4])[CH2:26][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(N)c2)CC1
Reactant: CCC(=O)Nc1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: O=C(Cl)C1CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Yield: 100 %

Procedure:
According to the procedure used for the synthesis of tert-butyl 4-[3-(propionylamino)phenyl]-1-piperidinecarboxylate, tert-butyl 4-(3-aminophenyl)-1-piperidinecarboxylate (16.47 g 0.0596 mol) and cyclopropanecarbonyl chloride (6.27 g, 0.0597 mol) provided the tert-butyl 4-{3-[(cyclopropylcarbonyl)amino]phenyl}-1-piperidinecarboxylate (18.1 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.55–7.46 (m, 2H), 7.29–7.21 (m, 2H), 6.96–6.89 (m, 1H), 2.79 (t, 2H, J=12.1 Hz), 2.68–2.58 (m, 1H) 1.84 (d, 2H, J=12.6 Hz), 1.83–1.76 (m, 4H), 1.48 (s, 9H), 1.19–1.12 (m, 1H), 1.09–1.05 (m, 2H), 0.89–0.75 (m, 2H); ESMS m/e: 345.5 (M+H)+.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1.C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:41][CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>C(Cl)Cl.CO>[CH3:14][N:13]([CH3:15])[C:11](=[O:12])[C:10]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[NH:8][C:6]1[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=[C:2]([NH:36][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:38][CH:37]=2)[N:7]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Nc4ccccc4C(=O)N(C)C)n3)cc2)CC1
Yield: 12 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N,N-dimethylbenzamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 12% yield (pale yellow oil that solidifies on standing) after flash chromatography eluent (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 8.28 (s, 1H), 8.15 (d, 1H, J=8.2 Hz), 7.44 (d, 2H, J=8.5 Hz), 7.30 (d, 2H, J=8.2 Hz), 7.21 (t, 1H, J=7.5 Hz), 7.02 (t, 1H, J=7.4 Hz), 6.81 (s, 1H), 3.50 (s, 2H), 3.09 (s, 3H), 2.96 (s, 3H), 2.49 (bs, 8H), 2.30 (s, 3H); MS (ESI): 514.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([OH:10])[CH2:6][CH2:7][CH2:8][Cl:9].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[CH2:4][CH:5]([O:10][S:20]([CH3:19])(=[O:22])=[O:21])[CH2:6][CH2:7][CH2:8][Cl:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CC(O)CCCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CC(CCCCl)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen, 6-chloro-3-hydroxy-hexanoic acid methyl ester (2); 66.5 g {(GC purity; 79.1%, pure amount; 52.6 g (0.295 mol)}, triethylamine (44.7 g, 0.443 mol) and toluene (250 ml) were added to a 500 ml capacity flask, followed by cooling to 5° C. Methanesulfonyl chloride (37.0 g, 0.325 mol) was added dropwise thereto, followed by stirring at 5° C. for 0.5 hour to obtain a toluene solution of 6-chloro-3-methanesulfonyloxy-hexanoic acid methyl ester (3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O-:19])=[O:18].[Na+].Br[CH2:22][C:23]([O:25]CC1C=CC=CC=1)=[O:24]>CN(C=O)C>[C:23]([O:25][O:18][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])(=[O:24])[CH3:22]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OOC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
50 g (0.166 moles) of sodium 2-[(2,6-dichlorophenyl)amino]phenylacetate were dissolved in 200 ml of N,N'-dimethylformamide under heating to 50° C., and 41.620 g (0.181 moles) of benzyl bromoacetate were added thereto. Under these conditions stirring was continued for 3 hours. Upon completion of the reaction, the solvent was removed at reduced pressure and the sodium salts were precipitated with addition of 400 ml of ether. The solution was then filtered and the ether phase was washed three times with 100 ml of water and dried on sodium sulphate. The resulting product was concentrated until an oil was obtained, which oil was washed twice with 100 ml of hexane and then crystallized with methanol, thus obtaining 45.28 (61%) of 2-[(2,6-dichlorophenyl)amino]phenylacetoxy acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][C:30]1([CH2:33][O:34][CH3:35])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]2([CH2:33][O:34][CH3:35])[CH2:32][CH2:31]2)=[CH:4][CH:3]=1
Reactant: COCC1(CBr)CC1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: COCC1(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3ccccc34)c3ccc(Cl)cc32)CC1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with 1-bromomethyl-1-methoxymethyl-cyclopropane (prepared as described in WO 2001032633) gave the title compound.
Reaction SMILES: [CH3:1][Li].[OH:3][C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[C:19](=[O:25])[CH2:18][C@@:17]2([CH3:26])[C@H:10]3[CH2:11][CH:12]=[C:13]2[C:14](=[O:16])[CH3:15])[CH2:5]1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[OH:3][C@@H:4]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[C@@H:6]([CH2:7][CH2:8][C@@H:9]3[C@@H:20]2[C:19](=[O:25])[CH2:18][C@@:17]2([CH3:26])[C@H:10]3[CH2:11][C@@H:12]([CH3:1])[C@@H:13]2[C:14](=[O:16])[CH3:15])[CH2:5]1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@@]21C
Reaction time: 0.5 h

Procedure:
To a stirred slurry of cuprous iodide (950 mg) in dry ether (75 ml) under dry nitrogen at 0° was added a solution of methyl-lithium in ether (1.6M; 6 ml.) until the initially formed yellow precipitate just rediseolved to give a clear solution. To the stirred solution at 0° was added a solution of 3α-hydroxy-5α-pregn-16-ene-11,20-dione (600 mg) in dry tetrahydrofuran (50 ml.). During the addition a bright yellow precipitate formed. The mixture was stirred at 0° for 30 minutes, and then poured into cold, saturated ammonium chloride solution (200 ml.) More ether (200 ml) was added and the organic layer was separated, washed with saturated ammonium chloride solution (200 ml) and with water (200 ml.) dried over sodium sulphate and purified by preparative t.l.c. in ethyl acetate to give a product which was further purified by preparative t.l.c. in ethyl acetate/chloroform, 1/1 to give a white solid (380 mg) which was recrystallised from ether/petrol to give title compound (248 mg) as colourless plates, m.p. 138°-140°, [α]D + 99°, (c 0.95).