Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][S:28]([C:31]2[C:32]3[N:33]=[CH:34][CH:35]=[N:36][C:37]=3[CH:38]=[CH:39][CH:40]=2)(=[O:30])=[O:29])[CH:19]=1>>[CH3:2][O:3][C:4](=[O:16])[C@@H:5]([NH:6][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][C:20]=1[NH:27][S:28]([C:31]1[C:32]2[N:33]=[CH:34][CH:35]=[N:36][C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:30])=[O:29])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(F)c(Br)c1)NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 4-chloro-2-(quinoxaline-5-sulfonylamino)-benzoic acid as in Example 1, Part C. HPLC: RT=10.09 min. MS (ESI−): mass calcd. for C25H19BrClFN4O5S, 621.86; m/z found, 619/621 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.24 (s, 1H), 8.98 (d, J=1.6, 1H), 8.92 (d, J=1.6, 1H), 8.58 (dd, J=7.3, 1.1, 1H), 8.33 (dd, J=8.5, 1.1, 1H), 7.92-7.86 (m, 1H), 7.76 (d, J=1.9, 1H), 7.28-7.25 (m, 1H), 7.19 (d, J=8.4, 1H), 7.06-6.94 (m, 2H), 6.92 (dd, J=8.4, 1.9, 1H), 6.48 (d, J=7.2, 1H), 4.92 (q, J=5.7, 1H), 3.81 (s, 3H), 3.22-3.09 (m, 2H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:14][C:15]1[CH:16]=[C:17]([NH:26][C:27]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=2)[CH:18]=[C:19]([C:21]2[CH:22]=[N:23][NH:24][CH:25]=2)[CH:20]=1>CN(C=O)C.CCOC(C)=O>[CH:2]1([N:23]2[CH:22]=[C:21]([C:19]3[CH:18]=[C:17]([NH:26][C:27]4[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=4)[CH:16]=[C:15]([CH3:14])[CH:20]=3)[CH:25]=[N:24]2)[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C3C=CCCC3)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3-Bromocyclohexene (0.18 mL, 1.57 mmol) and cesium carbonate (1.02 g, 3.13 mmol) were added to an oven-dried flask containing N-[3-methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (500 mg, 1.57 mmol) dissolved in DMF (5 mL). The mixture was warmed to 80° C. and stirred overnight. The mixture was cooled to room temperature, diluted with EtOAc, and washed with 1:1 water:brine (3×). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 80% EtOAc/hexanes) to afford racemic N-{3-[1-(cyclohex-2-en-1-yl)-1H-pyrazol-4-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine. MS ESI calcd. for C21H21F3N5 [M+H]+ 400. found 400.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.[CH3:10][O:11][NH:12][CH3:13].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:10][O:11][N:12]([CH3:13])[C:7](=[O:9])[CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1
Reactant: O=C(O)Cc1ccsc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccsc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A mixture of 2-(thiophen-3-yl)acetic acid (2.0 g, 14.1 mmol), O,N-dimethylhydroxylamine (1.68 g, 16.9 mmol), EDCI (2.95 g, 15.5 mmol), HOBT (2.15 g, 15.5 mmol), and TEA (3.7 mL, 31 mmol) in anhydrous DCM (50 mL) was stirred at room temperature under nitrogen for two hours. The reaction mixture was diluted with CH2Cl2, and the organic layer was washed with aqueous HCl solution (0.5 mol/L, 30 mL×2), saturated NaHCO3 (30 mL×2) and brine(30 mL), dried over Na2SO4, filtered, and concentrated to give the crude N-methoxy-N-methyl-2-(thiophen-3-yl)acetamide (2.0 g, yield 76.6%).
Reaction SMILES: [C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C:8]([C:17]([OH:19])=O)=[C:7]([CH3:20])[NH:6][C:5]1=[O:21])(=[O:3])[NH2:2].[C:22]1([CH:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:32]1([CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:29][CH2:30][NH:31][C:17]([C:8]2[CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=3)[N:4]([C:1](=[O:3])[NH2:2])[C:5](=[O:21])[NH:6][C:7]=2[CH3:20])=[O:19])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)N(C(N)=O)C(=O)N1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)N(C(N)=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
102 mg (0.329 mmol) of 3-carbamoyl-4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 83.5 mg (0.395 mmol) of (3,3-diphenylpropyl)amine were dissolved in 10 ml of DMF. 94.6 mg (0.494 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the basic silica gel chromatography (dichloromethane/methanol=100/1 to 10/1) to obtain the crude title compound.
Reaction SMILES: [C@H:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN(CC[N:55]2[CH2:60][CH2:59][CH:58]([OH:61])[CH2:57][CH2:56]2)CC1>>[OH:61][CH:58]1[CH2:59][CH2:60][N:55]([CH2:1][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[CH2:56][CH2:57]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c12
Agent: Cl
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCC(O)CC6)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 122 (see example 94) and amine 21.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]2=[N:4][C:3]=1[CH3:15].[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]=[O:36])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]>>[F:16][C:17]1[CH:18]=[CH:19][C:20]2=[C:21]([CH:37]=1)[O:22][CH2:23][C:24]1[CH:34]=[C:33]([CH:35]([OH:36])[C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]4=[N:4][C:3]=3[CH3:15])[CH:32]=[CH:31][C:25]=1/[C:26]/2=[C:27](/[CH3:30])\[C:28]#[N:29]
Reactant: Cc1nc2cc(C(F)(F)F)ccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C)nc4cc(C(F)(F)F)ccn34)cc2COc2cc(F)ccc21
Yield: 99.5 %

Procedure:
[step 3] Using 3-iodo-2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridine (730 mg, 2.24 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (328 mg, 1.12 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(3-fluoro-8-{hydroxy[2-methyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}dibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (550 mg, 99%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:36]1[CH2:38][CH:37]1[CH2:39][CH2:40]O.N>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:40][CH2:39][CH:37]3[CH2:38][CH2:36]3)=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Reactant: OCCC1CC1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2OCCC2CC2)cc1

Procedure:
The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-cyclopropane ethanol in place of isobutanol (yield: 0.1472 g, 100%). mp 111-117° C. 1H NMR (300 MHz, DMSO d6) δ −0.01 (m, 2H), 0.31 (m, 2H), 0.60 (m, 1H), 1.49 (q, J=6 Hz, 2H), 3.29 (s, 3H), 4.48 (t, J=6 Hz, 2H), 7.37 (m, 2H), 7.65 (m, 2H), 7.91 (m, 2H), 8.06 (m, 2H), 8.17 (s, 1H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal. calc. for C22H21FN2O4S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.59; H, 5.02; N, 6.45.
Reaction SMILES: [C:1]([N:4]([CH2:6][C@H:7]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[O:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)[CH3:5])(=[O:3])[CH3:2].C(OCC)(=O)C.Cl>>[ClH:20].[Cl:21][C:16]1[CH:15]=[C:14]([C@@H:13]2[O:12][CH2:11][CH2:10][NH:9][CH2:8][C@H:7]2[CH2:6][N:4]([CH3:5])[C:1](=[O:3])[CH3:2])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CC(=O)N(C)C[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N(C)C[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 140.8 %

Procedure:
To tert-butyl (6R,7R)-6-{[acetyl(methyl)amino]methyl}-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) was added 4.0 M hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 1 hr. The residue obtained by concentration under reduced pressure was separated by HPLC (C18, mobile phase: water/acetonitrile (containing 10 mM NH4HCO3)), and the obtained fraction was concentrated under reduced pressure to give the title compound (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[CH:14]1(N)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: NC1CCCCCC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCCCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.8 %

Procedure:
A mixture of 18.2 g of 4-chloro-1,2-dinitrobenzene and 31 g of cycloheptylamine in 55 ml of 95° EtOH is stirred for 15 hours at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of HCl and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using petroleum ether as the eluent to give 13 g of the expected product after crystallization from isopropanol.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=O)=[C:4](F)[CH:3]=1.C[NH:21][NH2:22]>C(O)CCC>[C:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:6]2[C:5]3[C:4](=[CH:3][C:2]([Br:1])=[CH:18][CH:17]=3)[NH:22][N:21]=2)[CH2:9][CH2:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2F)CC1
Reactant: CNN
Solvent: CCCCO
Product: CC(=O)N1CCC(c2n[nH]c3cc(Br)ccc23)CC1

Procedure:
A solution of 3.3 g of 4-(4-bromo-2-fluorobenzoyl)-1-acetylpiperidine, 1.1 g (0.013 mole) of methylhydrazine and 30 ml of n-butanol was heated under reflux for 16 hrs. The reaction mixture was concentrated in vacuo and the residue was diluted with water. The aqueous suspension was made basic with ammonium hydroxide solution and extracted with dichloromethane. The extract was washed with water, dried over anhydrous potassium carbonate and the solvent was concentrated to give 3-(1-acetyl-4-piperidinyl)-6-bromo-1H-indazole, as an oil.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[CH:17][CH:16]=2)[CH2:10]1)(C)(C)C.Cl.O1CCOCC1>>[ClH:28].[Cl:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:29])[C:22]=1[NH:21][C:18]1[CH:17]=[CH:16][C:15]([CH:11]2[O:12][CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:6]([OH:30])=[O:5])[CH2:10]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CCN1CCOC(c2ccc(Nc3c(Cl)cccc3Cl)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCN1CCOC(c2ccc(Nc3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 173.7 %

Procedure:
3-{2-[4-(2,6-Dichloro-phenylamino)-phenyl]-morpholin-4-yl}-propionic acid tert-butyl ester (0.36 g; 0.80 mmol) was treated with HCl in 1,4-dioxane (3.99 mL; 4.00 mol/L; 15.95 mmol) and stirred overnight at room temperature. The solvent was removed in vacuo and the residue treated with iPr2O. The formed precipitate was collected by filtration and dried in vacuo, overnight to afford 3-{2-[4-(2,6-Dichloro-phenylamino)-phenyl]-morpholin-4-yl}-propionic acid hydrochloride (0.30 g). 1H NMR (400 MHz, DMSO-d6) □ ppm 2.83-2.98 (1H, m) 2.98-3.20 (1H, m) 3.21-3.36 (1H, m) 3.38-3.48 (1H, m) 3.49-3.55 (1H, m) 3.97 (1H, t, J=12.6 Hz) 4.04-4.18 (1H, m) 4.72 (1H, d) 6.53 (1H, d) 7.14 (1H, d) 7.29 (1H, t, J=8.1 Hz) 7.57 (1H, d) 8.03 (1H, s).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:12]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(Oc2ccc(Br)cc2C(F)(F)F)cc1

Procedure:
Prepared analogously to Example 78a) starting from 4-fluorobenzaldehyde and 4-bromo-2-(trifluoromethyl)-benzenol.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@:7]3([O:30][C@@H:8]3[C@@H:9](Cl)[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32OCC[O:24]3)[CH2:6]1)(=[O:3])[CH3:2].O>O1CCCC1.C(O)(=O)C.[Zn]>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@:7]([OH:30])([CH:8]=[CH:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH:12]3[CH2:28][C@@H:13]3[C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H]([C@@H]5C[C@@H]5C45OCCO5)[C@@H]3[C@H](Cl)[C@H]3O[C@]32C1
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5CC5[C@H]4[C@@H]3C=C[C@]2(O)C1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
A solution of 21 g of 3β-acetoxy-7α-chloro-5β,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstane in 105 ml of tetrahydrofuran, 105 ml of acetic acid, and 27 ml of water is combined with 63 g of zinc dust and stirred for 1.5 hours at 80° C. The mixture is then decanted off from the zinc, washed with methylene chloride, and the organic phase is washed with sodium bicarbonate solution and water. After drying and evaporation, the residue is chromatographed on silica gel, thus obtaining 13.8 g of 3β-acetoxy-5-hydroxy-15,16β-methylene-5β-androst-6-en-17-one, mp 191°-194° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[Br:25]N1C(=O)CCC1=O.C1(C)C=CC=CC=1>O>[Br:25][C:4]1[CH:3]=[CH:2][C:1]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1
Reactant: c1ccc(Nc2ccccc2-c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(Nc2ccccc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
In a stream of nitrogen, a 100 mL three-necked flask was charged with 15.0 g (61.1 mmol) of N-phenyl-N-biphenylylamine. 100 mL of dimethylformamide and 10.8 g (61.1 mmol) of N-bromosuccinimide were added to the content, and the mixture was stirred at room temperature for 2 hours. To the thus-obtained reaction mixture, 10 mL of toluene and then 10 mL of pure water were added, and the reaction mixture was separated into an organic phase and an aqueous phase. The organic phase was washed with pure water and then with an aqueous saturated sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The thus-obtained solid was recrystallized from toluene to give 13.4 g (41.4 mmol) of N-(4-bromophenyl)-N-biphenylylamine as a grey powder (yield: 67%).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:14][N:15]=[C:16]=[O:17].CCN(C(C)C)C(C)C>ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:14][NH:15][C:16]([NH:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][Cl:2])[N:5]=1)=[O:17]
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a suspension of 4-(chloromethyl)thiazol-2-amine hydrochloride (7.55 g, 41 mmol) in dichloromethane (150 mL) at 0° C. was added 3,4-dichlorobenzyl isocyanate (8.27 g, 41 mmol). A solution of DIPEA in dichloromethane (30 mL) was added over a period of 30 min and the mixture was stirred overnight at room temperature. Evaporation of the volatiles in vacuo followed by purification by column chromatography (EtOAc/heptane 1/1) afforded 1-(3,4-dichlorobenzyl)-3-(4-(chloromethyl)thiazol-2-yl)urea as an off-white solid (10.5 g, 30 mmol) in 73% yield. 1H-NMR (ppm, DMSO-d6): 10.80 (bs, 1H), 7.60 (d, 1H), 7.55 (s, 1H), 7.11 (t, 1H), 7.05 (s, 1H), 4.63 (s, 2H), 4.30 (d, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][S:12][CH2:13][C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:51]1[CH2:56][CH2:55][S:54][CH2:53][CH2:52]1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][S:12][CH2:13][C:14](=[O:16])[N:51]1[CH2:56][CH2:55][S:54][CH2:53][CH2:52]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CSCCN1
Reactant: O=C(O)CSCCC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CCSCC(=O)N1CCSCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-Carboxymethylsulfanyl-propionic acid benzyl ester (763 mg, 3 mmol), HBTU (1.71 g, 4.5 mmol) and DIPEA (2.05 mL, 12 mmol) in DCM (10 mL) is added thiomorpholine (283 uL, 3 mmol). After stirring at rt during 2 h and evaporation of the solvent, the residue is dissolved with ethylacetate and washed with an aqueous 1N HCl solution and an aqueous saturated NaHCO3 solution. The organic phase is dried and evaporated to afford the title compound.
Reaction SMILES: C([BH3-])#N.[Na+].CS(O)(=O)=O.[Cl:10][C:11]1[CH:31]=[CH:30][C:14]2[C:15]3[C:16](=[CH:27][NH:28][CH:29]=3)[CH2:17][N:18]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:13]=2[CH:12]=1.[OH-].[Na+]>CO.O>[Cl:10][C:11]1[CH:31]=[CH:30][C:14]2[C:15]3[C:16](=[CH:27][NH:28][CH:29]=3)[CH2:17][NH:18][CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:13]=2[CH:12]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1c[nH]cc1-2
Agent: CS(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)NCc1c[nH]cc1-2
Reaction time: 8 h

Procedure:
In five portions 0.5 g (7.9 mmol) of sodium cyanoborohydride and 35 ml of a 1 M methanol solution of methanesulfonic acid was added over 4 hr to a solution of 2.0 g (6.1 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine in 50 ml of methanol which was cooled to 0°. When the addition was complete stirring was continued overnight at room temperature. The solution was basified with 40% aqueous sodium hydroxide and diluted with water. The resulting precipitate was collected by filtration to give a white solid. Recrystallization from a mixture of ether and methylene chloride gave colorless crystals, mp 211°-212°.
Reaction SMILES: C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C)[C:6]=1[CH3:12])C.[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24]CC#N>>[OH:16][CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][CH2:15][C:14]1[NH:3][C:4](=[O:13])[C:5]2[C:6]([CH:12]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCCN1CCC[C@@H]1CO
Product: O=c1[nH]c(CCCN2CCC[C@@H]2CO)cc2ccccc12
Yield: 16.8 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2,3-dimethylbenzamide (5.0136 g) and (R)-4-(2-hydroxymethylpyrrolidin-1-yl)butyronitrile (2.2 g), (R)-3-[3-(2-hydroxymethylpyrrolidin-1-yl)propyl]-2H-isoquinolin-1-one (627.3 mg) was obtained. 1N aqueous HCl solution (2.4 ml) was added thereto in an acetone solvent, and the precipitated crystals were collected by filtration to give (R)-3-[3-(2-hydroxymethylpyrrolidin-1-yl)propyl]-2H-isoquinolin-1-one hydrochloride (555.3 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15]CC=C)([CH3:4])([CH3:3])[CH3:2].[CH:19](OC(C)C)([CH3:21])[CH3:20]>>[CH2:21]([C:7]1[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]=1[OH:15])[CH:19]=[CH2:20]
Reactant: C=CCOc1ccc(C(C)(C)C)cc1C(C)(C)C
Reactant: CC(C)OC(C)C
Product: C=CCc1cc(C(C)(C)C)cc(C(C)(C)C)c1O

Procedure:
10 g of 2,4-di-tert-butylallyloxybenzene are heated under nitrogen to 245° C. for 45 minutes. The yellow crude oil is taken up in diisopropyl ether. The ether phase is washed with 3 % sodium hydroxide and then with water. After drying and evaporation of the solvent, the oil obtained (7.6 g) is chromatographed on silica gel 60 (eluent: 80/20 heptane/CH2Cl2). A pale-yellow oil of 2-allyl-4,6-di-tert-butylphenol is obtained (5.4 g, yield =54 %).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.CCOC(C)=O>[CH:13]1([CH2:12][CH2:11][NH:10][C:8]([C:5]2[N:6]=[N:7][C:2]([N:24]3[CH2:23][CH2:22][CH:21]([O:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[C:17]([F:16])([F:31])[F:32])[CH2:26][CH2:25]3)=[CH:3][CH:4]=2)=[O:9])[CH2:15][CH2:14]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nn1

Procedure:
A mixture of 6-chloro-N-(2-cyclopropylethyl)pyridazine-3-carboxamide (180 mg, 0.73 mmol), 4-[2-(trifluoromethyl)phenoxy]piperidine (150 mg, 0.67 mmol), potassium carbonate (184 mg, 1.33 mmol) and tetrabutylammonium iodide (7 mg, 0.02 mmol) in dioxane (10 mL) was refluxed for 2 days. After cooling, the mixture was diluted with EtOAc and filtered through celite. Solvent was removed in vacuo. Combi-Flash chromatography (10 g, 50-80% EtOAc in hexanes in 20 min, 20 mL/min, 18 mL/fraction) gave the title compound as a white powder. 1H NMR (500 MHz, acetone-d6): δ 0.11-0.13 (m, 2H), 0.45-0.49 (m, 2H), 0.76-0.84 (m, 1H), 1.56 (q, 2H), 2.13-2.20 (m, 4H), 3.52-3.56 (m, 2H), 3.91-3.97 (m, 2H), 4.00-4.06 (m, 2H), 5.01-5.05 (m, 1H), 7.12 (t, 1H), 7.37 (m, 2H), 7.61-7.67 (m, 2H), 7.92 (d, 1H), 8.24 (s, 1H); MS (+ESI) m/z 435 (MH+).