Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[S:24]1(=[O:30])(=[O:29])[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:4]=[CH:3][C:2]([N:25]4[CH2:26][CH2:27][CH2:28][S:24]4(=[O:30])=[O:29])=[CH:7][N:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=S1(=O)CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ncc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ncc(N4CCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 54.8 %

Procedure:
Using (5-bromopyrimidin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (188 mg) described in Preparation Example 229 and isothiazolidine 1,1-dioxide (61 mg) and by the reaction and treatment in the same manner as in Example 4, the title compound (114 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[C:5]([CH3:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:16]=1[OH:27].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][C:16]=1[O:27][C:6]1[C:5]([CH3:10])=[CH:4][C:3]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[C:7]=1[Cl:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Cl
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Oc1ccc(-c2ccccc2)cc1Cl
Temperature: 25 °C
Yield: 71.6 %

Procedure:
Into a 100 milliliter round bottom flask equipped with a thermometer, magnetic stirrer and condenser was added 12.0 grams (0.054 moles) of 2,5-dimethyl-3,4-dichloronitrobenzene, 14.5 grams (0.071 moles) of 2-chloro-4-phenylphenol, 12.0 grams (0.087 moles) of potassium carbonate and 20 milliliters of dimethylformamide (DMF) under a nitrogen atmosphere at ambient temperature. The reaction mixture was then heated in an oil bath at a temperature of 110° C.-120° C. for a periof of 72 hours. After cooling to ambient temperature, the reaction mixture was filtered through celite and concentrated (DMF removed under vaccum) to give an amber oil. The amber oil was dissolved in toluene and thereafter washed once with 4% sodium hydroxide, once with water and finally once with a saturated aqueous sodium chloride solution. The amber oil was then dried over sodium sulfate, concentrated (toluene removed under vacuum) and stirred into a hexane-ethyl acetate mixture (6:1 volume ratio). Crystallization from the hexane-ethyl acetate mixture and filtration afforded 15.02 grams of a tan powder having a melting point of 92.5° C.-94.0° C. Elemental analysis of the tan powder indicated the following:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[O:16]1[C:21]2[CH:22]=[CH:23][C:24]([CH:26]=O)=[CH:25][C:20]=2[O:19][CH2:18][CH2:17]1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:24]2[CH:23]=[CH:22][C:21]3[O:16][CH2:17][CH2:18][O:19][C:20]=3[CH:25]=2)[CH:8]=1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCCO3)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde using the method described in Example 1, Step A except the imine was formed in MeOH at reflux over 3 h. 1H NMR (400 MHz, CDCl3) δ 7.26-7.16 (m, 3H), 7.07 (d, 1H), 6.85-6.78 (m, 3H), 4.24 (s, 4H), 3.75 (s, 2H), 3.68 (s, 2H), 3.66 (s, 3H), 2.94 (t, 2H), 2.62 (t, 2H); MS 342 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)=[CH:4][CH:3]=1.[CH:28]([NH2:30])=[O:29]>C(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH:12]=[C:11]3[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:30][CH:28]=[O:29])=[CH:26][CH:27]=1
Reactant: Cn1c(=O)cc(-c2ccccc2)c2cc(C(=O)c3ccc(Cl)cc3)ccc21
Reactant: NC=O
Solvent: O=CO
Product: Cn1c(=O)cc(-c2ccccc2)c2cc(C(NC=O)c3ccc(Cl)cc3)ccc21
Temperature: 160 °C
Yield: 93 %

Procedure:
A mixture of 6-(4-chlorobenzoyl)-1-methyl-4-phenyl-2(1H)-quinolinone (24 g) in formamide (130 ml) and formic acid (100 ml) was stirred and heated at 160° C. for 12 hours. The mixture was poured into ice water and extracted with DCM. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The product was used without further purification, yielding 24.2 g (93%) of (±)-N-[(4-chlorophenyl)-(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)methyl]formamide (interm. 5-a).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27]([O:31][C@@H:32]([CH3:37])[C:33]([F:36])([F:35])[F:34])=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([O:16]C(C)(C)C)=[O:15]>ClCCl>[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27]([O:31][C@@H:32]([CH3:37])[C:33]([F:35])([F:36])[F:34])=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([OH:16])=[O:15]
Reactant: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)cc1Cl)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)O)cc2Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
Trifluoroacetic acid (4.4 mL, 58.7 mmol) was added to a solution of (S)-tert-butyl 5-chloro-4-((5-chloro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)oxy)-2-fluorobenzoate (Preparation 298, 9.2 g, 19.6 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 20 hours then concentrated in vacuo. The crude was purified by silica gel chromatography, eluting with heptane:ethyl acetate (from 95:5 to 40:60), to provide the title compound as a white solid (6.9 g, 85%).
Reaction SMILES: C([CH:3]1[CH2:8][CH:7]([C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][C:4]1=O)C.[NH:14]1[CH2:17][CH:16]([NH:18][C:19](=[O:36])[CH2:20][NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:10][C:9]([F:12])([F:11])[CH:7]1[CH2:8][CH2:3][CH:4]([N:14]2[CH2:15][CH:16]([NH:18][C:19](=[O:36])[CH2:20][NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:34])([F:33])[F:35])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH2:17]2)[CH2:5][CH2:6]1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCC1CC(C(F)(F)F)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(C(F)(F)F)CC2)C1

Procedure:
Reaction of ethyl 4-(trifluoromethyl)cyclohexanone with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product. 1H NMR (CHLOROFORM-d) δ: 8.60 (s, 1 H), 8.21 (t, J=5.4 Hz, 1 H), 8.12 (s, 1 H), 7.71-7.81 (m, 2 H), 6.92 (d, J=7.8 Hz, 1 H), 4.49-4.66 (m, 1 H), 4.28 (d, J=5.6 Hz, 2 H), 3.57 (t, J=7.5 Hz, 2 H), 2.85-3.00 (m, 2 H), 2.31 (t, J=3.2 Hz, 1 H), 1.89-2.14 (m, 2 H), 1.53-1.78 (m, 5 H), 1.28-1.42 (m, 2 H); ESI-MS (m/z): Calcd. For C21H23F6N5O: 475.18. found: 476 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12](OC)OC)[C:5]([NH2:7])=[O:6].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)[N:25]([CH3:38])[CH2:24][CH2:23][CH2:22]2.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[CH2:29][CH2:30][N:31]1[CH2:32][CH2:33][CH:34]([N:1]3[C:2]4[C:10](=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=4)[CH:11]=[CH:12]3)[CH2:35][CH2:36]1)[N:25]([CH3:38])[CH2:24][CH2:23][CH2:22]2
Reactant: COc1cc2c(cc1CCN1CCC(=O)CC1)N(C)CCC2
Reactant: COC(Cc1ccc(C(N)=O)cc1N)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)N(C)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
129 mg of 3-amino-4-(2,2-dimethoxyethyl)benzamide and 87 mg of 1-(2-(6-methoxy-1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)ethyl)piperidin-4-one were dissolved in 4 ml of acetic acid. Thereafter, 0.49 g of sodium sulfate was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 0.12 g of sodium triacetoxyborohydride was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 4 ml of water was further added to the reaction solution, and the obtained mixture was then stirred at 100° C. for 2 hours. The reaction solution was cooled to a room temperature, followed by concentration under a reduced pressure. A saturated sodium bicarbonate aqueous solution was added to the residue, followed by extraction with chloroform. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol) and by NH silica gel column chromatography (ethyl acetate), so as to obtain 70 mg of the subject compound.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16](OC(C)(C)C)=O)[CH2:12][CH2:11]2)[N:8]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.[Br:30][C:31]1C(Cl)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1>C(Cl)Cl>[Br:30][C:31]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][C:7]3[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[S:5][CH:6]=3)[CH2:15][CH2:14]2)=[C:33]([N+:38]([O-:40])=[O:39])[C:34]([NH2:37])=[N:35][CH:36]=1
Reactant: CC(C)c1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)cs1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reaction time: 1 h
Yield: 64.7 %

Procedure:
tert-Butyl 4-((2-isopropylthiazol-4-yl)methyl)piperazine-1-carboxylate (0.380 g, 1.15 mmol, 1.0 eq) was dissolved in DCM (3.6 mL) and the mixture cooled in an ice-water bath before the dropwise addition of TFA (3.6 mL). Stirring was continued at this temperature for 1 h and the solvents were removed in vacuo. The resulting crude material was azeotroped with toluene and dried. The resulting 2-isopropyl-4-(piperazin-1-ylmethyl)thiazole (supposedly 0.260 g, 1.15 mmol, 1.1 eq) was suspended in iPrOH (3.5 mL) and DIPEA (0.9 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.270 g, 1.05 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.300 g, 59%); 1H-NMR (500 MHz, DMSO-d6): δ 1.31 (d, J=7.0 Hz, 6H, iPr—CH3), 2.53-2.65 (br s, 4H, piperazine N(CH2)2), 3.06 (m, 4H, piperazine N(CH2)2), 3.20-3.33 (m, 1H, iPr—CH), 3.61 (s, 2H, NCH2), 6.96 (s, 2H, NH2), 7.31 (s, 1H, thiazole 5-H), 8.15 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.81 min—4411443 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:15]([CH2:16][CH2:17][C:18]=2[CH:19]=1)=[C:14]1[C:10]([C:11]([CH3:21])([CH3:20])[CH2:12][CH2:13]1)=[CH:9][CH:8]=3>O>[CH3:20][C:11]1([CH3:21])[C:10]2[C:14](=[C:15]3[C:7](=[CH:8][CH:9]=2)[C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:19][C:18]=2[CH2:17][CH2:16]3)[CH2:13][CH2:12]1
Reactant: COc1ccc2c(c1)CCc1c-2ccc2c1CCC2(C)C
Solvent: O
Product: CC1(C)CCc2c1ccc1c2CCc2cc(O)ccc2-1

Procedure:
A mixture of 26 parts of 7,15,16,17-tetrahydro-3-methoxy-17,17-dimethyl-6H-cyclopenta[ a]phenanthrene (Bull. soc. chim. France, 1968, 4886) and 150 parts of freshly-fused pyridine hydrochloride is heated in an atmosphere of nirogen at 220° for 1 1/2 hours. The reaction mixture is then poured into 200 parts of water, whereupon insoluble solids are filtered out, washed with water, dried in air, and crystallized from a mixture of ether and hexane to give 7,15,16,17-tetrahydro-17,17-dimethyl-6H-cyclopenta[a]phenanthren-3-ol melting at approximately 152°-153°, and having the formula ##STR6##
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:45][C:44]2[CH:46]=[CH:47][CH:48]=[C:42]([O:41][C:32]3[C:31]4[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=4)[N:35]=[CH:34][N:33]=3)[CH:43]=2)=[O:19])[N:7]([C:20]2[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cc1ncccc1-n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccnc4C)c3)c2cc1OC
Yield: 20 %

Procedure:
Phenyl 3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (105 mg, 0.3 mmol) was treated with 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.30 mmol) (prepared as described in Example 113A) using the procedure in Example 115C to afford 1-(3-tert-butyl-1-(2-methylpyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (33 mg, 0.06 mmol, 20%). 1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.60 (d, 1H), 8.54 (s, 1H), 8.35 (s, 1H), 7.80 (d, 1H), 7.54 (s, 2H), 7.45-7.32 (m, 3H), 7.12 (d, 1H), 6.91 (d, 1H), 6.35 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 2.20 (s, 3H) 1.25 (s, 9H); LC-MS (ESI) m/z 554 (M+H)+.
Reaction SMILES: [BrH:1].CN(C)[CH:4]=[CH:5][C:6]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)=[CH:7][C:8]#[N:9]>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[CH:5]=[CH:4][N:9]=1
Reactant: COc1cc(C(C=CN(C)C)=CC#N)cc(OC)c1OC
Reactant: Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2ccnc(Br)c2)cc(OC)c1OC
Yield: 62 %

Procedure:
Gaseous HBr was bubbled into a solution of 18 (3.6 g, 16.1 mmol) in chloroform for 15 minutes. The reaction was diluted with dichloromethane, washed with water, washed with brine, dried (MgSO4), and evaporated in vacuo to afford 3.2 g (62%) of 19 as an off-white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[CH3:46][C:47]([CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)=O>>[CH:49]1([CH:47]([N:42]2[CH2:43][CH2:44][CH2:45][C@@H:40]([CH2:39][NH:38][C:36]([C@H:32]3[CH2:33][CH2:34][CH2:35][N:31]3[C:29]([C@@H:4]3[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]3[C:7](=[O:28])[CH2:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:30])=[O:37])[CH2:41]2)[CH3:46])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: O=C(NC[C@@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)C1CCCCC1
Product: CC(C1CCCCC1)N1CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3R)-3-piperidylmethyl)pyrrolidine-2-carboxamide and cyclohexyl methyl ketone. The compound was obtained as a white solid.
Reaction SMILES: Br[CH:2]1[CH:6]2[O:7][C:8](=[O:11])[CH:9]3[CH2:10][CH:3]1[CH2:4][CH:5]23.[OH-:12].[Na+].Cl>O>[O:12]=[C:6]1[CH:5]2[CH2:4][CH:3]([CH2:10][CH:9]2[C:8]([OH:7])=[O:11])[CH2:2]1
Reactant: O=C1OC2C(Br)C3CC1C2C3
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC2CC(=O)C1C2

Procedure:
6-bromohexahydro-2H-3,5-methanocyclopenta[b]furan-2-one, 72a, (28.0 g, 129.0 mmol) was treated with NaOH (258.0 mL of 2 M solution, 516.0 mmol) in H2O (350 mL) for 2 hour at room temperature. The reaction mixture was acidified with conc. HCl, extracted with Et2O. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% MeOH/CH2Cl2 gradient) to provide 16 g of 6-oxonorbornane-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C[CH:13]([S:17][CH:18](S(C)=O)C)[S:14]([CH3:16])=[O:15].CO>C1COCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[C:13](/[S:14]([CH3:16])=[O:15])\[S:17][CH3:18]
Reactant: CC(SC(C)S(C)=O)S(C)=O
Reactant: COc1cccc(C=O)c1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(/C=C(\SC)S(C)=O)c1Cl

Procedure:
To a solution of 2-chloro-3-methoxybenzaldehyde (1.74 g, 10.0 mmol, 1.0 eq.) and methyl(methylsulfinyl)methyl sulfide (1.72 mL, 16.1 mmol, 1.6 eq.) in THF (9 mL), benzyltrimethylammonium hydroxide solution in methanol (2.3 mL, 10.0 mmol, 1.0 eq.) was added. The resulting solution was refluxed for 18 hours. The solvent was removed in vacuo. The residue was taken up in AcOEt and washed with 1M aq. HCl soln., water, and sat. aq. NaCl soln. The org. layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane+20% AcOEt to Heptane+65% AcOEt) to yield 2-chloro-1-((E)-2-methanesulfinyl-2-methylsulfanyl-vinyl)-3-methoxy-benzene as a pale orange oil.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15](=[NH:19])OCC.C(N(CC)CC)C.[C:27]1([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:41]3[C@H:37]([CH2:38][NH:39][CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:43]1([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:41]3[C@H:37]([CH2:38][N:39]([C:15](=[NH:19])[CH2:14][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[O:7][CH3:6])[CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reactant: CCOC(=N)Cc1ccccc1OC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=N)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Yield: 57 %

Procedure:
A solution of 1.56 g of ethyl (2-methoxyphenyl)-acetimidate tetrafluoroborate and 0.96 cm3 of triethylamine in 20 cm3 of dry dichloromethane is added to a solution of 2 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol in 30 cm3 of dry dichloromethane, and the reaction mixture is then refluxed for 2 hours. 10 cm3 of a 10% aqueous solution of potassium carbonate are then added, the mixture is decanted and then the organic phase is washed with 20 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on an alumina column (diameter 3.6 cm, height 31 cm), eluting under a nitrogen pressure of 0.1 bar with a dichloromethane and methanol mixture (95/5 by volume) and collecting fractions of 50 cm3. Fractions 5 to 30 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is washed with isopropyl oxide, drained and dried. 1.4 g of (3aR,4S,7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl]-4-perhydroisoindolol are obtained in the form of white crystals; melting point 105° C., with decomposition.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[F:17][C:18]1[CH:19]=[C:20]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:21]=[C:22]([CH3:24])[CH:23]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:20]3[CH:21]=[C:22]([CH3:24])[CH:23]=[C:18]([F:17])[CH:19]=3)=[O:32])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1cc(F)cc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: Cc1cc(F)cc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure Z2, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-fluoro-5-methyl-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:18])=[C:4]2[NH:10][C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[C:3]([Cl:18])=[C:4]2[NH:10][C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH:15][S:27]([C:24]4[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=4)(=[O:29])=[O:28])=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(-c2nc3ncc(Cl)c(Cl)c3[nH]2)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(-c3nc4ncc(Cl)c(Cl)c4[nH]3)cc2)cc1

Procedure:
By a procedure similar to Example 261 but using 4-(6,7-dichloro-1H-imidazo[4,5-b]pyridin-2-yl)aniline and 4-methoxybenzenesulfonyl chloride the title compound was obtained as the trifluoroacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([OH:21])=O)[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH:10]([CH3:26])[N:9]=1.O[N:28]1[C:32]2C=[CH:34][CH:35]=[CH:36][C:31]=2N=N1.N1CCCCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([CH2:18][C:19]([N:28]3[CH2:34][CH2:35][CH2:36][CH2:31][CH2:32]3)=[O:21])[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH:10]([CH3:26])[N:9]=1
Reactant: Cc1nnc2n1-c1sc(CC(=O)O)cc1C(c1ccccc1Cl)=NC2C
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: Cc1nnc2n1-c1sc(CC(=O)N3CCCCC3)cc1C(c1ccccc1Cl)=NC2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
To a solution of 1.1 g of 2-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]acetic acid in 15 ml of dimethylformamide are added 0.4 g of N-hydroxybenzotriazole and 0.3 g of piperidine and stirred at room temperature for 10 minutes. To the mixture is added 0.65 g of dicyclohexyl carbodiimide under ice-cooling and stirred for 1 hour and furthermore stirred at room temperature for 21 hours. The resulting dicyclohexylurea is filtered off and to the filtrate is added 100 ml of chloroform. The solution is washed with 5% aqueous sodium hydrogen-carbonate solution and water and dried over anhydrous magnesium sulfate. After separating by filtration, the filtrate is concentrated under reduced pressure and the residue is crystallized from isopropyl ether. The precipitated crystals are collected by filtration and recrystallized from ethyl acetate to give 0.9 g of 2-[4-(2-chlorophenyl)-6,9-dimethyl-6H-thieno[3,2-f][1,2,4 ]triazolo[4,3-a][1,4]diazepin-2-yl]acetic acid piperidide as colorless crystals, melting at 182°-183° C.