Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O>[N:29]1([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:1])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C1CCNCC1
Reactant: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@@H]6O[C@@H]6C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1
Solvent: O
Product: CN1CCN([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCCCC6)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2O)CC1

Procedure:
14.8 g (0.03 mole) of 2α,3α-epoxy-17β-hydroxy-16β-N-methyl-piperazino-5α-androstane (Example 10) are dissolved in 168 ml (1.65 moles) of piperidine and 24 ml of water, whereafter the reaction mixture is heated in a bomb tube of 72 hours at a temperature of 140° C. After the reaction is accomplished the reaction mixture is evaporated at reduced pressure. The residue is stirred in acetonitrile, filtered and the product above the filter is heated under reflux in acetonitrile. The crystallized product is filtered and dried. Yield: 12.4 g (69.0%) of 2β-piperidino-16β-N-methyl-piperazino-3α,17β-dihydroxy-5α-androstane; m.p. 154°-156° C; [α]D25 = +84.5° (c = 1 in chloroform).
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[NH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)=[O:23].[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48](O)=[O:49])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl>[O:23]=[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:32])([F:33])[F:34])[CH:25]=1)[CH2:21][NH:20][C:48]([CH:45]1[CH2:46][CH2:47][N:42]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:43][CH2:44]1)=[O:49]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCC(=O)c1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2cccc(OC(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.1 %

Procedure:
Add triethylamine (1.1 mL, 7.89 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (1.51 g, 7.87 mmol) to a solution of 2-amino-1-(3-(trifluoromethoxy)phenyl)ethanone (1.56 g, 6.10 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.66 g, 7.24 mmol) in CH2Cl2 (15 mL) at 0° C. Stir at 0° C. for 3 h, then at room temperature overnight. Concentrate the mixture in vacuo. Purify the residue by silica gel chromatography (80 g SiO2 eluting with 50% ethyl acetate/hexanes, 1 L) to provide tert-butyl 4-(2-oxo-2-(3-(trifluoromethoxy)phenyl)ethylcarbamoyl)piperidine-1-carboxylate (1.50 g, 57%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:44])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[C:34]([CH2:35][O:36]C3CCCCO3)=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:36][CH2:35][C:34]1[N:30]([C:26]2[CH:25]=[C:24]([C:23]3[CH2:22][C:21](=[O:44])[NH:20][C:9]4[CH:10]=[C:11]([CH3:19])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[N:31]=[N:32][CH:33]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-methyl-5-(methyl-propyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M80) (0.42 g, 0.71 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a pale yellow solid (200 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:8])=[CH:4][C:3]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: O=C(O)c1ccc(Br)c(OCC(F)(F)F)c1
Reactant: C1CCNC1
Product: O=C(c1ccc(Br)c(OCC(F)(F)F)c1)N1CCCC1

Procedure:
Starting with 4-bromo-3-(2,2,2-trifluoroethoxy)benzoic acid and pyrrolidin, Int06.06 was prepared analogously to the procedure for the preparation of Int02.05.
Reaction SMILES: [NH:1]([C:3]1[C:4]2[C:14](=O)[CH:13]([C:16]([O:18]CC)=[O:17])[CH2:12][N:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:5]=2[N:6]=[C:7]([S:9][CH3:10])[N:8]=1)[NH2:2].[OH-].[Na+]>C(O)C>[CH3:10][S:9][C:7]1[N:6]=[C:5]2[C:4]3[C:14](=[N:2][NH:1][C:3]=3[N:8]=1)[CH:13]([C:16]([OH:18])=[O:17])[CH2:12][N:11]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1CN(c2ccccc2)c2nc(SC)nc(NN)c2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc2c3c(n[nH]c3n1)C(C(=O)O)CN2c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 114.1 %

Procedure:
Crude ethyl 4-hydrazinyl-2-(methylthio)-5-oxo-8-phenyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (20 g), was dissolved in ethanol (300 mL). Aqueous sodium hydroxide (300 mL) (22.52 g, 563 mmol) was added. The reaction mixture was warmed to 60° C. and stirred for 3 h. Upon completion of the reaction (TLC, LCMS), ethanol was removed under reduced pressure and the aqueous layer was acidified using 10% citric acid. The aqueous layer was then extracted with dichloromethane (200 mL×3). The combined organic layers were washed with water (500 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give crude 7-(methylthio)-5-phenyl-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene-3-carboxylic acid (20 g). The crude product was used for decarboxylation in the next step without purification. LCMS [M+H]: 328
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][OH:18])[CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[H-].[Na+].Cl[C:22]1[CH:23]=[C:24]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:16])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH2:17][O:18][C:22]1[CH:23]=[C:24]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2ccc(F)cc2)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cc(F)c(Oc3ccc(F)cc3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (3,5-difluoro-4-(4-fluorophenoxy)phenyl)methanol, NaH and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1 (5H)-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:26]([CH3:25])[C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:15][C@@H:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:12][C@@H:11]3[CH2:13]2)[CH:17]=[N:18][CH:19]=1)=[O:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: CNCc1ccccc1
Product: CN(Cc1ccccc1)C(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1

Procedure:
The product from Example 33B and N-methylbenzylamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 437 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:28][CH2:27]3)=[O:24])=[CH:19][CH:18]=1)=[CH:13][CH:12]=[C:11]([Cl:39])[CH:10]=2)=[O:5])C.[OH-].[Na+].Cl>CO>[Cl:39][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH:26]4[CH2:27][CH2:28][N:29]([CH2:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH2:30][CH2:31]4)=[O:24])=[CH:21][CH:22]=3)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1cnc2cc(Cl)ccc2c1Nc1ccc(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2c(C(=O)O)cnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Yield: 64 %

Procedure:
7-Chloro-4-[[4-[[[1-(phenylmethyl)-4piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid ethyl ester (51.7 g, 95.2 mmol) was stirred in 550 ml of methanol and treated with 133 ml of 2.5 M NaOH. The reaction mixture was then refluxed for 45 m at which point the hot homogeneous solution was treated with 166 ml of 2 M HCl to precipitate the product. After the mixture cooled to room temperature, the product was filtered and washed with water, methanol and then ether. The yellow powdery material was then dried in vacuo overnight affording 31.3 g (60.9 mmol, 64% yield) of 7-chloro-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C(OCC)C>[CH:21]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1
Reactant: BrC1C=CCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(C3C=CCCC3)c2)OC1(C)C
Temperature: 90 °C
Reaction time: 8 h

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (250 mg, 1.29 mmol), 3-bromocyclohexene (0.17 mL, 1.42 mmol), and cesium carbonate (462 mg, 1.42 mmol) were added to an oven-dried flask, followed by DMF (4.3 mL). The reaction mixture was stirred at 90° C. overnight then cooled to room temperature, diluted with diethyl ether, washed with water (3×50 mL) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 1-(cyclohex-2-en-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H NMR (500 MHz, CD3OD) δ 7.82 (s, 1H), 7.69 (s, 1H), 5.81-5.62 (m, 2H), 4.15-4.09 (m, 1H), 2.24-1.41 (m, 6H), 1.31 (s, 12H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:41])([F:40])[C:28]1[C:29]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:30][CH:31]=[CH:32][CH:33]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:37]3[CH2:38][CH2:39][N:34]([C:29]4[C:28]([C:27]([F:41])([F:26])[F:40])=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:35][CH2:36]3)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
1-Benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid was coupled with 1-[3-(trifluoromethyl)pyrid-2-yl]piperazine to give the title compound as a colorless solid. MS: 593.7 ([M+H]+)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([OH:22])=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][CH:32]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:33]([OH:38])[C:34]([F:37])([F:36])[F:35].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:31][CH:32]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:33]([OH:38])[C:34]([F:35])([F:36])[F:37])=[O:22])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:31][CH:32]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:33](=[O:38])[C:34]([F:35])([F:36])[F:37])=[O:21])[C:15]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Reactant: COc1ccc(-c2ncc(NC(=O)OCc3ccccc3)c(=O)n2CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncc(NC(=O)OCc3ccccc3)c(=O)n2CC(=O)NC(Cc2ccccc2)C(=O)C(F)(F)F)cc1
Product: COc1ccc(-c2ncc(NC(=O)OCc3ccccc3)c(=O)n2CC(=O)NC(Cc2ccccc2)C(O)C(F)(F)F)cc1

Procedure:
2-[5-Benzyloxycarbonylamino-2-(4-methoxyphenyl)-6-oxo-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, [5-benzyloxycarbonylamino-2-(4-methoxyphenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 14, 5.00 g, 12.2 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 2.94 g, 13.4 mmol), WSCI hydrochloride (2.81 g, 14.7 mmol) and HOBT (3.29 g, 24.3 mmol) in DMF (40 mL) to give 7.23 g (97%) of the target compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:18]([O:25][C:26]1[CH:27]=[C:28](Br)[CH:29]=[CH:30][CH:31]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Mg].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:6]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:27]=2)[OH:7])[C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(C)c(C(O)c2cccc(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Reaction time: 2 h
Yield: 94.8 %

Procedure:
An anhydrous tetrahydrofuran (50 ml) solution of 3,4,5,6-tetramethoxy-2-methylbenzaldehyde (14 g, 0.058 mol) was added dropwise under ice cooling to a Grignard reagent (150 ml tetrahydrofuran solution) prepared from 3-(benzyloxy)bromobenzene (18.4 g, 0.070 mol) and magnesium (1.87 g, 0.077 mol), and the resulting solution was stirred for 2 hours. The reaction solution was poured in an aqueous solution of saturated ammonium chloride and extracted with ether. The extract was washed with saturated brine and then dried. The reaction solution was filtered, the filtrate was concentrated and the obtained crude product was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (23.5 g, 0.055 mol, 95%).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][O:12]C)=[CH:6][CH:5]=1.Cl>CC(C)=O>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]=[O:12])=[CH:8][CH:9]=1
Reactant: COC=Cc1ccc(OC(F)F)cc1
Agent: Cl
Solvent: CC(C)=O
Product: O=CCc1ccc(OC(F)F)cc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a solution of 1-difluoromethoxy-4-((E,Z)-2-methoxyvinyl)-benzene (E/Z ratio ˜3:2,) (1.58 g, 7.9 mmol, from step (i) above ) in acetone (20 mL) was added 3 M HCl (3.7 mL, 11.1 mmol) and the solution was stirred at 45° C. for 4 h. After concentration under reduced pressure, water (25 mL) was added to the residue and the aqueous phase was extracted with diethylether (2×50 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give 1.32 g of crude product as a yellow oil with a purity of ca. 80%. The crude product was used directly in the subsequent reduction step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:25][C@H:26]1[O:28][CH2:27]1)(=O)=O>CN(C)C=O>[O:28]1[CH2:27][CH:26]1[CH2:25][O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[CH2:10][C@H:11]1[CH2:16][CH2:15][O:14][C:12]1=[O:13]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=C1OCCC1Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCC[C@@H]1Cc1ccccc1OCC1CO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 106.2 %

Procedure:
Dimethylformamide (100 ml) and potassium carbonate (10 g) were added to α-(2′-hydroxybenzyl)-γ-butyrolactone (5.0 g), and (S)-glycidyl nosylate (6 g) was added. The mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure and water was added. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (6.1 g).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:13][C:14]1([CH3:17])[CH2:16][O:15]1>>[I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:13][C:14]([CH3:17])([OH:15])[CH3:16])[CH:6]=1
Reactant: CC1(C)CO1
Reactant: Ic1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(O)Cn1cnc(I)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
A mixture of 4-iodo-1H-imidazole, Cs2CO3 in 2,2-dimethyl oxirane was stirred at 120° C. for 20 min under irradiation with microwave. The reaction mixture was concentrated, and purified to give 1-(4-iodo-1H-imidazol-1-yl)-2-methylpropan-2-ol (Yield=71%). LC-MS: m/z=266 [M+H+] 1H NMR (CDCl3, 400 MHz): δ7.36 (s, 1 H), 7.06 (s, 1 H), 3.84 (s, 2 H), 1.22 (s, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH2:22][NH:21][CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1.C(N(CC)CC)C.[C:32]([Cl:40])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[ClH:40].[CH3:1][O:2][C:3]1[C:4]([O:23][CH3:24])=[CH:5][C:6]2[CH2:7][CH:8]3[CH2:22][N:21]([C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:20][CH2:19][N:9]3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]=2[CH:12]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N1CCNCC1C2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)C(c1ccccc1)N1CCN(C(=O)c3ccccc3)CC1C2
Product: Cl
Reaction time: 0.5 h

Procedure:
8,9-Dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline (the compound obtained in Example 1-(6)) (1.6 g) is dissolved in methylene chloride (10 ml), and thereto are added triethylamine (0.8 ml) and benzoyl chloride (0.6 ml) under ice-cooling, and the mixture is stirred for 30 minutes. The reaction solution is washed with a saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; chloroform:ethyl acetate=9:1). The resulting residue is dissolved in chloroform, and thereto is added a 4M hydrochloric acid in ethyl acetate, and the solvent is removed by evaporation under reduced pressure. The resultant is crystallized from ethyl acetate, and the crystals thus obtained are collected by filtration to give 8,9-dimethoxy-2-benzoyl-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino[1,2-b]isoquinoline hydrochloride (656 mg).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[CH3:32])[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][C:30]=4[CH3:32])[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc2ncnc(Cl)c12
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Product: Cc1cccc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c12

Procedure:
To 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (83 mg, 0.3 mmol) was added 4-chloro-5-methylquinazoline from the previous step (53 mg, 0.3 mmol) using the procedure described in Example 1B Step 1, to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH:13]=[O:14].[C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH3:16]>CC(=O)OCC>[C:19]([O:18][C:15](=[O:17])[CH2:16][CH:13]([OH:14])[C:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=2)[N:9]=[CH:8][CH:7]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc2nccc(C=O)c2n1
Reactant: CC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: COc1ccc2nccc(C(O)CC(=O)OC(C)(C)C)c2n1

Procedure:
The aldol reaction between 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (1.9 g, 10 mmol, WO 2006/032466) and tert-butyl acetate (1.2 g, 10.5 mmol) was carried out as described in the literature (J. Org. Chem. (1990), 55, 4744-4750). The title compound was isolated after chromatography on SiO2 (Hex/EA 1:1) as a beige solid (2.33 g, 77% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:49][CH3:50])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([O:44]COC)([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH3:48])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][C:19]=2[CH3:51])=[CH:14][CH:13]=1>ClCCl>[CH3:8][O:9][C:10](=[O:52])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:25][CH3:26])([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[C:34][C:35]([OH:44])([C:40]([F:41])([F:43])[F:42])[C:36]([F:39])([F:37])[F:38])=[C:29]([CH3:48])[CH:28]=3)[CH2:49][CH3:50])=[CH:20][C:19]=2[CH3:51])=[CH:14][CH:13]=1
Reactant: CCC(CC)(c1ccc(C#CC(OCOC)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
Trifluoroacetic acid (0.2 mL) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-methoxymethoxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 45-(1); 44.9 mg, 0.071 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the target compound as a colorless oil (20 mg, 48%).