Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=O)[O:22]C(C)(C)C)[N:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=2)[N:6]=1.[C:28]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH3:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:22])[CH2:5][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:15]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(NC(=O)OC(C)(C)C)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(-c2nc(NC(=O)Cc3ccccc3)sc2-c2ccnc(NC(=O)Cc3ccccc3)n2)c1
Temperature: 80 °C
Reaction time: 14 h
Yield: 26.6 %

Procedure:
To a solution of tert-butyl 4-[2-amino-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyrimidinylcarbamate (0.50 g, 1.3 mmol) in N,N-dimethylacetamide (5 mL) was added phenylacetylchloride (0.52 mL, 3.9 mmol) and the mixture was stirred at 80° C. for 14 hrs. Into the reaction mixture was poured aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried and concentrated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate=7:3), and the obtained oil was recrystallized from ethyl ether to give the title compound (0.09 g, yield 13%).
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[CH2:11][CH:10]([NH:12]C(=O)C)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:16]3[C:21](=[O:22])[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:36]5[NH:40][C:39](=[O:41])[O:38][N:37]=5)=[CH:26][CH:25]=4)=[C:19]([CH2:42][CH2:43][CH3:44])[N:18]=[C:17]3[CH3:45])[CH:8]=2)[O:3]1>Cl.O1CCOCC1.C(OCC)(=O)C>[NH2:12][CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:16]3[C:21](=[O:22])[C:20]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:36]5[NH:40][C:39](=[O:41])[O:38][N:37]=5)=[CH:28][CH:29]=4)=[C:19]([CH2:42][CH2:43][CH3:44])[N:18]=[C:17]3[CH3:45])[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:46])[CH2:11]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(NC(C)=O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(N)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Yield: 89.4 %

Procedure:
N-{2,2-Dimethyl-6-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]-3,4-dihydro-2H-chromen-4-yl}acetamide (0.30 g) was dissolved in 6 M hydrochloric acid (1 mL) and 1,4-dioxane (2 mL), and the mixture was stirred at 90° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.25 g, 90%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH2:29]OCC4C=CC=CC=4)(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[ClH:38].[CH3:39][OH:40]>[Pd]>[ClH:38].[ClH:38].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH2:29][CH2:39][OH:40])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCOCc4ccccc4)cc3)cc3ccccc23)CC1
Reactant: CO
Agent: [Pd]
Agent: Cl
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)CCCO)cc3)cc3ccccc23)CC1
Reaction time: 24 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-[4-(2-benzyloxyethyl)sulfonylphenyl]isoquinoline (2.56 g) was converted into a hydrochloride in a conventional manner. The resulting hydrochloride was then dissolved in methanol (50 ml), followed by the addition of 10% palladium/carbon catalyst (0.07 g), and the catalytic reduction was conducted at atmospheric pressure overnight. The 10% palladium/carbon catalyst (0.05 g) was additionally added thereto, and the catalytic reduction was conducted at atmospheric pressure for 1 day. The catalyst was filtered off, while the solvent was evaporated. Water was added to the resulting residue, followed by the addition of a 1N aqueous solution of sodium hydroxide to adjust to pH 8, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1.23 g of the free compound of the title compound as a pale yellow amorphous.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C)c(C(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J23) (290 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (330 mg, 63%).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C.[OH-].[Na+]>OS(O)(=O)=O.CO>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: COC(=O)C(C)O
Reactant: CCCCCCCCCCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCOC(=O)C(C)O
Yield: 180.9 %

Procedure:
A 250 mL round bottom flask equipped with a spin bar and a distillation column was charged with 100 g (0.96 moles) of methyl lactate, 304.1 g (1.92 moles) of decyl alcohol, and 500 mg of H2SO4. The reaction was heated until methanol formation ceased. The reaction was then neutralized with 0.1N NaOH (100 mL) and extracted with ether. The organic layer was dried over MgSO4, filtered and dried in vacuo to give 400 g of crude mixture. The fractional distillation was carried out three times to give 98.5 g (45% yield, 100% pure by GC) of a clear colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1.Cl>O1CCCC1.O>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)[OH:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([S:35]([C:38]2[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1
Reactant: O=C[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Reactant: Brc1ccccn1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(O)c2ccccn2)C1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 55.6 %

Procedure:
2-Bromopyridine (6.50 g, 40 mmol) was added to isopropyl magnesium chloride (2.0 M solution in tetrahydrofuran, 20 mL, 40 mmol) at room temperature. The mixture was stirred for 10 minutes then warmed to 30° C. and stirred for 105 minutes. The mixture was cooled to −10° C. and a solution of (R)-1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (5.5 g, 10 mmol) in tetrahydrofuran (9 mL) was added dropwise. The reaction mixture was stirred for 15 minutes at −10° C. followed by stirring at room temperature for 1 hour. The reaction mixture was cooled and treated with water (20 mL) followed by aqueous hydrochloric acid (1.0 M, 40 mL). The mixture was stirred for 10 minutes then extracted with dichloromethane (×2) and the combined organic phases dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue purified by column chromatography on silica gel (gradient: 20-80% ethyl acetate in cyclohexane) to afford the diastereoisomeric (2:1) mixture (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)-(R/S)-methanol as an off-white foam (3.25 g). 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J=4.8 Hz, 1 H); 8.00 (d, J=8.2 Hz, 2 H); 7.84-7.86 (m, 3 H); 7.44-7.46 (m, 1 H); 7.29-7.30 (m, 1.5 H); 7.09-7.10 (m, 3.5 H); 6.95-6.97 (m, 2.5 H); 6.41 (s, 0.5 H); 6.18 (s, 1 H); 5.11 (s, 0.5 H); 5.04 (s, 1 H); 4.87 (s, 1 H); 4.50 (d, J=11.8 Hz, 1 H); 4.10 (d, J=13.3 Hz, 2.5 H); 3.80 (d, J=12.1 Hz, 0.5 H); 3.69 (s, 0.5 H); 3.24 (d, J=16.6 Hz, 1 H); 3.09-3.13 (m, 1.5 H); 2.54-2.58 (m, 2.5 H); 2.25-2.27 (m, 1 H); 2.11 (d, J=16.6 Hz, 1 H); 1.43 (s, 0.5 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[CH:2].CCOC(C)=O>CO.[Pd]>[NH2:10][C:6]1[C:7]([F:9])=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=1
Reactant: C#Cc1cc(F)c([N+](=O)[O-])cc1CC(=O)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)Cc1cc(N)c(F)cc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
Ethyl 2-(2-ethynyl-4-fluoro-5-nitrophenyl)acetate (160 mg, 0.64 mmol) was dissolved in MeOH (5 mL) and EtOAc (5 mL) and then Pd—C (20 mg) was added. The reaction mixture was shaken in a Parr hydrogenator (46 psi) overnight at RT. The reaction mixture was filtered, washed with methanol, and concentrated to obtain ethyl 2-(5-amino-2-ethyl-4-fluorophenyl)acetate (135 mg, 93% yield). MS (ESI) m/z: 226.2 (M+H+).
Reaction SMILES: F.N1C=CC=CC=1.[Si]([O:25][CH2:26][C@@H:27]([NH:48][C:49]([C:51]1[S:52][C:53]2[CH2:54][N:55]([CH3:60])[CH2:56][CH2:57][C:58]=2[N:59]=1)=[O:50])[C@H:28]([NH:35][C:36]([C:38]1[NH:39][C:40]2[C:45]([CH:46]=1)=[CH:44][C:43]([Cl:47])=[CH:42][CH:41]=2)=[O:37])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1>[Cl:47][C:43]1[CH:44]=[C:45]2[C:40](=[CH:41][CH:42]=1)[NH:39][C:38]([C:36]([NH:35][C@@H:28]([C@H:27]([NH:48][C:49]([C:51]1[S:52][C:53]3[CH2:54][N:55]([CH3:60])[CH2:56][CH2:57][C:58]=3[N:59]=1)=[O:50])[CH2:26][OH:25])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:37])=[CH:46]2
Reactant: CCOC(=O)C[C@@H](NC(=O)c1cc2cc(Cl)ccc2[nH]1)[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1nc2c(s1)CN(C)CC2
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C[C@@H](NC(=O)c1cc2cc(Cl)ccc2[nH]1)[C@@H](CO)NC(=O)c1nc2c(s1)CN(C)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
After hydrogen fluoride.pyridine (0.4 ml) was added dropwise to a mixture sulution composed of the compound (0.54 g) obtained in Example 175, pyridine (4.0 ml) and tetrahydrofuran (10 ml) under ice cooling, the reaction mixture was stirred for 18 hours while the temperature thereof was gradually raised to room temperature. The reaction mixture was concentrated, and the resultant residue was purified by column chromatography on silica gel (chloroform:methanol=9:1) to obtain the title compound (0.31 g).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2C=C[CH:49]=[C:50]([NH:51][C:52]([NH:54][N:55]([CH3:57])[CH3:56])=[O:53])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.CCO[CH2:62][CH3:63].CO.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:50]([NH:51][C:52]([NH:54][N:55]([CH3:56])[CH3:57])=[O:53])[CH:49]=[CH:62][C:63]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(NC(=O)NN(C)C)cccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCc1nc2ccc(NC(=O)NN(C)C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared in analogous manner to Example 58b from 4'-[(2-n-butyl-4-dimethylaminoaminocarbonylamino-benzimidazol-1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and hydrochloric acid in ether/methanol/methylene chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:23]#[N:24])[CH:5]=[CH:6][C:7]=1[Br:8].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]([C:23]#[N:24])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([Br:8])=[C:2]([Br:1])[CH:3]=1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Nc1ccc(Br)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Br)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
A mixture of 4.90 g (10.9 mmol) of 4-[(3,4-dibromophenyl)amino]-6-nitro-quinoline-3-carbonitrile and 12.4 g (54.7 mmol) of SnCl2 dihydrate in 200 mL of ethanol was refluxed under N2 for 1.5 h. After cooling to 25° C., the reaction was diluted with ice water, neutralized with sodium bicarbonate and stirred for 2 h. This solution was then extracted with chloroform, treated with Darco, dried(magnesium sulfate) and evaporated. After drying in vacuo (40° C.), there was obtained 1.25 g of brown solid: mass spectrum (electrospray, m/e): M+H 417, 419, 421.
Reaction SMILES: [BH4-].[Na+].[N:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([C:6]3=[O:13])[CH2:4]1)[CH2:10]2>CO.[Cl-].[Na+].O>[N:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH:6]3[OH:13])[CH2:4]1)[CH2:10]2
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC1C2CC3CC1CN(C3)C2
Temperature: 0 °C

Procedure:
Sodium borohydride (0.7 g) is added to 20 ml of ice-chilled MeOH. Then 1.88 g (0.012 mole) of 1-azatricyclo[3.3.1.13,7 ]decane-4-one, in 20 ml MeOH, is added dropwise over 5 minutes. A further 0.8 g NaBH4 (total 1.5 g, 0.04 mole) is added portionwise over 5 minutes. The reaction is stirred in ice one-half hour more, and then 1 hour at room temperature. The reaction is diluted with 20 ml brine, and extracted into ether. The ether is dried over MgSO4 and stripped to dryness, to give 1-azatricyclo-[3.3.1.13,7 ]decane-4-ol.
Reaction SMILES: ClC1C=CC=CC=1[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=O.[C:19]([O:25][CH3:26])(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22]>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:9]1[O:22][C:21]([CH3:23])=[C:20]([C:19]([O:25][CH3:26])=[O:24])[CH:8]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(Cc1ccccc1Cl)c1ccc(F)cc1F
Product: COC(=O)c1cc(-c2ccc(F)cc2F)oc1C
Yield: 57.3 %

Procedure:
An operation similar to that in Example 1 (1) was performed using 2-chloro-2′,4′-difluorophenylacetophenone (19 g) and methyl acetoacetate (11 g) to give the title compound (10.3 g, 41%) as a yellow crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:20]([OH:23])[C:21]#[CH:22]>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([C:22]#[C:21][CH2:20][OH:23])[CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2CC(c3cccc(I)c3)=NO2)cc1
Reactant: C#CCO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCC#Cc1cccc(C2=NOC(c3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of the product of Step 1, above (13, 5.5 g, 15 mmol) in triethylamine (40 ml), was added bis(triphenylphosphine)palladium (II) chloride (0.63 g, 0.9 mmol) and propargyl alcohol (1.4 g, 25 mmol) under a nitrogen atmosphere. After stirring at room temperature for 1 hour, Cul (0.25 g, 1.3 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 18 hours, insolubles were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and water (100 ml) and the aqueous layer were separated and extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with aqueous 1N HCl (150 ml), aqueous NaHCO3 (150 ml) and brine (150 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent=ethyl acetate:n-hexane, 1:4) to give 4.3 g (95% yield) of the title compound (14) as pale yellow solids.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11]Br)[S:9][CH:10]=1)=[O:5])[CH3:2].[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:16]([O:28][CH3:29])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:27][C:24]2[CH:23]=[CH:22][C:21]([C:17]3[CH:18]=[C:19]([F:20])[C:14]([F:13])=[CH:15][C:16]=3[O:28][CH3:29])=[CH:26][CH:25]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)n1
Temperature: 130 °C
Yield: 89.5 %

Procedure:
A mixture of 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (prepared according to US 2004/0266856 A1) (3.0 g, 11.99 mmol), 4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (3.09 g, 13.08 mmol), potassium carbonate (6.5 g, 47.03 mmol) and potassium iodide (1.1 g, 6.626 mmol) in DMF (25 mL) was heated under microwave conditions at 130° C. for 15 min. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3×150 mL). The organic layers were combined, washed with 1/1 water/brine (2×100 mL) and brine (100 mL), dried (MgSO4), filtered, concentrated and purified by flash chromatography (silica, 120 g, 20% to 100% ethyl acetate in hexanes) to give 2-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid ethyl ester (4.35 g, 89.5%) as an orange oil. LC-MS (ES) calculated for C20H17F2NO4S, 405.42; found m/z 406 [M+H]+.
Reaction SMILES: C([N:11]=[C:12]([NH:25]C(OCC1C=CC=CC=1)=O)[NH:13][CH2:14][CH2:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21](=[O:23])[CH3:22])[C:18]1=[O:24])(OCC1C=CC=CC=1)=O.[ClH:36]>[Pd].CO.C(OCC)(=O)C>[ClH:36].[NH:13]([CH2:14][CH2:15][CH2:16][CH:17]1[CH2:20][N:19]([C:21](=[O:23])[CH3:22])[C:18]1=[O:24])[C:12]([NH2:25])=[NH:11]
Reactant: CC(=O)N1CC(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(CCCNC(=N)N)C1=O
Yield: 69 %

Procedure:
A methanol/ethyl acetate (2.5 mL/2.5 mL) solution of compound 20 (255 mg, 0.58 mmol) and 1N HCl (0.58 mL), containing 10% palladium on carbon, was stirred under a hydrogen atmosphere until TLC indicated the disappearance of the starting material (about 10 min). The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 99 mg (69%) of the title compound as a yellow foam.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.[H-].[Na+].F[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[CH3:23])[C:19](=[O:24])[N:18]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH:17]=[CH:16]2>CC(N(C)C)=O>[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=2[CH3:23])[C:19](=[O:24])[N:18]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[CH:17]=[CH:16]3)[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@H](N)CC4)c(C)cc3c2=O)cc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.48 g (9.75 mmol) of trans-4-aminocyclohexanol hydrochloride in 20 ml of dimethylacetamide were added 1.95 g (48.77 mmol) of sodium hydride (60%) and the mixture was stirred for 15 minutes. Subsequently 2.90 g (9.75 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one in 30 ml of dimethylacetamide were added and the reaction mixture was heated to 80° C. for 2 days. After cooling, the mixture was poured into 300 ml of ice water and the precipitated crude product was purified by chromatography. First the remaining starting material was eluted with ethyl acetate/heptane (2:1) and finally the desired product was eluted by pure methanol giving 1.98 g 6-(trans-4-amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=2)[N:4]=1.O[CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[F:18][C:2]([F:17])([F:1])[C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[C:10]([CH3:16])[CH:9]=2)[N:4]=1
Reactant: OCCCCc1cccnc1
Reactant: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(-c2noc(C(F)(F)F)n2)cc(C)c1OCCCCc1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.2 %

Procedure:
To a suspension of 0.44 g (1.8 mmol) of 4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenol, 0.25 g (1.66 mmol) of 3-(4-hydroxybutyl)-pyridine, and 0.52 g (1.99 mmol) of triphenylphosphine in 30 ml of methylene chloride under nitrogen at 0° C. was added dropwise a solution of 0.35 g (1.97 mmol of DEAD in methylene chloride, and the resulting mixture was allowed to warm to room temperature. After adding 70 mg of triphenylphosphine, the mixture was stirred at room temperature for 2 days. The solution was concentrated in vacuo and the residue was purified by MPLC (26 id Kieselgel 60 column; hexane/ethyl acetate 3:1) to yield 0.56 g (86.1%) of 3-[4-[4-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-2,6-dimethylphenoxy]-butyl]-pyridine, as a pale yellow oil.
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([C:21]4[CH:26]=[CH:25][CH:24]=CN=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:12][CH2:11]2)[N:6]=[CH:5]1.C([Sn](CCCC)(CCCC)C1[O:45]C=CC=1)CCC>>[ClH:1].[ClH:1].[O:45]1[CH:24]=[CH:25][CH:26]=[C:21]1[C:19]1[CH:18]=[CH:17][C:16]2[N:10]([CH2:9][C:7]3[N:6]=[CH:5][NH:4][CH:8]=3)[CH2:11][CH2:12][N:13]([C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:28])[CH2:14][C:15]=2[CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccccn3)cc2C1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(-c3ccco3)cc2C1
Yield: 11 %

Procedure:
Example 38 was prepared as a green solid in 11% yield from Compound A of Example 37 and 2-(tributylstannyl)furan as described for Compound B of Example 37.