Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH2:50][OH:51])[CH2:48][OH:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:52]1([CH3:62])[CH:57]=[CH:56][C:55]([S:58](Cl)(=[O:60])=[O:59])=[CH:54][CH:53]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[O:11][C:10]1([CH2:48][O:49][S:58]([C:55]1[CH:56]=[CH:57][C:52]([CH3:62])=[CH:53][CH:54]=1)(=[O:60])=[O:59])[CH2:50][OH:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1ccc(Cc2cc([C@@H]3OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1ccc(Cc2cc([C@@H]3OC(CO)(COS(=O)(=O)c4ccc(C)cc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 319.9 %

Procedure:
To a stirred solution of {(3S,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-hydroxymethyl-tetrahydro-pyran-2-yl}-methanol (Example 9, 500 mg, 0.70 mmol) in pyridine (15 mL) was added p-toluene sulfonyl chloride (670 mg, 0.21 mmol). After stirring for overnight at room temperature, reaction mixture was heated to 80° C. for another 18 h. The volatiles were evaporated, resulting residue was taken in ethyl acetate and washed with 1N HCl, brine, concentrated to furnish toluene-4-sulfonic acid (3S,4R,5S,6S)-3,4,5-tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-2-hydroxymethyl-tetrahydro-pyran-2-ylmethyl ester (580 mg). The crude product was used as such for next step without purification which also contains small amount of bis-tosylate.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6]([OH:16])=[C:7]([C:13]([OH:15])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>O>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:13]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[OH:16])=[CH:4][CH:3]=[C:2]([F:1])[C:11]=3[F:12])=[O:15])=[CH:37][CH:36]=1
Reactant: O=C(O)c1cnc2c(F)c(F)ccc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)ccc2c1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a mixture of 0.25 g of 7,8-difluoro-4-hydroxy-3-quinolinecarboxylic acid and 10 mL of dimethyformamide is added 0.20 g of carbonyldiimidazole. The mixture is stirred 18 h at 50° C. and then it is cooled to 25° C. The mixture is treated with 0.10 mL of distilled water and stirred for 5 min. To the resulting solution is added 0.15 mL of 4-chlorobenzylamine. After stirring for 18 hours the solvent is evaporated at reduced pressure and the residue is dissolved in 10 mL of refluxing glacial acetic acid. Hot (100° C.) water is added dropwise until the solution becomes cloudy, and the mixture is allowed to cool to 25° C. The precipitate is collected by filtration and it is washed with two successive 5 mL portions of 50% aqueous acetic acid. It is dried for 18 h at 20 torr and 90° C. This procedure yields the title compound as 280 mg of a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:21][CH3:22])=[C:11]([O:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=2)[CH:7]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH3:32])[CH:25]=1)=[O:5])[CH3:2].[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:21][CH3:22])=[C:11]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:33](=[O:35])[CH3:34])[CH:12]=2)[CH:7]1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH3:32])[CH:25]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)N1C=Cc2cc(OCCCO)c(OC)cc2C1Cc1cccc(OCC)c1
Solvent: c1ccncc1
Product: CCOC(=O)N1C=Cc2cc(OCCCOC(C)=O)c(OC)cc2C1Cc1cccc(OCC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a stirred solution of 6-(3-hydroxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (160 mg, 0.59 mmol) in pyridine (4.2 mL) was added acetic anhydride (2.1 mL). The reaction mixture was stirred at room temperature for 15 hrs. The mixture was concentrated in vacuo to afford 6-(3-acetoxy-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (285 mg, 99% yield). The crude product was used without further purification.
Reaction SMILES: COC([N:5]1[C:9]2=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=[C:8]2[CH:7]=[C:6]1[CH3:15])=O.[OH-].[Na+]>CO>[Cl:14][C:11]1[N:10]=[C:9]2[NH:5][C:6]([CH3:15])=[CH:7][C:8]2=[CH:13][CH:12]=1
Reactant: COC(=O)n1c(C)cc2ccc(Cl)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2ccc(Cl)nc2[nH]1

Procedure:
6-Chloro-2-methyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid methyl ester (0.225 g, 1 mmol) is dissolved in methanol (30 ml) and 1M NaOH (10 ml) and stirred at room temperature overnight. The methanol is removed in vacuo and the resulting white suspension is extracted with chloroform (3×20 ml), dried (MgSO4) and concentrated in vacuo to yield a white powder which is dried under high vacuum to yield the titled product. (MH+ 167).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1CN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN1C(=O)c2ccccc2C1=O
Temperature: 40 °C

Procedure:
A 1 gallon autoclave was charged with 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxy-phenyl]-acrylic acid tert-butyl ester (196 g, 0.517 mol), ethyl acetate (2.6 L) and 5% palladium on carbon (75 g). The autoclave was kept at 25° C. under 60 psi of hydrogen for 21 h. The temperature of the reaction was increased to 40° C., and the pressure was increased to 75 psi for 5 h. The mixture was filtered through a pad of hyflo and concentrated to the title compound (186 g, 94.4%): MS (ESI) m/z 380.2 (M−H)−.
Reaction SMILES: [I:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[F:12][C:13]1[C:21]2[CH2:20][CH2:19][S:18][C:17]=2[C:16](O)=[CH:15][CH:14]=1>>[F:12][C:13]1[C:21]2[CH2:20][CH2:19][S:18][C:17]=2[C:16]([O:5][C@@H:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2][I:1])=[CH:15][CH:14]=1
Reactant: Oc1ccc(F)c2c1SCC2
Reactant: O[C@@H](CCI)c1ccccc1
Product: Fc1ccc(O[C@H](CCI)c2ccccc2)c2c1CCS2

Procedure:
using (S)-1-iodo-3-phenyl-3-propanol with 4-fluoro-2,3-dihydrobenzo[b]thiophen-7-ol, to give 243 mg of the title compound as a colourless solid: δH (300 MHz, CDCl3) 7.32-7.12 (5H, m, 3-ArH), 6.46-6.27 (3H, m, ArH), 5.15-5.06 (1H, m, CHO), 3.43-3.11 (6H, m CH2CH2HI and SCH2CH2), 2.50-2.31 (1H, m, CHHCH2I) and 2.27-2.09 (1H, m, CHHCH2I).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[CH3:28][SH:29].C(N(CC)CC)C>C1COCC1>[F:27][C:5]1[N:6]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[C:3]([CH2:2][S:29][CH3:28])[N:4]=1
Reactant: CS
Reactant: Fc1nc(CCl)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1

Procedure:
4-Chloromethyl-2-fluoro-1-triphenylmethylimidazole was treated with methanethiol and triethylamine in THF solution to give 2-fluoro-4-methylthiomethyl-1-triphenylmethylimidazole. This was condensed with t-butyl 3-acetoxymethyl-7-aminoceph-3-em-4-carboxylate as for the starting material of Example 42 to give t-butyl 3-acetoxymethyl-7-(4-methylthiomethylimidazol-2-yl)aminoceph-3-em-4-carboxylate, having the following n.m.r. spectrum in d6DMSO: 1.5 (s, 9H); 2.0 (s, 6H); 3.5 (d, 2H); 3.8 (d, 2H); 4.7 (d, 1H); 5.0 (d, 1H); 5.25 (d, 1H); 5.65 (d, 1H); 7.0 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[O:9][C:8]([F:10])=[CH:7][C:6]=2[CH:11]=1.FC1(F)OC2C=C(C)C(C3N=C[C:26]([NH:29][C:30](=O)[C:31]4[CH:36]=[CH:35]C=CC=4F)=[N:27]C=3)=CC=2O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC>C(#N)C.O1CCOCC1.O>[F:10][C:8]1[O:9][C:5]2[CH:4]=[C:3]([CH3:12])[C:2]([C:31]3[CH:36]=[CH:35][C:26]([NH2:27])=[N:29][CH:30]=3)=[CH:11][C:6]=2[CH:7]=1
Reactant: Cc1cc2oc(F)cc2cc1Br
Reactant: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)OC(F)(F)O2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2oc(F)cc2cc1-c1ccc(N)nc1
Temperature: 85 °C
Yield: 56.8 %

Procedure:
A mixture of 5-bromo-2-fluoro-6-methyl-benzofuran (230) (78.5 mg, 0.34 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (151 mg, 2 eq), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (48 mg, 10% mol) and K3PO4 (145 mg, 0.69 mmol) in 2 ml ACN, 2 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 85° C. for 3 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected to silica gel flash column chromatography (0-100% B, A: hexane; B: EA) to give 5-(2-fluoro-6-methylbenzo[b]furan-5-yl)-2-pyridylamine (231) (46.8 mg, purity>95%, yield: 56.8%) as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6]CC)=O.[C:15](#[N:17])[CH3:16].[H-].[Na+].CCOCC>O1CCCC1>[Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([CH2:16][C:15]#[N:17])=[O:6]
Reactant: CCOC(=O)c1cc(F)c(Cl)cc1Cl
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCC(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 34.5 %

Procedure:
A mixture of 47.4 g of ethyl 2,4-dichloro-5-fluoro-benzoate and 8.2 g of anhydrous acetonitrile are added dropwise to a suspension of 6.1 g of 80% strength sodium hydride in 100 ml of anhydrous tetrahydrofuran under reflux in the course of about 1 hour. The mixture is heated at the boiling point under reflux for a further hour and cooled to room temperature, and 150 ml of ether are added. The precipitate is filtered off with suction and dissolved in 50 ml of ice-water and the solution is acidified to pH=6 with 10% strength hydrochloric acid. The precipitate is filtered off cold with suction, rinsed with ice-water and dried in vacuo at 40° C. 16 g of 2,4-dichloro-5-fluoro-benzoylacetonitrile of melting point 96°-98° C. are obtained.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([CH3:18])[C:14]([F:17])([F:16])[F:15])(=O)=O)=CC=1.[F:20][C:21]([F:31])([F:30])[CH2:22][CH2:23][S:24]([CH2:27][C:28]#[N:29])(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[F:15][C:14]([F:17])([F:16])[CH:13]([CH3:18])[CH2:12][CH2:11][CH:27]([S:24]([CH2:23][CH2:22][C:21]([F:20])([F:30])[F:31])(=[O:25])=[O:26])[C:28]#[N:29]
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)C(F)(F)F)cc1
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(CCC(C#N)S(=O)(=O)CCC(F)(F)F)C(F)(F)F
Reaction time: 16 h
Yield: 45.5 %

Procedure:
To a solution of 1.0 g of 4,4,4-trifluoro-3-methylbutyl p-toluenesulfonate and 0.7 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 50 ml of dimethyl sulfoxide was added 0.5 g of potassium carbonate at room temperature, and then stirred at the same temperature for 16 hours. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.50 g of 6,6,6-trifluoro-5-methyl-2-(3,3,3-trifluoropropylsulfonyl)hexanenitrile (hereinafter referred to as the present compound (10)).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:9]=[CH:8][N:7]=1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2nccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of ethyl {4-[((2-methoxyethyl){4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)methyl]-2-methylphenoxy}acetate (80 mg, 0.16 mmol) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was added 2M sodium hydroxide (1.5 mL). The resulting mixture was stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue was diluted with water (10 mL) acidified with 2M HCl and extracted ethyl acetate (2×30 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo, to afford the title compound as a cream solid (72 mg).
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1C=CC=CC=1>[C:2]1([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]4)[CH2:3]2)[CH2:9]3)[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: c1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 120 °C

Procedure:
Add 1-bromoadamantane (10 g, 46.5 mmols), potassium carbonate (7.7 g, 55.8 mmols) and palladium on carbon (250 mg, catalytic) in benzene and heat to 120° C. for 1 week. Cool the reaction to room temperature and filter over Celite® rinsing with EtOAc. Concentrate under reduce pressure to provide the title compound. 1H NMR (400 MHz; CDCl3) δ 7.2-7.4(m, 5H), 2.10(s, 3H), 1.92(s, 6H), 1.77(s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([O:14][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=3)[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1cc(-c2ccccc2)nc(-c2ccc(Cl)cc2)n1
Reactant: Fc1ccc(CBr)cc1
Product: Fc1ccc(COc2cc(-c3ccccc3)nc(-c3ccc(Cl)cc3)n2)cc1

Procedure:
The title compound was prepared from 2-(4-chloro-phenyl)-6-phenyl-pyrimidin-4-ol (which was obtained in Intermediate 1) and 4-fluorobenzyl bromide according to Method A; LC retention time 4.35 min; MS: m/z (ESI) 391 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[N:3]1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)=[N:3]1
Reactant: Cn1ccc(-c2ccc(C=O)cc2)n1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: Cn1ccc(-c2ccc(C=CC=O)cc2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1-methyl-1H-pyrazol-3-yl)benzaldehyde (prepared as described in J. Med. Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 213 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.C1COCC1.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][C:5]([CH3:13])=[CH:6]2
Reactant: CC1Cc2c(Br)ccc(F)c2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1=Cc2c(F)ccc(Br)c2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 48.4 g (199 mmol) of 4-bromo-7-fluoro-2-methylindan-1-one in 270 ml of a mixture of THF-methanol (2:1, vol.), 11.3 g (299 mmol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 500 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined organic extract was dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 500 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 4 h using a Dean-Stark trap to remove water formed and then passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic extract was evaporated to dryness. The residue was dried in vacuum to give the title compound. Yield 38.9 g (86%).
Reaction SMILES: [O:1]=[C:2]([NH:5][C:6]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9]CC)=O)[CH2:3][CH3:4].[H][H]>C(O)(=O)C>[O:9]=[C:7]1[C:6]([NH:5][C:2](=[O:1])[CH2:3][CH3:4])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:17][C:18]2=[CH:19][CH:20]=[CH:21][C:22]3=[C:27]2[N:26]1[CH2:25][CH2:24][CH2:23]3
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1cccc2cccnc12)(NC(=O)CC)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)C1(NC(=O)CC)Cc2cccc3c2N(CCC3)C1=O
Yield: 77.8 %

Procedure:
A mixture of diethyl ((1-oxopropyl)amino)(8-quinolinylmethyl)-propanedioate (17.47 g, 0.047 mol) and platnium oxide (0.72 g) in glacial acetic acid (150 mL) was hydrogenated (50 lb initial pressure) until hydrogen uptake ceased (1.8 equiv). The mixture was filtered through celite and the solvent removed under reduced pressure. The product was crystallized from ethyl acetate to give 12.08 g of crystals, mp 136°-140° C. A sample was recrystallized from ethyl acetate for analysis; mp 137°-141° C. Anal. Calcd. for C18H22N2O4 ; C, 65.44; H, 6.71; N, 8.48. Found: C, 65.66; H, 6.64; N, 8.43.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]([NH2:18])[NH:15][N:14]=1)(=[O:12])=[O:11].C(O)(=O)C.[C:23](OCC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]2[N:18]=[C:25]([CH3:27])[CH:24]=[C:23]([OH:28])[N:15]2[N:14]=1)(=[O:12])=[O:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(O)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reaction time: 24 h
Yield: 74.8 %

Procedure:
A solution of 5.0 g (14.3 mmol) of N-(2,6-dichlorophenyl)-5-amino-1,2,4-triazol-3-sulfonamide, 0.5 ml of acetic acid, and 2.0 ml (15.6 mmol) of ethyl acetoacetate in 100 ml of absolute methanol was heated at reflux for 48 hr. After 24 hr a solid began to form. The solution was cooled and the solid collected. After drying, 4.0 g (75 percent) of the desired product was obtained as a white powder; mp 302° C. decomposes.
Reaction SMILES: [CH:1]([N:3]1[CH2:12][CH2:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2/[C:4]/1=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:2]>CO>[CH:1]([N:3]1[CH2:12][CH2:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]1=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:2]
Reactant: COc1ccc(/C=C2/C3=C(CCCC3)CCN2C=O)cc1
Solvent: CO
Product: COc1ccc(C=C2C3=C(CCCC3)CCN2C=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
Into a Schlenk's tube which had previously been dried and purged with argon was weighed and charged 18.8 mg (0.0081 mmol) of [Ru((-)-T-BINAP)SnCl6 ]2NEt3 as a catalyst. Then, 40 ml of degassed anhydrous methanol was added thereto, and the solution was stirred in the presence of hydrogen at room temperature for 2 hours. Separately, a solution of 516 mg (1.82 mmols) of (Z)-N-formyl-1-(4-methoxyphenylmethylene)-3,4,5,6,7,8-hexahydroisoquinoline added to 20 ml of degassed anhydrous methanol was prepared. A fraction of 4.30 ml (molar ratio of substrate/catalyst =1000/1) was taken from the catalyst solution and mixed with a substrate solution. The mixture was transferred into an autoclave and stirred at 75° C. for 47 hours under a hydrogen pressure of 35 kg/cm2. After completion of the stirring, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 520 mg of (+)-N-formyl-1-(4-methoxyphenylmethylene)-1,2,3,4,5,6,7,8-octahydroisoquinoline. The yield was 100%.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH3:8].[OH:9][C:10]1[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1[C:23]([CH3:26])([CH3:25])[CH3:24].Cl>O>[OH:9][C:10]1[C:11]([C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:12][C:13]([C:14]([NH:2][N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[CH3:8])=[O:15])=[CH:17][C:18]=1[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1nccn1N
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: O
Product: Cc1nccn1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
1.0 g of 1-amino-2-methylimidazole hydrochloride and 2.0 g of 4-hydroxy-3,5-di-tert.-butylbenzoyl chloride are mixed and heated on an oil-bath for 40 minutes to 200°-210° (bath temperature), whereby the flask content melts with the evolution of HCl and then again becomes solid. The cooled flask content is dissolved in 30 ml of water, whereupon the solution is filtered and the filtrate is adjusted to pH 9 with 10% sodium carbonate solution. The separated precipitate is removed by filtration and dissolved in 25 ml of hot ethanol, whereupon the still hot solution is treated with 10 ml of water. After cooling, the separated solid is removed by filtration and recrystallized from ethyl acetate. There is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzoylamino)-2-methylimidazole of m.p. 322°-324° (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
4-amino-5-chloro-2-methoxybenzoic acid (compound of formula 9) (16.6 g, 82.28 mmol) was dissolved in dimethylformamide (166 mL) and the solution was cooled to 0° C. Then, tertiary butyl 4-(aminomethyl)piperidine-1-carboxylate (21.16 g, 98.74 mmol), triethylamine (11.56 mL, 246.84 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 20.51 g, 106.96 mmol), and 1-hydroxybenzotriazole (HOBT, 16.68 g, 123.42 mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 4 hours, and extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (31.4 g, 96%).