Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Ag-]=O.C1(C)C=CC=CC=1>[CH2:12]([O:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(C)c(C#N)c(O)n1
Agent: O=[Ag-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C#N)c(OCc2ccccc2)n1
Temperature: 110 °C
Yield: 94.4 %

Procedure:
A mixture of 2-hydroxy-4,6-dimethylnicotinonitrile (5.3 g, 36 mmol), benzyl chloride (5.7 mL, 45 mmol), silver(I)oxide (9.2 g, 40 mmol) and toluene (50 mL) were heated at 110° C. in a sealed tube for 20 hours. The mixture was cooled to room temperature and the solids were filtered and rinsed with dichloromethane. The filtrate was concentrated under vacuum and purified by column chromatography (40% EtOAc/Heptane) to give 2-(benzyloxy)-4,6-dimethylnicotinonitrile (Cpd II, 8.1 g, 94% yield) as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)=[O:4].Cl.[C:15]1([S:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC#N.C(N(CC)CC)C>CCOC(C)=O.O.CCCCCC>[F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:27]2[CH2:28][CH2:29][N:24]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[CH2:25][CH2:26]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(c1ccc(N2CCN(S(=O)(=O)c3ccccc3)CC2)cc1)C(F)(F)F
Temperature: 110 °C
Yield: 50.9 %

Procedure:
A 125 ml, pressure tube was charged with 2,2,2-trifluoro-1-(4-fluorophenyl)ethanone (7.31 g, 38.1 mmol, Sigma-Aldrich, St. Louis, Mo.), 1-(phenylsulfonyl)piperazine hydrochloride (5.00 g, 19.0 mmol), 20 mL of CH3CN, and triethylamine (7.96 mL, 57.1 mmol). The tube was sealed and heated at 110° C. for 3 h. After that time, the mixture was diluted with EtOAc (100 mL) and water (50 mL). The organics were separated, dried (MgSO4) and concentrated to give a white solid. This solid was slurried with hexane (150 mL) to give 2,2,2-trifluoro-1-(4-(4-(phenylsulfonyl)-1-piperazinyl)phenyl)ethanone (3.85 g) as a bright white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:20]([NH:28][C:29]1[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:30]=1[C:31]([O:33]C)=[O:32])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:37]2[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[C:29]([NH:28][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:38]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)cc1
Temperature: 90 °C
Reaction time: 11 h
Yield: 7.5 %

Procedure:
56 mg of 4-(acetamido)phenylboronic acid, 55 mg of sodium carbonate and 30 mg of polymer supported bis(acetato)triphenylphosphine palladium(11) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of methyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 11 hours. After the reaction mixture was cooled to room temperature, 19 mg of 4-(acetamido)phenylboronic acid was added and the mixture was stirred at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, 11 mg of sodium carbonate and 30 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added and stirred at 90° C. for 14 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.2 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. 1 mL of 1.0 mol/L aqueous sodium hydroxide and 2 mL of ethanol were added to the obtained residue and stirred at room temperature for 1 hour. 0.6 mol/L hydrochloric acid was added, and solid substances were separated by filtration and purified with reversed-phase silica gel column chromatography [eluent; 40-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to obtain 5.9 mg of 4-(4-(acetamido)phenyl)-2-(benzamido)benzoic acid as white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:26])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:19]=[N:20][C:21](F)=[CH:22][C:23]=4[CH3:24])=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.COC1C=CC(C[NH2:34])=CC=1>O>[NH2:34][C:21]1[N:20]=[CH:19][C:18]([C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[C:6]([CH3:26])=[CH:5][C:4]([CH:1]4[CH2:3][CH2:2]4)=[CH:9][N:8]=3)[CH2:11][CH2:12]2)=[O:17])=[C:23]([CH3:24])[CH:22]=1
Reactant: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Reactant: COc1ccc(CN)cc1
Solvent: O
Product: Cc1cc(N)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 74.4 %

Procedure:
A mixture of [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (1.45 g) described in Preparation Example 140 and 4-methoxybenzylamine (1.12 g) was stirred at 100° C. for 5 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in dichloromethane (10 mL), trifluoroacetic acid (20 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (1.07 g).
Reaction SMILES: [Na+].[C:2]([NH:12][CH:13]1[C:36](=[O:37])[N:15]2[C:16]([C:33]([O-:35])=[O:34])=[C:17]([CH:20]([S:27][C:28]3[NH:32][N:31]=[N:30][N:29]=3)[CH2:21][CH2:22][NH:23][C:24]([NH2:26])=[O:25])[CH2:18][S:19][C@H:14]12)(=[O:11])[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Cl>>[C:2]([NH:12][CH:13]1[C:36](=[O:37])[N:15]2[C:16]([C:33]([OH:35])=[O:34])=[C:17]([CH:20]([S:27][C:28]3[NH:32][N:31]=[N:30][N:29]=3)[CH2:21][CH2:22][NH:23][C:24]([NH2:26])=[O:25])[CH2:18][S:19][C@H:14]12)(=[O:11])[C@@H:3]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:4]
Reactant: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)[O-])N2C(=O)C(NC(=O)[C@H](O)c3ccccc3)[C@H]2SC1
Agent: Cl
Agent: [Na+]
Product: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)[C@H](O)c3ccccc3)[C@H]2SC1

Procedure:
An aqueous solution of 7-D-mandelamido-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid sodium salt is acidified with 3 N HCl to pH 2.5 and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and evaporated to dryness to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[N:21]([CH3:38])[CH:22]=[C:23]([C:25](=[O:37])[NH:26][C:27]4[C:32]([CH2:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:35][CH3:36])[CH:24]=3)[C:17]([CH3:39])=[CH:16][N:15]=2)=[C:9]([CH3:40])[CH:8]=1)(C)(C)C.O>ClCCl.FC(F)(F)C(O)=O>[CH2:35]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][CH3:34])[C:27]=1[NH:26][C:25]([C:23]1[CH:24]=[C:20]([C:18]2[C:17]([CH3:39])=[CH:16][N:15]=[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:41])=[O:5])=[CH:8][C:9]=3[CH3:40])[N:19]=2)[N:21]([CH3:38])[CH:22]=1)=[O:37])[CH3:36]
Reactant: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3C)ncc2C)n(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)c1cc(-c2nc(Nc3ccc(C(=O)O)cc3C)ncc2C)n(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 4-{4-[4-(2,6-Diethyl-phenylcarbamoyl)-1-methyl-1H-pyrrol-2-yl]-5-methyl-pyrimidin-2-ylamino}-3-methyl-benzoic acid tert-butyl ester (438 mg, 0.790 mmol) in dichloromethane (20 ml), trifluoroacetic acid (1.2 ml) was added. The mixture was stirred at room temperature overnight. Water was added and the mixture extracted with ethylacetate. The organic solvent evaporated to dryness to give 393 mg of the title compound in quantitative yield.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][N:21]([CH3:38])[CH2:22][CH2:23][CH2:24][N:25]([CH3:37])[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][C:27]=1[C:33]([F:36])([F:35])[F:34]>>[CH3:38][N:21]([CH3:20])[CH2:22][CH2:23][CH2:24][N:25]([CH3:37])[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)=[CH:28][C:27]=1[C:33]([F:34])([F:36])[F:35]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CN(C)CCCN(C)c1ccc(N)cc1C(F)(F)F
Product: CN(C)CCCN(C)c1ccc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-[(3-dimethylamino-propyl)-methyl-amino]-3-trifluoromethyl-phenylamine (Step 5.1). Title compound: ES-MS: 511.0 [M+H]+; single peak at tR=3.33 min (System 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(Cl)cc2)cc1
Yield: 57.4 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 4-chloro-benzyl bromide (125 mg, 0.6 mmol) to afford the title product (120 mg, 58% yield); LCMS; 100% APCI+, Calcd: 417.94. Found m/z: 418.23 (M). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.43 (m, 2H), 3.69-3.91 (m, 1H), 4.02-4.18 (m 2H), 4.97 (s, 2H), 6.86 (s, 4H), 7.35 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:9](Cl)(Cl)=[S:10]>C(Cl)Cl.O>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:9]=[S:10])=[CH:7][N:6]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Cl)nc1
Solvent: O
Solvent: ClCCl
Product: S=C=Nc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.5 %

Procedure:
A mixture of 5-amino-2-chloropyridine (5.0 g, 38.11 mmol) and thiophosgene (3.6 ml, 45.73 mmol) in DCM (75 ml) and water (35 ml) was stirred at r.t. for 18 h. The organic phase was dried (Na2SO4) and evaporated in vacuo to give the title compound as an off-white solid (6.6 g, 95%). δH (CDCl3) 8.35 (1H, dd, J 0.5, 2.2 Hz), 7.54 (1H, dd, J 2.2, 8.5 Hz), 7.40 (1H, dd, J 0.5, 8.5 Hz). LCMS (ES+) RT 3.61 minutes, 171 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH3:6].[CH3:7][C:8]1[O:9][CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[NH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[OH2:4].[OH2:9].[CH2:5]([O:4][CH2:3][CH2:2][N:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:15]2[N:14]([CH2:13][C:12]3[CH:11]=[CH:10][O:9][C:8]=3[CH3:7])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH2:29][CH2:28]1)[CH3:6]
Reactant: CCOCCCl
Reactant: Cc1occc1Cn1c(NC2CCNCC2)nc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCN1CCC(Nc2nc3cccnc3n2Cc2ccoc2C)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
A mixture of 1.2 parts of 1-chloro-2-ethoxyethane, 3.1 parts of 3-[(2-methyl-3-furanyl)methyl]-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 1.6 parts of sodium carbonate and 45 parts of N,N-dimethylformamide was stirred overnight at 70° C. The reaction mixture was poured into 50 parts of water. Petroleum ether was added and after stirring, the crystallized product was filtered off, washed with water and petroleum ether and stirred in 1,1'-oxybisethane. The product was filtered off and dried at room temperature, yielding 1.6 parts (38.1%) of N-[1-(2-ethoxyethyl)-4-piperidinyl]-3-[(2-methyl-3-furanyl)methyl]-3H-imidazo-[4,5-b]pyridin-2-amine dihydrate; mp. 84.5° C. (compound 32).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[H-].[Na+].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].Cl>CN(C=O)C>[C:1]([CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])[C:4]([O:6][CH3:7])=[O:5])#[N:2]
Reactant: COC(=O)CC#N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C#N)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
6.3 A solution of 180 ml of methyl cyanoacetate in 300 ml of DMF is added dropwise at 0-50° with stirring and under a nitrogen atmosphere to a solution of 88 g of NaH suspension in 2 litres of DMF. The mixture is stirred for a further 30 minutes without cooling. A solution of 106 ml of o-fluoronitrobenzene in 100 ml of DMF is subsequently added dropwise, and the mixture is stirred at room temperature for a further 14 hours. The mixture is acidified using 10% HCl and subjected to conventional work-up, giving 165 g of methyl cyano(2-nitrophenyl)acetate (“FC”), m.p. 58-60°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH:13]=[CH2:14])=[CH:5][N:6]=[C:7]2[Cl:12].[CH2:15]([N:22]([CH:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>ClCCl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(OCC)(=O)C.CO>[CH2:15]([N:22]([C@H:30]1[CH2:31][CH2:32][C@H:33]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[C:4]([CH:13]=[CH2:14])=[CH:5][N:6]=[C:7]3[Cl:12])[CH2:34][CH2:35]1)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C=Cc1cnc(Cl)c2cccc(N)c12
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCC(=O)CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: C=Cc1cnc(Cl)c2cccc(N[C@H]3CC[C@H](N(Cc4ccccc4)C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 5-amino-1-chloro-4-vinylisoquinoline (0.6 g) and Intermediate 9 (1.8 g) in dichloromethane (13 ml) was added with titanium tetraisopropoxide (1.7 ml) at room temperature, and stirred at room temperature for 22 hours. The reaction mixture was added with methanol (13 ml), and sodium borohydride (444 mg), and stirred at room temperature for two hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate (60 ml), and ethyl acetate (60 ml), and the precipitates were removed by filtration. Then, the organic layer was separated, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:acetone=5:4) to obtain the title compound (890 mg).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][CH:2]2[C:10]3[C:5](=[CH:6][C:7]([O:11][C:12]4[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: NCCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCCc2ccccc2)nc1
Yield: 58.6 %

Procedure:
Using a method similar to Example 1, using 6-(]-oxo-indan-5-yloxy-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), 3-phenylpropylamine (486 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (681 mg) as a light yellow solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.35 (d, 1H), 7.30-7.25 (m, 2H), 7.22-7.16 (m, 3H), 6.99 (s, 1H), 6.95 (d, 1H), 5.85 (br. s, 2H), 4.23 (t, 1H), 3.00 (m, 1H), 2.83 (m, 1H), 2.78 (t, 2H), 2.70 (m, 2H), 2.43 (m, 1H), 1.87 (m, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[N:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10](OCC)=[O:11].O.[OH-].[Na+]>O1CCCC1>[OH:11][CH2:10][C:9]1[C:8]([CH3:7])=[N:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cccnc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncccc1CO
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a suspension of lithium aluminum hydride (6.2 g) in tetrahydrofuran (400 ml) was added dropwise ethyl 2-methylnicotinate (25 g) at -20° C. After stirring for 1 hour, to the reaction mixture was added dropwise in turn water (6.2 ml), 4N-aqueous sodium hydroxide (6.2 ml) and water (18.6 ml). The precipitate was filtered off and the filtrate was concentrated in vacuo to give 3-hydroxymethyl-2-methylpyridine (16.2 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([O:11][CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[O:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH3:24][O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Br.[I-].[K+].C(N(CC)C(C)C)(C)C>C1COCC1.ClCCl.O>[CH3:24][O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([O:11][C:9]2[C:10]3[C:2]([Br:1])=[C:3]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:4][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:13]1
Reactant: Brc1c(-c2ccccc2)oc2ncnc(OC3CCCNC3)c12
Reactant: COC(=O)CCCBr
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCN1CCCC(Oc2ncnc3oc(-c4ccccc4)c(Br)c23)C1

Procedure:
Heat a mixture of 550 mg (1.47 mmol) of rac-5-bromo-6-phenyl-4-(piperidin-3-yloxy)furo[2,3-d]-pyrimidine, 532 mg (2.94 mmol) of 4-bromobutyric acid methyl ester, 24.4 mg (0.147 mmol) of potassium iodide and 0.77 ml (4.41 mmol) of N,N-diisopropylethylamine in 1.5 ml of THF under reflux for 2 h. After cooling, dilute with dichloromethane and add to water. After phase separation, extract the aqueous phase with dichloromethane. Combine the organic phases, wash with satd. sodium hydrogencarbonate solution, dry over magnesium sulphate and concentrate under reduced pressure. From the residue, after purification by preparative RP-HPLC (eluent: acetonitrile/water), 780 mg of the target product are isolated, which are used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH3:8][CH:9]([CH2:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:13]Cl)[CH3:10].O>CN(C=O)C>[CH3:10][CH:9]([CH2:11][C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:13][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[CH3:8]
Reactant: c1nc[nH]n1
Reactant: CC(C)CC(O)(CCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(O)(Cn1cncn1)c1ccccc1
Temperature: 25 °C

Procedure:
1,2,4-Triazole (0.03 mol, 2.07 g) was added portionwise to 100% sodium hydride (0.03 mol, 0.72 g) in dry DMF (30 ml) and stirred at room temperature until the effervescence ceased. 2-Methyl-4-phenyl-5-chloropentan-4-ol (0.01 mol, 2.1 g) in dry DMF (10 ml) was added dropwise at room temperature and then the solution was stirred at 100° for 6 hours. On cooling to room temperature the solution was poured into water to precipitate out a solid which was recrystallised from petroleum (60°-80°)/chloroform giving the title compound (60%) as a white crystalline solid, m.p. 94°-95°.
Reaction SMILES: C([N:3](CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[C:8]([NH2:3])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccccc1

Procedure:
To a stirred mixture of 2.5 parts of compound 36, 0.44 parts of N,N-diethylethanamine and 399 parts of dichloromethane were added 0.85 parts of benzoyl chloride. The whole was refluxed for 18 hours. After cooling, the reaction mixture was washed with 50 parts of water, dried, filtered and evaporated. The residue was solidified in acetonitrile. The product was filtered off and dried, yielding 2.3 parts (75.4%) of N-5-[2-[4-[bis (4-fluorophenyl)-methylene]-1-piperidinyl]ethyl]-3,4-dihydro-3,6-dimethyl-4-oxo-2-pyrimidinyl]benzamide; mp. 239.6° C. (comp. 56).
Reaction SMILES: [OH:1][CH:2]([P:9](=[O:14])([O:12]C)[O:10]C)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[Si](Br)(C)C>C(Cl)Cl>[OH:1][CH:2]([P:9](=[O:10])([OH:14])[OH:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COP(=O)(OC)C(O)c1ccccc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.2 %

Procedure:
4 (0.15 g, 0.69 mmol, 1 eq) was dissolved in dry DCM (5 mL). TMSBr (0.77 mL, 5.52 mmol, 8 eq) was added to the solution under an inert atmosphere. The reaction was stirred for 20 h at room temperature. The solvent was then evaporated, and MeOH (5 mL) was added to the reaction mixture and stirred for 1 h. The solvent was evaporated and the crude product was dissolved in water (5 mL), filtered and freeze dried, yielding 6 as a white powder (130 mg, 70%). 1H NMR (400 MHz, D2O) δ 7.52-7.31 (m, 5H), 4.99 (d, J=12.3 Hz, 1H). 13C NMR (101 MHz, D2O) δ 137.45, 128.78 (d, JC-P=2.3 Hz), 128.52 (d, JC-P=2.9 Hz), 127.39 (d, JC-P=5.7 Hz), 71.02 (d, JC-P=158.3 Hz). 31P NMR (162 MHz D2O) δ 20.98 (s). ESIMS calculated for C-7H9O4PNa [M+Na]+211.01, found: 211.02; mp 160-162° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11](=[O:34])[CH:12]([CH2:29][S:30][C:31](=[O:33])[CH3:32])[CH:13]([C:15]1[CH:16]=[N:17][C:18]([NH:21]C(OC(C)(C)C)=O)=[CH:19][CH:20]=1)[CH3:14])[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:34])[CH:12]([CH2:29][S:30][C:31](=[O:33])[CH3:32])[CH:13]([C:15]1[CH:16]=[N:17][C:18]([NH2:21])=[CH:19][CH:20]=1)[CH3:14])[CH3:9]
Reactant: CCOC(=O)C(CSC(C)=O)C(C)c1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CSC(C)=O)C(C)c1ccc(N)nc1
Reaction time: 1 h
Yield: 132.3 %

Procedure:
TFA (2 mL) was added to a solution of 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-butyric acid ethyl ester (178 mg, 0.449 mmol) in methylene chloride (2 mL). The mixture was stirred for 60 min and concentrated under reduced pressure. Flash chromatography (toluene/EtOAc, 1:6) gave unpure 2-acetylsulfanylmethyl-3-(6-amino-pyridin-3-yl)-butyric acid ethyl ester (176 mg, 95%). Further purification by HPLC (10→70% acetonitrile in water, 0.1% TFA) gave 2-acetylsulfanylmethyl-3-(6-amino-pyridin-3-yl)-butyric acid ethyl ester (104 mg, 56%) as the TFA salt.