Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4](=[O:29])[CH2:5][C@H:6]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[Li].[Cl:32][C:33]1[CH:38]=[C:37](I)[CH:36]=[C:35]([Cl:40])[N:34]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([C:4](=[O:29])[CH2:5][C@H:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH:36]=[C:35]([Cl:40])[N:34]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: CON(C)C(=O)C[C@H](c1ccc(-c2ccc(C(=O)O)cc2)cc1)c1ccccc1C
Agent: [Li]
Product: Cc1ccccc1[C@H](CC(=O)c1cc(Cl)nc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 74, step 5, from (R)-4′-(3-(methoxy(methyl)amino)-3-oxo-1-tolylpropyl)biphenyl-4-carboxylic acid, lithium salt and 2,6-dichloro-4-iodopyridine was prepared the title compound as light brown foam, MS (ESI−): m/z=488.2 ([M−H]−, 1Cl).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH3:9][O:10][CH2:11][CH2:12][CH2:13]C1C=CN=CC=1CO>>[CH3:9][O:10][CH2:11][CH2:12][CH2:13][C:3]1([CH2:7][OH:8])[CH:4]=[CH:5][CH:6]=[N:1][CH2:2]1
Reactant: COCCCc1ccncc1CO
Reactant: O=Cc1cccnc1
Product: COCCCC1(CO)C=CC=NC1

Procedure:
Following the general method of Example 1, 21.7 g (0.2 mol) of 4-chloro-1-methoxypropane and 21.4 g (0.2 mol) of pyridine-3-carboxaldehyde were converted to 18.87 g (52%) of (4-methoxypropyl-3-pyridinyl)methanol.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][CH2:4][C:5]12[CH2:12][N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH:9]1[CH2:8][CH2:7][O:6]2>O.C(O)(C)(C)C>[CH2:13]([N:11]1[CH2:12][C:5]2([CH2:4][NH:3][C:7]([O:6][C:5]([CH3:12])([CH3:9])[CH3:4])=[O:1])[CH:9]([CH2:8][CH2:7][O:6]2)[CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCC12CN(Cc3ccccc3)CC1CCO2
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NCC12CN(Cc3ccccc3)CC1CCO2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2 g of NaOH in 45 ml of water are added to 10.4 g (44.7 mmol) of 1-aminomethyl-7-benzyl-2-oxa-7-azabicyclo[3.3.0]octane in 56 ml of tert-butanol, and 10.2 g (47 mmol) of di-tert-butyl pyrodicarbonate are then added dropwise. The mixture is stirred at room temperature for 15 hours, and then extraction with chloroform, drying over potassium carbonate, concentration and distillation are carried out.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[C:7](O)[CH:6]=[CH:5][N:4]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][NH:26][CH3:27])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>P(Cl)(Cl)(Cl)=O.CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:27])[C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:8]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1ccnc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)c1ccnc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 28.7 %

Procedure:
A stirred solution of 2-trifluoromethylpyridin-4-ol (12.5 g, 76.6 mmol) and dimethylformamide (3.00 mL) in phosphorus oxychloride (75 mL) is heated under reflux for 2 hours before excess phosphorus oxychloride is removed in vacuo. The residue is poured onto an ice-water mixture and extracted into ethyl acetate (×5). The combined organic extracts dried (sodium sulfate), filtered and concentrated in vacuo. The non-basic components of the mixture are eluted through a SCX column washing with a 1:1 mixture of methanol-dichloromethane. A stirred suspension of the residue, 1-t-butoxycarbonyl-4-[(methylamino)methyl]piperidine (1.11 g, 4.85 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in dimethylformamide (38 mL) is heated at 90° C. for 13 hours. Excess dimethylformamide is removed in vacuo, the residue is taken into chloroform and washed with 2.5% hydrogen chloride solution. The aqueous layer is extracted into chloroform (×3) and the combined organic extracts are dried (sodium sulfate), filtered and concentrated in vacuo. Flash column chromatography eluting with a gradient of 30% ethyl acetate-hexane to 50% ethyl acetate-hexane provides 1-t-butoxycarbonyl-4-{[(methyl)(2-trifluoromethylpyridin-4-yl)amino]methyl}piperidine (520 mg, 2%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH2:11]([N:13]1[C:17]2=[N:18][C:19]3[C:24]([C:25]([NH:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:16]2[CH:15]=[N:14]1)=[CH:23][C:22]([OH:34])=[CH:21][CH:20]=3)[CH3:12].[OH-].[K+]>CS(C)=O>[CH2:11]([N:13]1[C:17]2=[N:18][C:19]3[C:24]([C:25]([NH:26][CH2:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:16]2[CH:15]=[N:14]1)=[CH:23][C:22]([O:34][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[CH:21][CH:20]=3)[CH3:12]
Reactant: ClCCN1CCOCC1
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(O)ccc3nc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(OCCN4CCOCC4)ccc3nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
A mixture of DMSO (6 ml), chloroethylmorpholine hydrochloride (1.23 g, 6.6 mmol), 1-ethyl-6-hydroxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (2 g, 6.6 mmol) and KOH (1 g) is stirred at room temperature overnight. The reaction mixture is partitioned between CH2Cl2 and water and the CH2Cl2 layer is separated and evaporated. The residue is purified by column chromatography on silica gel eluting with 10% ethanol/ethyl acetate to afford the product as the free base. The free base is recrystallized from hot ethyl acetate/hexane to afford 0.425 g of 1-ethyl-6-[2-(4-morpholinyl)ethoxy]-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow powder, m.p. 176°-178° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1>>[F:11][C:4]1[CH:3]=[C:2]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: OB(O)c1cccnc1
Product: O=C(O)c1ccc(-c2cccnc2)cc1F

Procedure:
The title compound is prepared as described in EXAMPLE 31, Part I, but with 4-bromo-2-fluorobenzoic acid and 3-pyridinylboronic acid as starting materials. 1H NMR (DMSO) δ 8.97 (d, 1H), 8.66-8.58 (m, 1H), 8.22-8.12 (m, 1H), 8.00-7.91 (m, 1H), 7.81-7.62 (m, 2H), 7.55-7.45 (m, 1H). ESI MS (M+1)+: 218.
Reaction SMILES: [C:1]([CH:3]=[CH:4][C:5]1[C:6]([O:15][CH3:16])=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:2].C(O)(=O)C>[C].[Pd].CO>[C:1]([CH2:3][CH2:4][C:5]1[C:6]([O:15][CH3:16])=[N:7][CH:8]=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])#[N:2]
Reactant: COC(=O)c1cnc(OC)c(C=CC#N)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cnc(OC)c(CCC#N)c1
Temperature: 70 °C
Reaction time: 40 h
Yield: 57.2 %

Procedure:
To a mixture of methyl 5-(2-cyanovinyl)-6-methoxynicotinate (1.02 g), acetic acid (20 ml) and methanol (20 mL) was added 10% palladium-carbon (504 mg), and the mixture was stirred under a hydrogen atmosphere at 70° C. for 40 hr. The reaction mixture was filtered, and the filtrate was diluted with THF and ethyl acetate. The diluted solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (589 mg) as white crystals.
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C[O-].[Na+].[C:22]1(C)C=CC=C[CH:23]=1>C(OCC)(=O)C>[CH3:22][C:23]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1
Reactant: Cc1ccccc1
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 74 %

Procedure:
5.04 g. 2-(theophyllin-7-yl)-acetamidoxime, 2.16 g. of sodium methylate, 10 cm3 ethyl acetate and 200 cm3 of toluene are heated under stirring by using a water condenser for 20 hours and further 10 cm3 ethyl acetate are added to the mixture in five portions. The solvent is distilled off. After crystallization from water 4.1 g. (74% yield) 7-[(5-methyl-1,2,4-oxadiazol-3-yl)-methyl]-theophylline are obtained. M.p.: 135°-136° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:6]([CH:9]=1)[CH:7]=O.[CH3:19][NH2:20].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH:20][CH3:19]
Reactant: O=Cc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(Br)ccc1Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.3 %

Procedure:
To a mixture of 5-bromo-2-(3,4-dichloro-phenoxy)-benzaldehyde (4.74 g, 13.8 mmol) in MeOH (250 mL) was added MeNH2 (40% aq.; 20 mL, 260 mmol), and the resulting mixture was stirred at rt until homogeneous. The mixture was cooled to 0° C. and treated with NaBH4 (1.05 g, 27.8 mmol) portionwise. After 24 h, the mixture was concentrated and the residue was diluted with 1 N NaOH and extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by FCC to provide the desired product (4.80 g, 97%). MS (ESI): mass calcd. for C14H12BrCl2NO, 358.95; m/z found, 360.1 [M+H]+. 1H NMR (CDCl3): 7.61 (d, J=2.5, 1H), 7.40-7.37 (m, 2H), 7.03 (d, J=2.8, 1H), 6.82-6.79 (m, 2H), 3.72 (s, 2H), 2.44 (s, 3H), 1.30-1.21 (m, 1H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[C:26]2[C:22](=[CH:23][N:24]([CH3:27])[N:25]=2)[C:21]([CH:28]=O)=[CH:20][CH:19]=1.O>O1CCCC1>[F:17][C:18]1[C:26]2[C:22](=[CH:23][N:24]([CH3:27])[N:25]=2)[C:21](/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cn1cc2c(C=O)ccc(F)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(F)c2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a suspension of sodium hydride (0.467 g, 11.7 mmol) in tetrahydrofuran (10 mL) was added a solution of ethyl diethylphosphonoacetate (2.34 mL, 11.7 mmol) in tetrahydrofuran (3 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 7-fluoro-2-methyl-2H-indazole-4-carbaldehyde (1.60 g, 8.98 mmol) in tetrahydrofuran (5 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (1.85 g, yield 83%).
Reaction SMILES: [CH:1]1([NH:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:21]=[N+:22]=[N-:23]>C1C=CC=CC=1>[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]1[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:23]=[N:22][N:21]=1
Reactant: [N-]=[N+]=N
Reactant: O=C(CCCCCl)NC1CCCCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: ClCCCCc1nnnn1C1CCCCC1
Temperature: 18 °C
Reaction time: 2 h

Procedure:
A stirred solution of N-cyclohexyl-5-chloropentanamide (4.36 g, 0.020 mol) in benzene (30 ml) at 0° C. was treated with phosphorous pentachloride (4.4 g, 0.021 mol) in portions over 10 minutes. When the addition was complete the reaction was stirred for an additional 2 hours at 18° C. The solution was then cooled to 0° C. and treated with a solution of hydrazoic acid (0.04 mol) in benzene (50 ml) (prepared according to the method described in Reagents for Organic Synthesis, Volume 1, L. F. Fieser and M. Fieser, John Wiley and Sons (New York: 1967). The resulting solution was stirred at 0° C. for an additional 1.5 hours and at 18° C. for 48 hours and then heated under reflux for an additional 3 hours. The solvent was evaporated off under reduced pressure and the resulting residue was dissolved in ethyl acetate (250 ml). The resulting solution was washed with saturated aqueous sodium hydrogen carbonate (3×100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield a crude product. The crude product was purified by recrystallization from ethyl acetate-hexane to yield 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole as a colorless crystalline solid, having a melting point of 50°-51° C. and the following physical characteristics:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7](=[N:20][OH:21])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(=NO)c2ccc(OC)cc2)cc1
Yield: 93.3 %

Procedure:
242 g (1 mole) of 4,4'-dimethoxybenzophenone was suspended in 2,000 ml of ethanol and 210 g (3 mole) of hydroxylamine hydrochloride and 300 ml (3 mole) of a 10N aqueous solution of NaOH were added thereto. Then the obtained mixture was heated under reflux. After two or thee hours, the ethanol was distilled off in vacuo and then a saline solution was added thereto followed by extracting with chloroform. The chloroform phase was washed with water and dried over magnesium sulfate. After distilling the chloroform off, the residue was recrystallized from ethanol. Thus 240 g of the title compound was obtained in the form of colorless needles.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH2:29][C:30]([F:33])([F:32])[F:31])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)([CH3:6])[C:3](O)=[O:4].[CH2:36]([CH2:38][NH2:39])[OH:37]>>[OH:37][CH2:36][CH2:38][NH:39][C:3](=[O:4])[C:2]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH2:29][C:30]([F:31])([F:33])[F:32])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)([CH3:6])[CH3:1]
Reactant: CC(C)(C(=O)O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1
Reactant: NCCO
Product: CC(C)(C(=O)NCCO)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 453, 2-Methyl-2-(4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-pyrazol-1-yl)-propionic acid was reacted with ethanolamine to give 324. MS(ESI+) 548.1. 1H NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 8.30-8.25 (m, 2H), 8.07 (s, 1H), 7.52 (dd, J=8.3, 1.5, 1H), 7.41 (d, J=1.5, 1H), 7.20 (t, J=5.4, 1H), 5.86 (q, J=8.7, 2H), 4.59 (t, J=5.4, 1H), 4.40 (t, J=4.8, 2H), 3.47 (t, J=4.9, 2H), 3.36 (q, J=6.0, 2H), 3.12 (q, J=6.0, 2H), 1.75 (s, 6H)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A mixture of 0.52 mmol 4-(4-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 2 ml dichloromethane was treated with 0.2 ml trifluoroacetic acid. The mixture was stirred at 40° C. for 3 hrs then concentrated and treated with water/NaOH and extracted with dichloromethane. The combined organic phases were washed with saturated NaCl, dried with MgSO4 and evaporated to yield the title compound. MS (m/e): 228.3 (MH+, 100%)
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)=[O:36].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:33][O:34][C:35](=[O:36])[C:37]1[CH:42]=[CH:41][C:40]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]2)=[O:24])=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)cc1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-methoxycarbonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (67%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:6][CH:7]=1.C([O-])(=[O:15])C.[Na+]>>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:5]1[O:6][CH:7]=[C:3]([CH2:2][OH:15])[N:4]=1
Reactant: CC(=O)[O-]
Reactant: ClCc1coc(-c2cccs2)n1
Agent: [Na+]
Product: OCc1coc(-c2cccs2)n1
Yield: 80 %

Procedure:
In substantially the same manner as in Reference Example 77, 4-chloromethyl-2-(2-thienyl)oxazole was allowed to react with sodium acetate, and then hydrolyzed to give 2-(2-thienyl)oxazolylmethanol. The yield was 80%. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 98-99° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH2:15](I)[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([N:6]1[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]12)[CH:16]([CH3:18])[CH3:17]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Product: CC(C)Cn1c(=O)oc(=O)c2ccccc21

Procedure:
Reagents: Isatoic anhydride (6.13 mmols, 1 g); Sodium hydride (9.2 mmols, 0.22 g); isobutyl iodide (18 mmols, 3.4 g). Yield: 0.6 g (46%), white solid, m.p.=85° C.-86° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=Cc1cc(Cl)cc(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1cc(Cl)cc(Cl)c1

Procedure:
3,5-dichloro-iodo-benzene (5 g, 18 mmol) was stirred at room temperature as a solution in DMF (50 mL) containing tert butyl acrylate (6.5 mL, 2.5 eq), tetrabutyl ammonium chloride hydrate (5.1 g, 1 eq), potassium acetate (5.4 g, 3 eq) and palladium (II) acetate (˜200 mg, 30 mol %) for 5 hours. Reaction mixture was reduced in vacuo, partitioned between water and ethyl acetate. Ethyl acetate fractions were dried over magnesium sulfate, filtered over a small plug of silica gel. Silica gel plug washed with 10% Ethyl acetate/n-heptanes to afford 3-(3,5-Dichloro-phenyl)-acrylic acid tert butyl ester after evaporation as a white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.46 (s, 9H) 6.69 (d, J=16.04 Hz, 1H) 7.49 (d, J=16.04 Hz, 1H) 7.59 (t, J=1.89 Hz, 1H) 7.81 (d, J=1.77 Hz, 2H). A solution of 3-(3,5-Dichloro-phenyl)-acrylic acid tert butyl ester (4 g, 14 mmol) in ethanol (100 mL) was charged with platinum oxide (800 mg), after purging reaction mixture with nitrogen. Attached balloon of hydrogen and stirred vigorously at room temperature over night. After removal of excess hydrogen, catalyst was removed by filtering mixture over a pad of celite and the resulting solution was evaporated to afford 3-(3,5-dichloro-phenyl)-propionic acid tert-butyl ester as an oil (3.8 g; 94% isolated yield). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.41 (s, 9H) 2.52 (s, 2H) 2.85 (s, 2H) 7.08 (s, 2H) 7.18 (s, 1H).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[C:18]([Br:25])[N:17]=2)=[O:15])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].Cl>CO.O>[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[N:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[C:18]([Br:25])[N:17]=2)=[O:15])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(C(=O)c2nc(Br)c3ccccn23)ccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(C(=O)c2nc(Br)c3ccccn23)cc1C(=O)O
Yield: 98 %

Procedure:
60 ml (60 mmol) of a 1N aqueous solution of sodium hydroxide are added, at ambient temperature, to 3.74 g (10 mmol) of methyl 2-amino-5-[1-bromo(imidazo[1,5-a]pyridin-3-yl)carbonyl]benzoate in 300 ml of methanol and 125 ml of water. The reaction medium is refluxed for 6 hours and then 140 ml of a 1N aqueous solution of hydrochloric acid are added. After concentration of the methanol under reduced pressure, the precipitate obtained is filtered off, washed with water, and then dried under reduced pressure at 40° C. for 18 hours. 3.53 g of a yellow solid are obtained.
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])[NH:10][C:9]2[N:8]=[C:7]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:6]=[CH:5][C:4]=2[CH2:3]1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:7]2[N:8]=[C:9]3[C:4]([CH2:3][CH:2]([CH3:1])[C:11](=[O:12])[NH:10]3)=[CH:5][CH:6]=2)[CH2:29][CH2:28]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: CC1Cc2ccc(OCCCC=O)nc2NC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC1Cc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2NC1=O
Reaction time: 0.08 h

Procedure:
To a solution of crude 4-(6-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde (0.5 g, 2.0 mmol, 1.0 equiv) in anhydrous methanol (40 mL) cooled to 0° C. was added 2,3-dichlorophenylpiperazine (1.1 g, 4.0 mmol, 2.0 equiv). The mixture was stirred for 5 min and NaBH(OAc)3 (2.14 g, 10.0 mmol, 5.0 equiv) was added. The reaction mixture was brought to room temperature and stirred overnight. TLC indicated a trace amount of aldehyde was still left. More NaBH(OAc)3 was added and stirring continued for one more hour. TLC indicated the reaction was complete. The reaction mixture was concentrated to dryness. The resultant pale green residue was dissolved in ethyl acetate and washed with 0.5 N HCl (1×10 mL), saturated NaHCO3 solution (1×10 mL) and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, 2% MeOH/CH2Cl2) to afford the title compound as a colorless viscous material (0.63 g, 75% over 2 steps). The enantiomers were separated by chiral HPLC (Chiralpak AD, 40:60 Hexane/EtOH) to give the enantiomers D6a and D6b. MS: APCI: M+1: 463.1 (Exact Mass: 462.16).