Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[C:14]([N:24]1[CH2:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@H:37]([CH2:39][NH2:40])[O:36][C:35]3=[O:41])=[CH:30][C:29]=2[F:42])[CH2:25]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:42][C:29]1[CH:30]=[C:31]([N:34]2[CH2:38][C@H:37]([CH2:39][NH:40][C:7](=[O:9])[CH3:8])[O:36][C:35]2=[O:41])[CH:32]=[CH:33][C:28]=1[CH:26]1[CH2:27][N:24]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:25]1
Reactant: NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Pyridine (1.0 mL), acetic anhydride (1.0 mL) and a few crystals of 4-dimethylaminopyridine were added to a stirred solution of (S)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 8, 1.42 g, 3.56 mmol) in methylene chloride (30 mL), then stirred for 1 hr. The solvents were removed at 38°/0.75 mm and the residue chromatographed over silica gel (50 g, 40-60 μm) eluting with 1-2% methanol-chloroform. The title compound was isolated as a white foam. FAB-HRMS: theory 442.1778 (M+1); meas. 442.1777.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][C:28]([C:32]([O:34]C)=[O:33])=[CH:29]4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1.CO.[OH-].[Na+]>O1CCCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:31]=[C:30]4[C:25]([CH:26]=[CH:27][C:28]([C:32]([OH:34])=[O:33])=[CH:29]4)=[CH:24][CH:23]=3)=[CH:20][CH:21]=2)=[C:12]([CH:36]([CH3:38])[CH3:37])[O:11][N:10]=1
Reactant: COC(=O)c1ccc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3ccc(C(=O)O)cc3c2)cc1
Temperature: 100 °C
Yield: 77 %

Procedure:
A solution of methyl 7-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-naphthalenecarboxylate (0.126 g, 0.2 mmol) in tetrahydrofuran (2.0 mL) was placed in a microwave reaction tube. Methanol (1.0 mL) was added followed by 1 N sodium hydroxide (0.3 mL, 0.3 mmol). The tube was sealed and heated in a microwave reactor to 100° C. for 600 seconds. The solution was neutralized and concentrated. Water was added and the mixture was filtered. The resulting solid was dried in a vacuum oven at 45° C. with P2O5 to yield the title compound (0.082 g, 73.9% as 0.30 tetrahydrofuran) 1H NMR (DMSO-d6): δ 13.3-12.6 (broad s, approximately 1H), 8.61 (s, 1H), 8.29 (s, 1H), 8.02-7.87 (m, 4H), 7.68 (d, J=9 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 7.54 (dd, J=7, 9 Hz, 1H), 6.91 (d, J=9 Hz, 2H), 4.86 (s, 2H), 3.44 (septet, J=7 Hz, overlapping H2O, 1H), 1.33 (d, J=7 Hz, 6H). HRMS C30H23NO4Cl2 m/z 532.1082, (M+H)+cal; 532.1087 (M+H)+Obs.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH:5]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26]CCC)=[CH:21][CH:20]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([N:1]2[CH2:4][CH:3]([CH:5]([C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=3)[C:6]([O:8][CH3:9])=[O:7])[CH2:2]2)[CH3:26])=[CH:21][CH:20]=1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Reactant: CCCCC(=O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(C)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.015 g (0.054 mmole) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate, 0.020 g (0.101 mmol) of 1-(4-chlorophenyl)pentan-1-one and 0.015 mL (0.12 mmol) of triethylamine in 5 mL of dichloroethane was stirred at room temperature. After 5 min, 0.050 g (0.237 mmol) of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 6 h. The reaction was quenched by addition of saturated K2CO3 solution and the mixture was partitioned between 10 mL ether and 2 mL saturated K2CO3 solution. The layers were separated and the organic layer was dried over Na2SO4, and concentrated. The residue was purified by reverse phase chromatography (Waters Xterra C18, 19 mm×10 mm) using a gradient of CH3CN—H2O-Et3N (20:80:0.1 to 60:40:0.1). Homogenous fractions were pooled and concentrated to afford the title compound as a mixture of isomers; Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl). Mass Spectrum: m/e=422 (M+1 35Cl and 424 (M+1 37Cl).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:11]([C:6]2[N:7]=[CH:8][C:9]3[N:10]=[C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[S:3][C:4]=3[N:5]=2)[CH3:32])[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: O=C(Cl)C1CC1
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (151 mg, 340 μmol) in N,N-dimethylacetamide (4 mL) was added cyclopropanecarbonyl chloride (389 μL, 4.32 mmol), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The solid which crystallized in the extract was collected by filtration to give the title compound (119 mg, 68%) as colorless crystals.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=3[CH3:25])=[C:9]([C:14]#[N:15])[CH:10]=[N:11]2)=[CH:6][C:5]=1[N+:26]([O-])=O)=[N+]=[N-].[H][H]>[Pd].C(O)C.O1CCCC1>[NH2:26][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[NH2:1])[N:11]=[CH:10][C:9]([C:14]#[N:15])=[C:8]2[NH:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[CH3:25]
Reactant: [H][H]
Reactant: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C)c(Nc2c(C#N)cnc3cc(N)c(N)cc23)c1
Yield: 72.4 %

Procedure:
A mixture of 0.65 g (1.73 mmol ) of 7-azido-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile and 0.12 g of 10% palladium on carbon in a 1:1 mixture of ethanol/tetrahydrofuran is shaken on Parr apparatus with hydrogen gas at 40 psi for 2 hours. The mixture is filtered through a pad of diatomaceous earth, washed with methanol and tetrahydrofuran, then dried to provide a dark solid. The crude product is purified by silica gel chromatography, utilizing a gradient of methylene chloride/methanol (95:5 to 88:12) to yield 0.4 g of 6,7-diamino-4-(5-methoxy-2-methylanilino)-3-quinolinecarbonitrile as a dark solid, mp 245° C. (dec).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[S:17]1C=[CH:20][CH:19]=[C:18]1[Mg]Br.[Cl-].[NH4+].O>C1COCC1>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Br[Mg]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1cccs1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 12 (2.24 g, 10 mmole) in absolute THF (10 ml) was added dropwise to a 1M solution of thiophen-2-yl-magnesium bromide in THF (20 ml, 20 mmole) under argon and while cooling with ice, and stirred for 20 hours at RT. To work up the reaction mixture saturated ammonium chloride solution (10 ml) and water (10 ml) were added while cooling with ice and the mixture was extracted with diethyl ether (3×10 ml). The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated by evaporation.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:10]=1)=[O:8])[CH3:5].[CH3:27][O-:28].[Na+]>CN1CCCC1=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:7]2[O:8][C:3]([CH2:2][O:28][CH3:27])=[C:4]([CH3:5])[N:6]=2)=[N:10]1
Reactant: C[O-]
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2F)c2ccccc12
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COCc1oc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1C
Yield: 25.6 %

Procedure:
136 mg of 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene (0.267 mmol) and 47 mg of sodium methylate were stirred in 0.6 ml of N-methylpyrrolidone at 100° C. under argon overnight. The crude mixture was cooled and purified directly by column chromatography (SiO2). 24 mg (20%) of 2-[1-(2-fluorobenzyl)-indazol-3-yl]-5-methoxymethyl-4-methyl-oxazole were isolated as yellowish crystals.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=1
Reactant: O=Cc1ccc(-n2cnnc2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-n2cnnc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4H-1,2,4-triazol-4-yl)-benzaldehyde (prepared as described in WO 98/03476) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:6])[CH3:5].[OH-].[K+].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[C:12]([Cl:18])[CH:11]=1>O1CCCC1.C(OCC)C.C1OCCOCCOCCOCCOCCOC1>[Cl:18][C:12]1[CH:11]=[C:10]([F:9])[CH:17]=[CH:16][C:13]=1[CH2:14][N:3]([O:2][CH3:1])[C:4](=[O:6])[CH3:5]
Reactant: CONC(C)=O
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CON(Cc1ccc(F)cc1Cl)C(C)=O
Temperature: 25 °C
Yield: 33.5 %

Procedure:
To a stirred mixture of 1.95 g (0.0219 mole) of N-methoxyacetamide, 1.23 g 0.022 mole) of powdered potassium hydroxide, and a small amount (~0.05 g) of 18-crown-6 in 10 ml of tetrahydrofuran was added a solution of 5.05 g (0.0226 mole) of 4-fluoro-2-chlorobenzyl bromide in 15 ml of tetrahydrofuran. This mixture was heated at reflux for approximately 17 hours and then was allowed to cool to room temperature. The mixture was diluted with 125 ml of diethyl ether and was washed with an aqueous, saturated sodium chloride solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure leaving a yellow oil. This oil was purified by column chromatography on silica gel, eluting with ethyl acetate:n-heptane (25:75) followed by ethyl acetate:n-heptane (50:50) , to yield 1.7 g of N-(2-chloro-4-fluoro-benzyl)-N-methoxyacetamide as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C[O:17][C:18]([C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19].C1COCC1.[Li+].[OH-]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:26][C:25]2[C:20]([C:18]([OH:19])=[O:17])=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1ncccc1N
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(O)c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Prepared from 0.60 g (2.17 mmol) of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride and 0.30 g (1.97 mmol) of 3-amino-pyridine-2-carboxylic acid methyl ester in 3 mL pyridine using procedure x. The solvent was switched to THF, followed by the addition of 1 M aqueous LiOH and the mixture stirred for 1 h. The pH of the mixture was adjusted to neutral and the product was extracted with ethyl acetate. LC-MSD, m/z for C13H8ClF3N2O4S [M+H]+=380.9, 383.0; HPLC retention time: 1.8 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[Cl-].[CH2:39]([C:41]1[S:42][CH:43]=[C:44]([CH2:46][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:45]=1)[CH3:40].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:39]([C:41]1[S:42][CH:43]=[C:44](/[CH:46]=[CH:13]\[C:12]2[C:8]([O:7][CH2:6][C:5]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]4[N:27]=[C:28]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[S:29][C:30]=4[CH3:31])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:9][N:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:11]=2)[N:45]=1)[CH3:40]
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(N4CCOCC4)sc3C)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.6 %

Procedure:
A mixture of 3-({3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.75 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.89 g), potassium carbonate (0.29 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give 4-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-thiazol-2-yl]morpholine as colorless crystals (0.25 g, yield 28%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 112-114° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17]COC(=O)C(C)(C)C)=[O:16])=[C:13]([CH3:26])[N:12]([CH2:27][O:28][CH3:29])[C:11]([CH3:30])=[C:10]1[C:31]([O:33][CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[O:32]>C(OC(C)C)(C)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:31]([O:33][CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:38])([CH3:39])[CH3:40])=[O:32])=[C:11]([CH3:30])[N:12]([CH2:27][O:28][CH3:29])[C:13]([CH3:26])=[C:14]1[C:15]([OH:17])=[O:16]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2cccc(Cl)c2Cl)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: O
Solvent: CC(C)OC(C)C
Product: COCN1C(C)=C(C(=O)O)C(c2cccc(Cl)c2Cl)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
In 15 ml of isopropyl ether saturated with water was dissolved 614 mg of bis(pivaloyloxymethyl) 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-3,5-pyridinedicarboxylate obtained in Example 6, and 100 mg of Lipase B was added thereto, followed by stirring at 25° C. for 4 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 405 mg (yield: 81%) of (+)-4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-1-methoxymethyl-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a colorless crystal.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8](Cl)=[O:9].CCOC(C)=O>C1COCC1>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8]([N:2]([CH3:3])[CH3:1])=[O:9]
Reactant: CNC
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(OC)c1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of dimethylamine (42 mL, 84 mmol) in THF at 0° C. is added 2,6-dimethoxybenzoyl chloride (5.58 g, 27.8 mmol) and it is warmed to RT and stirred for 18 h. The mixture is poured to EtOAc, washed with water, 1 N HCl solution and brine. The solvent is removed and concentrated to give the title compound and it is used in the next step.
Reaction SMILES: CC1(C)[C@H]2CC[C@]1(CS(O)(=O)=O)C(=O)C2.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH2:26])[CH2:20]2.O.[C:28](Cl)(=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCOC(C)=O>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH:26][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1Cc2ccc(Br)cc2C1
Agent: CC1(C)[C@H]2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1Cc2ccc(Br)cc2C1)OCc1ccccc1
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To (S)-5-bromo-2,3-dihydro-1H-inden-2-amine((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (13.95 mmol, 6.2 g) in EtOAc (93 mL)/Water (93 mL) was added benzyl carbonochloridate (15.35 mmol, 2.62 g) dropwise at 0° C. under an argon atmosphere. The reaction was left to stir for 18 hrs. The aqueous layer was removed before washing the organic with brine. The organics were dried over MgSO4 before filtering and removing the solvent in vacuo to give the title compound as a white solid (4.8 g, 99%). 1H NMR (400 MHz, CDCl3) δ 2.79 (m, 2H), 3.25 (m, 2H), 4.53 (d, 1H), 4.93 (brs, 1H), 5.10 (s, 2H), 7.08 (d, 1H) 7.31 (m, 7H).
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1)#[N:3].[H-].[Na+].[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[CH2:42][O:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=O)=[CH:46][CH:45]=1>CN(C=O)C>[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[CH2:42][O:43][C:44]1[CH:45]=[CH:46][C:47]([CH:48]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:29][CH:28]=2)=[CH:50][CH:51]=1
Reactant: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: N#Cc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 5.51 g (13.29 mmol) of (4-cyanobenzyl)triphenylphosphonium chloride in 100 ml of dry DMF under positive nitrogen atmosphere is cooled to 0° C. and 0.50 g (20.77 mmol), of an 80% NaH in oil dispersion is added in small portions. The suspension is aged for 15 minutes at 0° C. followed by 45 minutes at room temperature to assure complete anion formation. The flask is cooled back to 0° C. and 3.5 g (13.29 mmol) of 4-(2-quinolinylmethyloxy)benzaldehyde in 20 ml of DMF is dropped in over a period of 15 minutes. The reaction is allowed to equilibrate to room temperature and stirred for 2 hours. The resultant mixture is poured into ice water and filtered. The precipitate is dissolved in CH2Cl2, dried, and concentrated in vacuo. The crude product is recrystallized from ether to give 4-(4-(2-quinolinylmethyloxy)styryl)benzonitrile. (M.P. 116° C. -118° C.)
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1C=CC=CC=1.[CH3:11][C:12]([C:19]([F:22])([F:21])[F:20])([C:16](F)=[O:17])[C:13](F)=[O:14]>C(COC)OC>[CH3:11][C:12]1([C:19]([F:22])([F:21])[F:20])[C:16](=[O:17])[NH:4][C:2](=[O:3])[NH:1][C:13]1=[O:14]
Reactant: CC(C(=O)F)(C(=O)F)C(F)(F)F
Reactant: NC(N)=O
Solvent: c1ccncc1
Solvent: COCCOC
Product: CC1(C(F)(F)F)C(=O)NC(=O)NC1=O
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a suspension of 1.50 g (0.025 mol) of urea in 30 ml of glyme and 4.0 g (0.050 mol) of pyridine was added dropwise with stirring a solution of 5.0 g (0.026 mol) of methyltrifluoromethylmalonyl fluoride in 20 ml of glyme. Urea dissolved during a mildly exothermic reaction and the homogeneous solution was allowed to stand overnight. The mixture was then refluxed briefly, solvent was removed under vacuum, and the residue was stirred with 25 ml of water. Filtration and rinsing with water gave 3.80 g of 5-methyl-5-trifluoromethylbarbituric acid, mp 205°-206.5°C. A second crop, mp 205°-207°C, 0.84 g, brought the yield to 88% (4.64 g). Recrystallization from water gave an analytical sample, mp 205°-206°C; ir (KBr): 3.07 and 3.17 (NH), 5.67 shoulder and 5.80 (C=O), and 8-8.5 μ (CF); nmr ((CD3)2CO): 1H at ca. 7.0 (very broad, 2 (partly exchanged into acetone-d6), NH) and 1.72 ppm (quartet, JHF = 0.7 Hz, 3, CH3); 19F at -70.8 ppm (quartet, JHF = 0.7 Hz, CF3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: CN1CCC(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CC1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 4-amino-1-methylpiperidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1-methylpiperidin-4-yl)terephthalamide. MS (Q1) 483 (M)+.