Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][NH:8][CH:3]([CH2:4][CH2:5]2)[CH2:2]1.[ClH:9].O.[OH-].[K+].[C:13]1([C:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH2:22][CH2:23]Br)[C:20]#[N:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1C=CC=CC=1>[ClH:9].[C:25]1([C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([CH2:22][CH2:23][N:8]2[CH2:7][CH:6]3[CH2:5][CH2:4][CH:3]2[CH2:2][CH2:1]3)[C:20]#[N:21])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: C1CC2CCC1CN2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: N#CC(CCN1CC2CCC1CC2)(c1ccccc1)c1ccccc1
Yield: 76.8 %

Procedure:
To a stirred solution of 0.85 part of 2-azabicyclo-[2.2.2.]octane hydrochloride in 20 parts of water is added 0.71 part of potassium hydroxide under a nitrogen atmosphere. Then, 1.90 parts of 2,2-diphenyl-4-bromobutyronitrile is added, and the mixture heated to reflux for 3.5 hours. This reaction mixture is cooled to about 60° C., whereupon 13 parts of benzene is added. The aqueous layer is separated and extracted with 15 parts of benzene. To the combined benzene extracts is added dropwise 2 parts by volume of a solution of hydrochloric acid in isopropanol. The volume of this solution is reduced by heating on a steam bath. Cooling affords a white precipitate which is washed with benzene and dried at 100° C. for about 2 hours. The resulting product, 2,2-diphenyl-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile hydrochloride, is obtained in approximately 76.8% yield. This product melts at about 194° - 197° C., and is represented by the following structural formula. ##STR11##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:24])[C:14]=1B1OC(C)(C)C(C)(C)O1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][O:8][CH2:7]1.Br[C:26]1[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][C:27]=1[F:36].CCN(C(C)C)C(C)C>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:24][C:13]1[CH:12]=[C:4]([O:5][CH:6]2[CH2:11][CH2:10][CH2:9][O:8][CH2:7]2)[CH:3]=[C:2]([F:1])[C:14]=1[C:26]1[N:31]=[C:30]([C:32]([O:34][CH3:35])=[O:33])[CH:29]=[CH:28][C:27]=1[F:36]
Reactant: CC1(C)OB(c2c(F)cc(OC3CCCOC3)cc2F)OC1(C)C
Reactant: COC(=O)c1ccc(F)c(Br)n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(OC3CCCOC3)cc2F)n1
Temperature: 120 °C

Procedure:
A mixture of 3-[3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]tetrahydro-2H-pyran (0.436 g, 1.28 mmol), methyl 6-bromo-5-fluoropyridine-2-carboxylate (0.300 g, 1.28 mmol) and DIPEA (0.67 mL, 3.8 mmol) in 1,4-dioxane (6 mL) and water (0.3 mL) was purged with nitrogen and then bis(tri-tert-butylphosphine)palladium (65.5 mg, 0.128 mmol) was added. The reaction mixture was sealed and heated at 120° C. for 40 min., then cooled and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to give methyl 6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][Cl:5].[CH3:7][O-:8].[Na+].[CH3:10][OH:11]>>[CH3:1][O:2][C:3](=[O:6])[CH2:4][C:7]([O:11][CH3:10])=[O:8].[CH3:1][O:2][C:3](=[O:6])[CH3:4].[CH3:1][O:2][C:3](=[O:6])[CH2:4][Cl:5]
Reactant: C[O-]
Reactant: CO
Agent: COC(=O)CCl
Agent: [Na+]
Product: COC(=O)CC(=O)OC
Product: COC(C)=O
Yield: 5.5 %

Procedure:
As in Example 1, but with 25 g of Co2 (CO)8 and 2.5 l of methanol, at 5.2 at. CO and 60° C., 868 g (8 moles) of chloroacetic acid methyl ester is reacted for 51/2 hours at a pH of approximately 8.0 with 1.67 kilograms of 17.8% sodium methylate (5.5 moles) in methanol. After processing, 660 g of malonic acid dimethyl ester is obtained (yield 91%) plus 22 g of acetic acid methyl ester (yield 5.5%) and about 20 g of high-boiling compounds, and 271 g of chloroacetic acid methyl ester.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]([F:33])([F:32])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]=3[N:22]=[C:23]([CH2:25][O:26][CH3:27])[N:24]=2)=[CH:14][CH:13]=1.Cl[C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][N:36]=1>O1CCOCC1.C(N(CC)C(=O)C)C>[Cl:41][C:40]1[C:35]([N:29]2[CH2:30][CH2:31][C:20]3[C:19]([NH:18][C:15]4[CH:16]=[CH:17][C:12]([C:11]([F:10])([F:32])[F:33])=[CH:13][CH:14]=4)=[N:24][C:23]([CH2:25][O:26][CH3:27])=[N:22][C:21]=3[CH2:28]2)=[N:36][CH:37]=[CH:38][CH:39]=1
Reactant: Clc1cccnc1Cl
Reactant: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCNC2
Agent: CCN(CC)C(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Yield: 11.9 %

Procedure:
A mixture of diisopropylethylamine (490 mg, 3.8 mmol), N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine (˜1.9 mmol) and 2,3-dichloropyridine (562 mg, 3.8 mmol) in dioxane (5 mL) and N,N-diethylacetamide (1.0 mL) was irradiated in microwave at 180° C. for 10 h. Solvent was removed in vacuo and the residue was purified by column chromatography. The product was obtained as a beige solid (102 mg).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:11]([CH3:15])[C:12]([OH:14])=O)=[CH:5][CH:4]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[N:24][CH:25]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C=O>[Cl:26][C:23]1[N:24]=[CH:25][C:20]([CH2:19][NH:18][C:12](=[O:14])[C:11](=[N:10][NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:16])=[CH:8][CH:7]=2)[CH3:15])=[CH:21][CH:22]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=NNc1ccc(C(F)(F)F)cc1)C(=O)NCc1ccc(Cl)nc1
Yield: 78 %

Procedure:
2-(4-Trifluoromethylphenyl hydrazono) propionic acid (12.31 g, 50.0 mmol) was dissolved in dichloromethane (250 ml) and N,N-dimethylformamide (25 ml), and 5-aminomethyl-2-chloropyridine (7.13 g, 50.0 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloric acid salt (9.59 g, 50.0 mmol) were added thereto. 30 hours later, the mixture was washed with 1N hydrochloric acid, a saturated sodium bicarbonate water and a saturated brine, and dried on sodium sulfate and then filtrated. The residue obtained by concentrating the resulting filtrate was purified with a silica gel chromatography to obtain N-(6-chloro-3-pyridylmethyl)-2-(4-trifluoromethylphenyl hydrazono) propionic acid amide (Compound No. 63) (14.47 g, 39.02 mmol, 78%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@:5]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[CH3:6].CCN(C(C)C)C(C)C.Cl[C:37]([O:39][CH3:40])=[O:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:13][C:9]1[CH:8]=[C:7]([C@@:5]([C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)([O:4][CH2:3][CH2:2][NH:1][C:37]([O:39][CH3:40])=[O:38])[CH3:6])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](C)(OCCN)c2cccc(Cl)c2)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(2-aminoethoxy)-1-(3-chlorophenyl)ethyl)piperidine-1-carboxylate (0.410 g, 1.07 mmol), DMAP (0.380 g), DIPEA (4 mL), and methyl chloroformate (0.960 g) in CH2Cl2 was stirred at rt for 20 h. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to afford (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-(methoxycarbonylamino)ethoxy)ethyl)piperidine-1-carboxylate. MS ESI +ve m/z 465 (M+Na).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[CH:19]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]2)=[C:5]([N+:25]([O-])=O)[CH:4]=1)#[N:2].[CH:28](OCC)(OCC)OCC.C(O)=O.C(Cl)Cl.CO.[OH-].[NH4+]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[CH:19]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20]3)[CH:28]=[N:25][C:5]=2[CH:4]=1)#[N:2]
Reactant: CN1CCC(c2c[nH]c3ccc(Nc4ccc(C#N)cc4[N+](=O)[O-])cc23)C1
Reactant: CCOC(OCC)OCC
Agent: [NH4+]
Agent: [OH-]
Solvent: O=CO
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(-n4cnc5cc(C#N)ccc54)cc23)C1
Yield: 22 %

Procedure:
5-(4-Cyano-2-nitrophenyl)amino-3-(N-methylpyrrolidin-3-yl)-1H-indole was used. Reduction was by catalytic hydrogenation, the cyclization reaction used triethyl orthoformate/formic acid, and the cyclization reaction was heated for 2 hours. Chromatography using 9:1:0.5 [methylene chloride/methanol/ammonium hydroxide] afforded the title compound (22%) as a light yellow solid: Rf =0.35 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 13C NMR (CDCl3) δ 145.7, 143.3, 137.5, 136.5, 127.5, 126.8, 126.7, 125.4, 123.0, 120.3, 119.9, 118.5, 115.8, 112.7, 111.9, 105.7, 62.8, 56.3, 42.3, 35.0, 32.3; FAB LRMS (m/z, relative intensity) 342 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][C:32]=2[C:34](O)=[O:35])[CH:27]=[CH:26][CH:25]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:33]=2[N:24]=[CH:25][CH:26]=[CH:27]3)=[O:35])=[O:10])[N:12]=1
Reactant: O=C(O)c1cccc2cccnc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3cccnc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with Quinoline-8-carboxylic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:35])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([C:25]2[N:24]=[C:23]([CH3:35])[C:22]([CH2:21][O:19][C:6]3[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]4[CH:18]=[CH:17][N:16]=[N:15]4)=[C:4]([CH3:3])[CH:5]=3)=[CH:27][CH:26]=2)=[CH:29][CH:30]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)ccc1CCl
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(Cl)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
33 mg (0.83 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 172 mg (0.79 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.79 mmol) 3-chloromethyl-6-(4-chloro-phenyl)-2-methyl-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, ethyl acetate, and ether. 324 mg (91%) of the title compound were obtained as slightly beige powder.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]1([C:25]([OH:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1.[C:28]([O:32][C:33](=[O:46])[C:34]([CH2:36][CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[CH2:35])([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[CH2:39]([O:38][CH2:37][CH2:36][CH:34]([C:33]([O:32][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:46])[CH2:35][C:19]1([C:25]([OH:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C=C(CCOCc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)C1=CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)C(CCOCc1ccccc1)CC1(C(=O)O)C=CCCC1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (8.8 mL, 62.8 mmol) in dry tetrahydrofuran (140 mL) at -50° C. was added a 2.5M solution of n-butyllithium in hexane (25 mL, 12.5 mmol). The mixture was stirred at a temperature from -50° C. to -20° C. over 30 minutes and then cooled again to -50° C. Solid 1-cyclohexene carboxylic acid (3.75 g, 29.7 mmol) was added and the resulting mixture was allowed to warm to room temperature with stirring over 1.5 hours. The reaction was cooled to -78° C. and a solution of 2-(2-benzyloxyethyl)acrylic acid tert-butyl ester (7.45 g, 28.4 mmol) in dry tetrahydrofuran (90 mL) was added over 15 minutes; stirring was continued at -78° C. for 5 hours. The mixture was then allowed to warm to -30° C. over 40 minutes and was quenched by the addition of saturated aqueous NH4Cl solution. After acidification using 3N HCl solution, the mixture was extracted with ether. The extract was washed with brine, dried over MgSO4 and evaporated under vacuum to leave a yellow oil from which 1-(4-benzyloxy-2-tert-butoxycarbonylbutyl)cyclohex-2-ene carboxylic acid (an oily mixture of the two diastereomers), 9.71 g (84%) was isolated by chromatography on silica gel eluting with methylene chloride and then 5% methanol in methylene chloride.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:44]([CH3:45])=[CH:43][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[C:30](OS(C(F)(F)F)(=O)=O)[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:53][NH2:54]>C1COCC1>[C:1]([O:5][C@@H:6]([C:12]1[C:44]([CH3:45])=[CH:43][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[C:30]([NH:54][CH3:53])[CH:29]=[CH:28]5)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:46]1[CH:47]=[CH:48][C:49]([Cl:52])=[CH:50][CH:51]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5nc(OS(=O)(=O)C(F)(F)F)ccc5c4)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CN
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5nc(NC)ccc5c4)c3)sc2c1-c1ccc(Cl)cc1

Procedure:
(S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(2-(trifluoromethylsulfonyloxy)quinolin-6-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (28.0 mg, 0.036 mmol) and 1.0 mL of methylamine at 2M in THF were heating at 80° C. for 3 days. Concentrated in vacuo and then purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C37H36ClN4O3S: 651.2; found: 651.3.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.CS(O[CH:13]([C:35]1[CH:40]=[CH:39][C:38](C(F)(F)F)=C[CH:36]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]2[CH2:22][C@H:23]([O:25][C:26]3[CH:31]=[N:30][C:29]([CH:32]4[CH2:34][CH2:33]4)=[CH:28][N:27]=3)[CH2:24][C@H:18]2[CH2:17]1)=[O:15])(=O)=O.[F:45][CH2:46][CH2:47][NH2:48].C(N)C>>[CH:32]1([C:29]2[N:30]=[CH:31][C:26]([O:25][C@H:23]3[CH2:22][N:19]4[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH:13]([NH:48][CH2:47][CH2:46][F:45])[C:35]5[CH:40]=[CH:39][CH:38]=[C:3]([C:2]([F:7])([F:6])[F:1])[CH:36]=5)[CH2:17][C@@H:18]4[CH2:24]3)=[N:27][CH:28]=2)[CH2:34][CH2:33]1
Reactant: CS(=O)(=O)OC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1ccc(C(F)(F)F)cc1
Reactant: NCCF
Reactant: O=C(O)C(F)(F)F
Agent: CCN
Product: O=C(C(NCCF)c1cccc(C(F)(F)F)c1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1

Procedure:
The title compound was prepared as a trifluoroacetic acid salt according to the procedure described in Example 194B, substituting the product from Example 179A for the product from Example 194A, and substituting 2-fluoroethanamine for ethylamine 1H NMR (300 MHz, CDCl3) δ ppm 0.88-1.06 (m, 4 H) 4.62-4.77 (m, 1 H) 4.78-4.93 (m, 1 H) 5.42-5.71 (m, 1 H) 7.63-7.76 (m, 3 H) 7.77-7.86 (m, 1 H) 7.88-7.95 (m, 1 H) 7.98-8.14 (m, 1 H); MS (ESI) m/z 508 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:28][C:29]3[CH:34]=[C:33]([CH3:35])[C:32]([OH:36])=[C:31]([CH3:37])[CH:30]=3)[C:19](=[O:27])[N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=2[NH:3]1.[CH3:42][C:43]1([OH:49])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.CC(O)=O.[Na].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:28][C:29]3[CH:34]=[C:33]([CH3:35])[C:32]([OH:36])=[C:31]([CH3:37])[CH:30]=3)[C:19]([N:20]3[CH2:21][CH2:22][CH:23]([N:46]4[CH2:47][CH2:48][C:43]([OH:49])([CH3:42])[CH2:44][CH2:45]4)[CH2:24][CH2:25]3)=[O:27])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=2[NH:3]1
Reactant: CC1(O)CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(=O)CC2)cc(C)c1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C)(O)CC3)CC2)cc(C)c1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 50 mg (0.09 mmol) of (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 79) in 1.5 mL DCM was combined with 21 mg (0.18 mmol) 4-methyl-piperidin-4-ol and 10.3 μl (0.19 mmol) AcOH, cooled to 0° C. and stirred for 2 h. Then 28 mg (0.19 mmol) sodium-triacetoxyborohydride were added and the mixture was stirred overnight at 0° C. After the solvent had been eliminated the residue was combined with 2 mL DMF and purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[NH:17]1[CH2:22][CH2:21]OCC1.[CH:23]1C=CC=C[CH:24]=1>>[CH:22]([NH:17][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4])([CH2:23][CH3:24])[CH3:21]
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: C1COCCN1
Reactant: c1ccccc1
Product: CCC(C)NCC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 4 h

Procedure:
10 g of 5-chloroacetyl-8-hydroxycarbostyril (IV) prepared in Example 4 or 8 was suspended in 60 ml of benzene, and 9 ml of morpholine was added to the suspension followed by allowing the mixture to react while heating under refluxing and stirring for 4 hours. The reaction mixture was cooled and the resulting precipitate was filtered. The precipitate was dissolved in 60 ml of isopropanol and the solution was adjusted to a pH of 2- 3 with concentrated hydrochloric acid. The resulting acidic solution was cooled with ice and the precipitate formed was filtered followed by recrystallization from ethanol. The precipitate was dissolved in 20 ml of water and the solution was adjusted to a pH 7.5- 8.0 with sodium bicarbonate and ice-cooled. The precipitate formed upon cooling was filtered and recrystallized from ethanol to obtain 4.2 g of white amorphous 5-morpholinoacetyl-8-hydroxycarbostyril (II) having a melting point of 238° - 239.5° C. (with decomposition). The product thus obtained was confirmed by IR and NMR spectral analyses and elemental analysis.
Reaction SMILES: [H-].[Na+].[O:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH2:4][CH3:5].[Br:13][C:14]1[C:15](Cl)=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1.CCOC(C)=O>CN(C=O)C.CC#N>[Br:13][C:14]1[C:15]([O:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:3][CH2:4][CH3:5])=[N:16][C:17]([Cl:20])=[N:18][CH:19]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CCOc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOc1ccccc1Oc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of NaH (0.42 g 60% in mineral oil, 10.5 mmol) in DMF (8.0 mL) was slowly added 2-ethoxylphenol (1.34 g, 9.7 mmol) in MeCN (4.0 mL) at 0° C. under N2. After the addition, the reaction mixture was allowed to warm up to room temperature for 0.5 hour. 5-bromo-2,4-dichloropyrimidine (2.0 g, 8.8 mmol) in MeCN (16.0 mL) was slowly added and then the resulting reaction mixture was stirred at room temperature for 24 hour. EtOAc (120 mL) was added and washed with NaOH (30 mL, 0.5N) and brine (25×2 mL). The organic layer was dried with MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10% to 30% EtOAc in Hexanes, gradient elution) to provide the 5-bromo-2-chloro-4-(2-ethoxyphenoxy)pyrimidine. MS m/z=330 [M+1]+. Calc'd for: C12H10BrClN2O2: 329
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=O)[O:16][CH:17]=3)=[CH:12][C:3]1=2.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1([CH3:20])[C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[N:22][OH:23])[O:16][CH:17]=3)[CH:10]=[CH:9][C:4]=2[NH:5][C:6](=[O:8])[O:7]1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3coc(C=O)c3)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1(C)OC(=O)Nc2ccc(-c3coc(C=NO)c3)cc21

Procedure:
A mixture of 4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbaldehyde (2.7 g, 10 mmol), hydroxylamine hydrochloride (0.75 g, mmol) and sodium acetate (0.87 g, 10.6 mmol) was heated at reflux in 80% ethanol (25 mL) for 2 hours. The title compound crystallized from the cooled reaction mixture as tan crystals (1.5 g, 52.4%): mp 236-238° C. 1H NMR (DMSO-d6) δ 11.97 (s, 1H), 10.26 (s, 1H), 8.2 (s, 1H), 7.63 (s, 1H), 7.56-7.52 (m, 3H), 6.91-6.88 (d, 1H, J=8.1 Hz), 1.66 (s, 6H). MS ESI m/z 285 [M−H]−. Anal. Calcd. For C15H14N2O4: C, 62.93; H, 4.93; N, 9.79. Found C, 62.77; H, 5.00; N, 9.79.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[OH:10]N1C(=O)N(O)C(=O)N(O)C1=O.[C:22]([OH:25])(=[O:24])[CH3:23].O=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.O>[C:7]([C:4]1[CH:5]=[CH:6][C:23]([C:22]([OH:25])=[O:24])=[CH:2][CH:3]=1)#[N:8].[C:7]([C:4]1[CH:5]=[CH:6][C:1]([CH:9]=[O:10])=[CH:2][CH:3]=1)#[N:8]
Reactant: Cc1ccc(C#N)cc1
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Reactant: CC(=O)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: O
Product: N#Cc1ccc(C(=O)O)cc1
Product: N#Cc1ccc(C=O)cc1

Procedure:
A mixture of 0.351 g of p-tolunitrile, 0.005 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (1% by mole relative to p-tolunitrile), 5 g of acetic acid and 0.004 g of cobalt(II) acetate.4 H2O was stirred at 100° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 14 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield 4-cyanobenzoic acid and 4-cyanobenzaldehyde in 74% and 1% yields, respectively, at 81% conversion of p-tolunitrile.