Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([NH:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:27](OCC)(=O)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:20]=[CH:19][C:11]([C:12]([N:14]([CH2:15][CH:16]3[CH2:17][CH2:18]3)[CH3:27])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCC1CC1)c1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(CC1CC1)C(=O)c1ccc(OCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 30 ml of N,N-dimethylformamide was dissolved 1.5 g of 4-(4-chlorobenzyloxy)-N-cyclopropylmethylbenzamide. To the solution was added 0.25 g of sodium hydride. The mixture was stirred at room temperature for 30 minutes and then at 60° C. for 30 minutes. The reaction mixture was ice-cooled, and 0.5 ml of methyl iodide was added thereto. The mixture was stirred overnight at room temperature. The reaction mixture was treated with ethyl acetate-water. The resulting ethyl acetate layer was separated, washed with water, dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent. The resulting residue was purified by column chromatography (eluant: dichloromethane/acetone=50/1) to obtain 1.4 g of 4-(4-chlorobenzyloxy)-N-cyclopropylmethyl-N-methylbenzamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=O)[S:6][CH:7]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:17][OH:18].O>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[N:17][OH:18])[S:6][CH:7]=1)#[N:2]
Reactant: NO
Reactant: N#Cc1csc(C=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1csc(C=NO)c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
11.6 g (84.6 mmol) of 4-cyanothiophene-2-carbaldehyde were dissolved in 140 ml of methanol and 12.3 g (116.1 mmol) of sodium carbonate were added. 6.5 [lacuna] (93.5 mmol) of hydroxylamine hydrochloride were subsequently added at 15° C. with cooling, a little at a time, and the mixture was stirred for 2 hours at 10° C. After 80 ml of water had been added, the reaction mixture was extracted five times using in each case 50 ml of diethyl ether, the organic phase was dried over sodium sulfate and the solvent was removed in vacuo. 12.5 g of the required product resulted as a yellow crystal powder (96% of theory).
Reaction SMILES: Cl([O-])=[O:2].[Na+].C(O)(=[O:7])C.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(OCC)(=O)C>[OH2:2].[O:7]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)O
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)C(=O)OCC
Product: O
Temperature: 25 °C
Reaction time: 3 h
Yield: 131.2 %

Procedure:
To a 100 mL four-necked flask equipped with a mechanical stirrer, a dropping funnel and a thermometer, 49.6 g (0.137 mole) of 25% sodium chlorite aqueous solution, and then 2.6 mL (0.046 mole) of acetic acid were slowly added. The pH in the reaction system was pH 4.4. Furthermore, 10 g (0.062 mole) diethyl malonate was slowly added under room temperature, and then the mixture was stirred under room temperature for 3 hours, and then 49 mL ethyl acetate was added to the reaction system to separate the liquids. The organic layer was separated, and ethyl acetate was distilled off under reduced pressure, to give 11.6 g of diethyl ketomalonate hydrate (melting point: 54.6 to 56.9° C.) (97% yield rate).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[CH:14]=[N:15][CH:16]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH3:25][N:17]([C:13]1[CH:14]=[N:15][CH:16]=[C:11]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=1)[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19]
Reactant: CCS(=O)(=O)Nc1cncc(-c2cc3ccccc3n2C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)c1cncc(-c2cc3ccccc3n2C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A flask is charged with ethanesulfonic acid [5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide (example 226, 100 mg, 0.317 mmol) and DMF (4 mL). The reaction is cooled to 0° C. and sodium hydride (15.85 mg, 0.396 mmol) is added. The reaction is stirred at 0° C. for 10 min, then methyl iodide (56.3 mg, 0.396 mmol) is added. The reaction is stirred for 1 hour at room temperature. The reaction is quenched with water (0.5 mL) and filtered. The filtrate is purified using Xbridge C18 eluting with a 10 to 100% acetonitrile-water gradient to afford ethanesulfonic acid methyl-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide. 1H NMR (400 MHz, MeOD) δ ppm 1.39 (t, J=7.5 Hz, 3H), 3.28 (q, J=7.5 Hz, 2H), 3.49 (s, 3H), 3.84 (s, 3H), 6.74 (s, 1H), 7.14 (t, J=7.6 Hz, 1H), 7.28 (ddd, J=7.6, 1.1 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 8.13 (t, J=2.1 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H), 8.70 (d, J=2.5 Hz, 1H). HRMS (ESI) m/z 330.1281 [(M+H)+ Calcd for C17H19N3O2S 330.1270].
Reaction SMILES: CC([O-])=O.CC([O-])=O.[Pd+2:9].[CH:10]1([P:16]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH:33]1([P:16]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.[Pd:9]
Reactant: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: [Pd]
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
A solution of the catalyst was prepared as follows: An oven-dried Wheaton vial equipped with a magnetic stir bar was charged with Pd(OAc)2 (5.60 mg, 0.025 mmol, 1.0 eq.) and 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (4d) (20.5 mg, 0.050 mmol, 2.0 eq.). Toluene (3.00 mL) was added and the vial was sealed with a PTFE-lined plastic cap. The resulting mixture was stirred at 23° C. for 45 min. resulting in a yellow Pd/4d catalyst solution (0.00833 N Pd in toluene).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]#[C:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[N:24][CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(O)(=O)C>[Fe].O>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([C:18]#[C:19][C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[N:24][CH:25]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
A mixture of tert-butyl [5-({2-[(tert-butoxycarbonyl)amino]-5-nitrophenyl}ethynyl)pyridin-3-yl]carbamate (1.60 g, 3.52 mmol), methanol (37 mL), acetic acid (7.3 mL), water (3.7 mL) and iron (905 mg, 16.2 mmol) was stirred at 60° C. for 3 h. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate and extracted with ethyl acetate once. The combined organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.40 g, 94%). LCMS calculated for C23H29N4O4(M+H)+: m/z=425.1.
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C)C=O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10](=[O:13])[N:11]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:12]=1
Reactant: O=c1ccc(Cl)n[nH]1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccc(Cl)nn1CC1CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Cyclopropylmethyl bromide (0.82 mL) was added to a mixture of 6-chloro-2H-pyridazin-3-one (1.0 g) and K2CO3 (2.10 g) in dimethylformamide (10 mL). The resulting mixture was stirred at 60° C. overnight. Then, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried (MgSO4). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 99:1:0.1) to afford the title compound as an oil.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Yield: 87.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-methylphenylboronic acid (124 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (180 mg, 87.8%) as an oil.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5])#[N:2].[C:11]([O:14][C:15](=O)C)(=O)[CH3:12].C(OCC)(OCC)OCC>>[C:1]([C:3](=[CH:15][O:14][CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5])#[N:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)COC(=O)CC#N
Solvent: CCOC(OCC)OCC
Product: CCOC=C(C#N)C(=O)OCC(C)C

Procedure:
A mixture of isobutyl cyanoacetate (30 g), acetic anhydride (58 ml) and triethyl orthoformate (43 ml) was heated under reflux for 6 hours. The volatile material was evaporated and the residue was distilled to give isobutyl 2-cyano-3-ethoxy-2-propenoate, b.p. 130°-133° C./0.4 mm. A solution of this (6 g) in ethanol (30 ml) was mixed with benzylmethylamine (4 ml). The mixture was heated under reflux for 10 minutes and then cooled and diluted with water (50 ml). The solid was filtered and recrystallised from ethanol giving isobutyl 3-(benzylmethylamino)-2-cyano-2-propenoate, mp 105°-106° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[ClH:1].[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]2[N:13]([CH3:25])[C:12]3[CH:26]=[CH:27][C:9]([N:8]([CH3:28])[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]5[CH:31]=[C:32]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:33]=[CH:34][CH:35]=5)[N:7]=4)=[CH:10][C:11]=3[N:15]=2)=[CH:19][CH:20]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccc(F)cc1)n2C)c1ccnc(Cl)n1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: CN(c1ccc2c(c1)nc(NCc1ccc(F)cc1)n2C)c1ccnc(Nc2cccc(S(N)(=O)=O)c2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-fluoro-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (99 mg, 0.25 mmol) and 3-amino-benzenesulfonamide (43 mg, 0.25 mmol) as a white solid (104 mg, 73%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 10.08 (br s, 1H), 9.57 (br s, 1H), 8.46 (s, 1H), 7.87 (d, J=1.8 Hz, 1H), 7.73 (m, 1H), 7.55-7.58 (m, 3H), 7.40 (d, J=3.3 Hz, 2H), 7.35 (s, 1H), 7.30 (s, 2H), 7.16-7.23 (m, 3H), 5.74 (d, J=4.5 Hz, 1H), 4.73 (d, J=4.2 Hz, 2H), 3.71 (s, 3H), 3.47 (s, 3H). MS (ESI) m/z=533 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16])[C:4]([Cl:7])([Cl:6])[Cl:5].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>O>[CH3:1][O:2][CH:3]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:24](=[O:26])[CH3:25])[C:4]([Cl:7])([Cl:6])[Cl:5]
Reactant: CC(=O)Cl
Reactant: COC(NC(=O)c1ccccc1O)C(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(NC(=O)c1ccccc1OC(C)=O)C(Cl)(Cl)Cl
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
To 2.5 g of N-(1'-methoxy-2',2',2'-trichloroethyl)-2-hydroxy benzamide was added 20 g of pyridine and maintained at below -10° C., 1.5 g of acetyl chloride was added dropwise and then allowed at room temperature for about 30 minutes, and poured into water to give a crystal which was recrystalized by using methanol to obtain 2.2 g white crystal of N-(1'-methoxy-2',2',2'-trichloroethyl)-2-acetoxy benzamide.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][O:39]1)(=O)=O>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CS(=O)(=O)OCCC1CCCCO1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCC3CCCCO3)c2n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
A mixture of N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt (200 mg) and potassium carbonate (236 mg) in dry DMF (2 mL) were heated at 60° C. with stirring for 1 h. 2-(Tetrahydro-2H-pyran-2-yl)ethyl methanesulfonate (142 mg) was added and the reaction was continued for 3 h at 60° C. The mixture was quenched with water and extracted with EtOAc (×3). The combined organics were washed with water and brine, dried using a hydrophobic frit and evaporated to give crude material (250 mg). The material was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to give 75 mg of material which was recrystallised from ether/light petrol yielding the title compound as a solid, 54 mg.
Reaction SMILES: [F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:12]([OH:15])(=O)[CH3:13].C(O[C:19]1(O[Si](C)(C)C)[CH2:21][CH2:20]1)C>C(O)C>[CH2:12]([O:15][N:5]([CH:19]1[CH2:21][CH2:20]1)[C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([F:1])[C:3]=1[O:10][CH3:11])[CH3:13]
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(=O)O
Reactant: COc1c(N)ccc(F)c1F
Solvent: CCO
Product: CCON(c1ccc(F)c(F)c1OC)C1CC1
Temperature: 25 °C
Yield: 83 %

Procedure:
Into a 200-ml four-necked flask provided with a reflux condenser, a thermometer and a stirrer were fed 7.96 g (0.05 mol) of 3,4-difluoro-2-methoxyaniline, 40 g (0.67 mol) of acetic acid and 100 ml of ethanol. To the resulting mixture being stirred at room temperature was dropwise added 9.24 g (0.053 mol) of 1-ethoxy-1-trimethylsilyloxycyclopropane. The resulting mixture was placed on an oil bath and refluxed at 80° C. for 3 hours with stirring, in a nitrogen current. The resulting reaction mixture was concentrated under aspirator vacuum by the use of a rotary evaporator. Lastly, the acetic acid remaining in the resulting residue was removed by the use of a vacuum pump to obtain 11.5 g of an oily substance. This oily substance was subjected to vacuum distillation to obtain 10.1 g (yield: 83.0%) of N-(1-ethoxy)cyclopropyl-3,4-difluoro-2-methoxyaniline.
Reaction SMILES: [CH2:1]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[C:18]([O:20]C)=[O:19])[O:11][C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Li+]>>[CH2:1]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[C:18]([OH:20])=[O:19])[O:11][C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH2:1]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[C:18]([O-:20])=[O:19])[O:11][C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H]1CCCCN1c1nc2ccc(CC(C)C)cc2o1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)Cc1ccc2nc(N3CCCC[C@H]3C(=O)O)oc2c1
Product: CC(C)Cc1ccc2nc(N3CCCC[C@H]3C(=O)[O-])oc2c1

Procedure:
The title compound was prepared by a similar method to Preparation 3 from methyl (2S)-1-(6-isobutyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate [see Preparation 41] and 1N aqueous lithium hydroxide solution, to afford (2S)-1-(6-isobutyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate acid as a foam.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:15][C:16]1([O:19][CH2:18]1)[CH3:17]>CN(C)C=O.O>[CH3:15][C:16]([OH:19])([CH3:18])[CH2:17][O:12][C:2]1([CH3:1])[CH2:11][CH2:10][C:5]2([O:6][CH2:7][CH2:8][O:9]2)[CH2:4][CH2:3]1
Reactant: CC1(C)CO1
Reactant: CC1(O)CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)COC1(C)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (4.01 g) in N,N-dimethylformamide (20 mL) was added 60% sodium hydride in oil (960 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To this mixture was added isobutylene oxide (2.52 g), and the mixture was stirred at 90° C. for 15 hr. The reaction mixture was cooled to room temperature, and diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→65/35 (volume ratio)] to give the title compound as a colorless oil (1.81 g, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]([CH3:22])([CH2:20][OH:21])[C:17](O)=[O:18].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]([CH2:20][OH:21])([CH3:22])[NH:15][C:9]2=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CC(N)(CO)C(=O)O
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(CO)NC(=O)N(c2ccc(Cl)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Yield: 41.4 %

Procedure:
1-Chloro-4-isocyanato-2-trifluoromethyl-benzene (4.40 g, 20 mmoL) and 2-amino-3-hydroxy-2-methyl-propionic acid (2.38 g, 20 mmoL) in dioxane (100 mL) was heated at 80° C. for 6 hrs. The reaction was cooled to room temperature and concentrated HCl (2 mL) was added and the reaction mixture was heated to refluxed for 4 hrs. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with sat. NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated, then recrystallization was conducted using ethyl acetate as solvent to afford the title compound as a white solid (2.65 g, yield 41%).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1>CN(C=O)C.O>[CH3:18][C:17]1[C:12]([S:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccnc1F
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccnc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of NaH (2.4 g, 99 mmol) in 100 mL of DMF cooled to 0° C. is added benzylmercaptan (12.3 g, 99 mmol). The solution was allowed to warm to room temperature than recooled to 0° C. 2-Fluoro-3-methylpyridine in 10 mL DMF was added dropwise and stirred at room temperature overnight. The solution was diluted with H2O, extracted twice with Et2O, twice with EtOAc, and the combined organics washed twice with saturated NaHCO3, dried and concentrated. The resulting oil was flash chromatographed (10% Et2O/hexane (v/v)) to yield 16.3 g of the desired product. NMR (200 MHz, CDCl3) δ 2.24 (s, 3H), 4.50 (s, 2H), 6.9 (dd, 1H), 7.2 (m, 5H), 7.4 (d, 1H) and 8.3 (d, 1H).
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[O:8])=[N:4][N:3]=[N:2]1.O.C(O)C.[OH-].[Na+]>[H][H].[Pd]>[NH:4]1[C:5]([NH:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[O:8])=[N:1][N:2]=[N:3]1
Reactant: [H][H]
Reactant: O=C(Nc1nnn[nH]1)c1cccc(C=Cc2ccccc2)n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(Nc1nnn[nH]1)c1cccc(CCc2ccccc2)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
A mixture of 2 g of N-(5-tetrazolyl)-6-styryl-2-pyridinecarboxamide, 30 ml of water, 15 ml of ethanol, 5 ml of an aqueous 10% sodium hydroxide solution and 0.18 g of 10% palladium-on-carbon is shaken at 40° C. for 2 hours and then at room temperature for 15 hours in hydrogen gas stream under atmospheric pressure. After the reaction, ethanol is added to the mixture to dissolve the precipitates therein. Insoluble materials are filtered off, and the filtrate is adjusted to pH 3 with 10% hydrochloric acid. The crystalline precipitates are collected by filtration, washed with water, dried and then recrystallized from a mixture of dimethylformamide and ethanol. 1.34 g of N-(5-tetrazolyl)-6-phenethyl-2-pyridinecarboxamide are thereby obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[C:18](=[O:19])[CH2:17][O:16][CH2:15][C:14]2=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:26][CH:27]=1.[OH-].[Na+:33]>>[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[CH2:15][O:16][CH2:17][C:18]([O-:29])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[Na+:33].[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=1)([O-:31])(=[O:30])=[O:29].[Na+:33]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1COCC(=O)N1CCCCCCN1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: O=C([O-])COCC(=O)NCCCCCCN1CCCCC1

Procedure:
Preparation in situ from 4-(6-piperidinohexyl)-3,5-dioxomorpholine.p-toluenesulfonate. 43 milligrams (0.095 millimole) of 4-(6-piperidinohexyl)-3,5-dioxomorpholine.p-toluenesulfonate (prepared as described in Example IX) was dissolved in 2 milliliters of 0.1N sodium hydroxide (0.2 millimole) to obtain an aqueous solution of sodium [2-(6-piperidinohexyl)amino-2-oxoethoxy]acetate and sodium tosylate. The solution had the following spectral characteristics: