Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][OH:25])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH3:37]N(C)C=O.[H-].[Na+].CI>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][O:25][CH3:37])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: CN(C)C=O
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methanol (0.30 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.030 g) at 0° C. After stirring the reaction mixture at 0° C. for 30 min, methyl iodide (0.11 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-furyl)-4-{[2-methoxy-4-({[4-(methoxymethyl)-1-phenyl-1H-pyrazol-3-yl]oxy}methyl)phenoxy]methyl}-5-methyl-1,3-oxazole as colorless crystals (0.20 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=O)=O.O>CC(C)=O>[I:1][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15]
Reactant: [I-]
Reactant: CS(=O)(=O)OCCCCCC(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)C(F)(F)CCCCCI
Yield: 85.8 %

Procedure:
Sodium iodide (27.37 g, 182.58 mmol) was added to a solution of 1-methanesulfonyloxy-6,6,7,7,7-pentafluoroheptane (17.3 g, 60.86 mmol) in acetone (500 ml), followed by heating under reflux for 12 hours. Water was added to the reaction mixture, which was then extracted twice with ether. The combined organic layers were washed with 1% aqueous sodium thiosulfate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give 1-iodo-6,6,7,7,7-pentafluoroheptane (16.5 g, Yield 86%).
Reaction SMILES: [Br-].[C:2]1([C:8]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][O:10][C:9]2=[N+:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[C:31]2[CH2:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[C:31]2[CH2:39][CH:40]2[CH2:41][CH2:42][N:43]([CH2:11][CH2:12][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([N:13]([CH3:15])[CH3:14])=[O:10])[CH2:44][CH2:45]2)=[CH:25][CH:24]=1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Reactant: Fc1ccc(Cn2c(CC3CCNCC3)nc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)C(CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A mixture of 5.55 parts of N-(dihydro-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide, 4.85 parts of 1-[(4-fluorophenyl)methyl]-2-(4-piperidinylmethyl)-1H-benzimidazole, 2 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred overnight at 70° C. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.8 parts (20%) of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 151.4° C. (150).
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3](OC)=[O:4].[CH3:11][NH:12][NH2:13]>C(OCC)C>[OH:4][C:3]1[N:12]([CH3:11])[N:13]=[C:1]([C:7]([O:9][CH3:10])=[O:8])[CH:2]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: CNN
Solvent: CCOCC
Product: COC(=O)c1cc(O)n(C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A diethyl ether solution (35 ml) of dimethyl acetylenedicarboxylate (5.0 g, 35 mmol) was cooled with a freezing medium (salt & ice). To this solution, a diethyl ether solution (15 ml) of methyl hydrazine (0.63 ml, 35 mmol) was added dropwise while maintaining the temperature at 0° C. or less. After completion of dropwise addition, the solution was stirred at 0° C. for one hour. The insoluble matter precipitated was obtained by filtration and washed with diethyl ether. The filter cake was heated to 130° C. for 30 minutes and cooled to room temperature. Methanol was added to the cake, which was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue and the residue was concentrated under reduced pressure. Ethyl acetate was added to the residue and the insoluble matter precipitated was obtained by filtration, washed with ethyl acetate, and dried to obtain methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (3.26 g) as light yellow powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.Cl.[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1ccc2ccccc2c1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc2ccccc2c1

Procedure:
Following General Procedure B′ and using 2-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B′ above), the title compound was prepared as a solid having a melting point of 128-129° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[CH2:22]([N:13]1[CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[N:11]=[CH:12]1)[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)CBr
Reactant: O=[N+]([O-])c1ccc(-c2c[nH]cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1cnc(-c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-nitrophenyl)-1H-imidazole (0.500 g, 2.64 mmol) in N,N-dimethylformamide (10 ml) was added cesium carbonate (1.292 g, 3.96 mmol) followed by 1-bromo-2,2-dimethylpropane (0.366 ml, 2.91 mmol). After heating at 85° overnight, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Normal phase chromatography provided the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClC1C=CC=CC=1.Cl[C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][N:16]=1>C(O)CO>[N:1]1([C:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17][N:16]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nsc2ccccc12
Solvent: OCCO
Solvent: Clc1ccccc1
Product: c1ccc2c(N3CCNCC3)nsc2c1
Yield: 92.3 %

Procedure:
215.4 g (2.50 mol) of piperazine, 50.0 g of chlorobenzene, 100.0 g of ethylene glycol were placed in a four-neck 1000 ml flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, 169.5 g (1.00 mol) of 3-chloro-1,2-benzisothiazole was added dropwise in the melted state at about 120° C. over 1 hour while stirring, which was thereafter stirred for 2 hours to complete the reaction. After excess piperazine was removed with water, the reaction mixture was made acidic with hydrochloric acid, extracted into an aqueous layer, which was made alkaline with aqueous sodium hydroxide to obtain 202.4 g (m.p. 89°-90° C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. Yield from 3-chloro-1,2-benzisothiazole was 92.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[F:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=S)[CH:26]=[CH:27][CH:28]=1.C[Si](C)(C)[Si](C)(C)C.[Li].[NH2:41][NH2:42].C(O)(=O)C>O.C1COCC1>[F:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[NH:42][N:41]=[C:9]3[C:10]4[C:6]([CH2:7][C:8]=23)=[CH:5][C:4]([O:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:3]([O:2][CH3:1])[CH:11]=4)[CH:26]=[CH:27][CH:28]=1
Reactant: Fc1cccc(N=C=S)c1
Reactant: COc1cc2c(cc1OCCCN1CCCC1)CCC2=O
Reactant: NN
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1OCCCN1CCCC1)Cc1c-2n[nH]c1Nc1cccc(F)c1

Procedure:
A mixture of 6-methoxy-5-(3-pyrrolidin-1-yl-propoxy)-indan-1-one (Intermediate K, 0.45 g, 0.00155 mole), 3-fluoro-phenyl isothiocyanate (Compound 4a) (0.19 mL, 0.0017 mole) and THF (1.5 mL) was added to lithium hexamethyldisilane (1.8 mL, 0.0018 mole) dropwise at room temperature with stirring. The reaction mixture was stirred for 4 hrs. Hydrazine (0.095 mL, 0.003 mole) and acetic acid (0.180 mL, 0.003 mole) were added to the reaction mixture. The reaction mixture was then heated at the reflux temperature for 18 hrs. The resulting mixture was first added to water (10 mL) and then extracted with CH2Cl2. The organic layers were combined and washed with aqueous NaHCO3 solution, then washed with water and brine solution, dried (Na2SO4), and solvent was removed in vacuo. The crude material was purified on the reverse phase HPLC. Lyophilization yielded the title compound, (3-Fluoro-phenyl)-[7-methoxy-6-(3-pyrrolidin-1-yl-propoxy)-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl]-amine as a white powder. MS m/z 423 (M+H)+; 1HNMR (DMSO-d6): 1.88(m, 2H), 2.00(m, 2H), 2.15(m, 2H), 3.02(m, 2H), 3.29(dd, 2H), 3.37(s, 2H), 3.61(m, 2H), 3.74(s, 3H), 4.04(t, 2H), 6.52(t, 1H), 6.93(d, 1H), 7.18(m, 4H), 8.8(br s, 1H), 9.7(br s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[C:9]1([S:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCCCCCCSc1ccccc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(Nc1cccc(C2CCN(CCCCCCSc3ccccc3)CC2)c1)C1CC1

Procedure:
Prepared by Procedure G and Scheme B1 using [(6-chlorohexyl)sulfanyl]benzene and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 437.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](C(OCC)=O)[N:3]=1.[CH3:13][Mg]Br.[O:16]1[CH2:20][CH2:19]CC1>>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:20]([OH:16])([CH3:19])[CH3:13])[N:3]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1nccc(N)n1
Reactant: C[Mg]Br
Product: CC(C)(O)c1nccc(N)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a solution of ethyl 4-aminopyrimidine-2-carboxylate (840 mg, 5.0 mmol) in anhydrous tetrahydrofuran (50 mL) cooled at −20° C. was added a solution of methylmagnesium bromide in THF (8.5 mL, 25.0 mmol, 3.0 M) over a period of 5 minutes. The reaction mixture was stirred at 0° C. for another 2 h. It was then quenched with saturated NH4Cl (20 mL) and concentrated under reduced pressure. The residue was extracted with ethyl acetate (5×40 mL). The combined organic layer was dried over anhydrous Mg2SO4, filtered, and evaporated under reduced pressure. The residue was purified by reverse-phase Combiflash to afford 264a as yellow solid (240 mg, 32%) MS-ESI: [M+H]+ 154.1
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]3)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1.[C:28]([O:31][CH2:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[CH:35][C:34]=1[N:48]1[CH2:60][CH2:59][N:51]2[C:52]3[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=3[CH:58]=[C:50]2[C:49]1=[O:61])(=[O:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[CH:35][CH:36]=[CH:37][C:38]=1[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]3)[C:5](=[O:26])[N:4]([CH3:27])[CH:3]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)c1=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: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, tert-butyl 6-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)-3,4-dihydroisoquinoline-2(1H)-carboxylate 120a (300 mg, 0.689 mmol), 114a (352 mg, 0.758 mmol), Pd(PPh3)4 (39.8 mg, 0.0345 mmol), Na2CO3 aqueous solution (1.0 N, 2.27 mL, 2.27 mmol), 1,2-dimethoxyethane (3.5 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 174a.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:21]=4)[O:16]3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[NH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][C:13]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:31][O:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][O:34]5)=[O:29])[CH:21]=4)[O:16]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)O)ccc2O3)cc1
Reactant: NOC1CCCCO1
Solvent: ClCCl
Product: Cc1ccc(CCN2CCC3(CC2)CC(=O)c2cc(/C=C/C(=O)NOC4CCCCO4)ccc2O3)cc1

Procedure:
(E)-3-{1′-[2-(4-Methyl-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (257 mg, 0.581 mmol) was suspended in DCM (5 ml). TEA (0.12 ml, 0.87 mmol) was added and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-[2-(4-methyl-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (265 mg) as a yellow solid. The resulting product was dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.5 ml, 2 mmol) as described in Example 55, Step D, giving the desired hydroxamic acid as a light yellow solid (204 mg, hydrochloride salt).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]([OH:55])([CH2:53][CH3:54])[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[C:50]([CH3:52])[N:51]=[C:25]23)[CH2:20][CH2:19]1)[CH3:14]>C(OCC)(=O)C>[CH2:13]([C:15]([OH:55])([CH2:53][CH3:54])[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:36][CH:37]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[C:50]([CH3:52])[N:51]=[C:25]23)[CH2:20][CH2:19]1)[CH3:14]
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)(CC)CC)CC2)c2nc(C)nn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)(CC)CC)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.27 g), sodium hydrogen carbonate (0.43 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(2-ethyl-2-hydroxybutoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.05 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.043 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.08 g, 48%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:10]([O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:7][C:6]2[CH:8]=[CH:9][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:14]=1)[CH3:11]
Reactant: CCOc1ccc(C=O)cc1
Reactant: CSc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ccc(CNc2ccc(SC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To 5.0 mL (40.19 mmol) of 4-(methylthio)aniline dissloved in 25 mL dichloromethane was added 5.59 mL (40.19 mmol) 4-ethoxybenzaldehyde followed by 12.78 g (60.28 mmol) sodium triacetoxyborohydride. The mixture was stirred at overnight at room temperature, partitioned between EtOAc and brine, dried over MgSO4 and concentrated. Crystallization from dichloromethane/hexane, provided 7.87 g of (4-Ethoxy-benzyl)-(4-methylsulfanylphenyl)-amine, pure by 1H NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:29]([O-])=O)[C:5]([CH:8](C(OCC2C=CC=CC=2)=O)[C:9](OCC2C=CC=CC=2)=[O:10])=[N:6][CH:7]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[NH:29][C:9](=[O:10])[CH2:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=C1Cc2ncc(Br)cc2N1
Temperature: 120 °C
Reaction time: 7 h
Yield: 53.3 %

Procedure:
Iron dust (0.82 g, 14.60 mmol) was added to a solution of dibenzyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (preparation 30b, 1.78 g, 3.70 mmol) in glacial acetic acid (50 mL) and the mixture was heated with stirring to 120° C. After 7 hours, the mixture was cooled and left to stand overnight. The reaction was poured onto ice-water and extracted first with ethyl acetate and then with chloroform. The combined organic extract was washed with brine, dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (98:2 dichloromethane/methanol) gave the title compound (0.42 g, 54%) as a pink solid.
Reaction SMILES: [Na].C(O)C.[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8][CH2:9][CH3:10])=O.C([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])C.Cl>C1(C)C=CC=CC=1>[CH2:9]([O:8][CH:6]([C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])[C:5]([O:12][CH2:13][CH3:14])=[O:11])[CH3:10]
Reactant: CCOCC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)C(OCC)C(=O)OCC
Temperature: 45 °C
Yield: 87 %

Procedure:
A stirred mixture of molten sodium metal (24.15 g, 1.05 mol) in toluene is treated with ethanol (55.2 g, 1.2 mol) over a 1 hr period at 100° C.-110° C., heated at reflux temperatures for 0.5 hr, cooled to 45° C., treated with a mixture of diethyl oxalate (160.6 g, 1.1 mol) and ethyl ethoxyacetate (132 g, 98%, 0.98 mol) over a 1 hr period at 45° C.-50° C., heated at 55° C.-60° C. for 1.5 hr and poured into 328 g of 14% HCl with cooling. The resultant mixture is separated. The title product is obtained as a 32% solution in the organic phase, identified by HRGC analysis, total yield is 198.2 g (87% yield).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH3:24])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=2)=[O:14])=[CH:5][CH:4]=1.C[Si](I)(C)C.CO>C(Cl)(Cl)Cl>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([CH2:9][NH:10][C:11]2[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[C:23][CH3:24])=[C:18]([C:25]([F:28])([F:26])[F:27])[CH:17]=2)=[O:14])[CH:5]=[CH:4]1
Reactant: CC#Cc1ccc(NC(=O)c2ccccc2NCc2ccc(OC)nc2)cc1C(F)(F)F
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC#Cc1ccc(NC(=O)c2ccccc2NCc2ccc(=O)[nH]c2)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 2-[[6-methoxy-3-pyridinyl]methyl]amino-N-[4-(1-propynyl)-3-(trifluoromethyl)-phenyl]benzamide (step 4.1; 1.10 g, 2.5 mmol) and trimethylsilyl iodide (Fluka, Buchs, Switzerland; 1.0 mL, 7.5 mmol) in chloroform (30 mL) is stirred at 60° C. for 16 hours under an argon atmosphere. The cooled mixture is then treated with methanol (2 mL) and stirred at room temperature for 10 minutes. The solvent is evaporated under reduced pressure and the residue is treated with an aqueous solution of ammonia (100 mL of 5%) and extracted with ethyl acetate (3×100 mL). The combined extracts are washed with saturated aqueous sodium chloride (50 mL), dried (MgSO4), filtered and the solvent is evaporated under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent ethyl acetate and recrystallised from hot ethyl acetate hexane to give the title compound as a colourless crystalline solid; m.p. 208–212° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[C:4]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][CH2:11][CH2:10][CH2:9][C:5]1[C:4]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[N:3][C:2]([NH2:1])=[N:7][C:6]=1[CH3:8]
Reactant: CCCCCNc1nc(N)nc(C)c1CCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCNc1nc(N)nc(C)c1CCCN
Yield: 84.6 %

Procedure:
The product from step (iv) (3.8 g) was dissolved in DCM (100 mL) and TFA (35 mL) and the reaction mixture stirred at rt for 16 h. The solvent was evaporated and the residue taken up in MeOH. The product was purified via SCX resin to give the subtitle compound 2.3 g.