Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[N:8]([NH2:13])[CH:9]=[C:10]([F:12])[CH:11]=1)=[O:6])[CH:2]=[CH2:3].[CH:14](=O)[CH2:15][CH:16]([CH3:18])[CH3:17].C([BH3-])#N.[Na+]>CO>[CH2:1]([O:4][C:5]([C:7]1[N:8]([NH:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:10]([F:12])[CH:11]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)CC=O
Reactant: C=CCOC(=O)c1cc(F)cn1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)c1cc(F)cn1NCCC(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.2 %

Procedure:
To a solution of 1-amino-4-fluoro-1H-pyrrole-2-carboxylic acid allyl ester (Example 14f, 0.5 g, 2.717 mmol) in methanol (20 mL) were added isovaleraldehyde (0.257 g, 2.988 mmol) and sodium cyanoborohydride (0.256 g, 4.075 mmol). The mixture was stirred for 20 h at 25° C. The solvent was removed in vacuo and the crude product was purified by flash column chromatography (Merck silica gel 60, 40-63 μm, 20% ethyl acetate in hexanes) to afford the desired product, 4-fluoro-1-(3-methyl-butylamino)-1H-pyrrole-2-carboxylic acid allyl ester (0.264 g, 1.039 mmol, 38.2% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.91 (3H, s), 0.93 (3H, s), 1.38-1.45 (2H, m), 1.63-1.80 (1H, m), 3.00-3.05 (2H, m), 4.74-4.76 (1H, m), 5.29 (1H, d, J=10.4 Hz), 5.38 (1H, d, J=18.8 Hz), 5.94-6.03 (1H, m), 6.52-6.56 (1H, m), 6.79-6.81 (1H, m).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([As:8]([OH:11])([OH:10])=[O:9])[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:18][CH2:19][C:20](Br)=[O:21]>O.ClCCl>[Br:18][CH2:19][C:20]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([As:8]([OH:10])(=[O:11])[OH:9])=[CH:4][CH:5]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc([As](=O)(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc([As](=O)(O)O)cc1
Temperature: 4 °C
Reaction time: 0.04 h

Procedure:
BRAA was prepared by a modification of the method described in Donoghue et al (2000) and WO 01/21628. p-Arsanilic acid (20.6 g, 95 mmol) was added in portions to a solution of sodium carbonate (20 g, 189 mmol) in water (200 mL). When all solids had dissolved, the solution was found to be pH 10, and was chilled at 4° C. for 2 hours. Bromoacetyl bromide (15 mL, 173 mmol) in dry dichloromethane (35 mL) was added in two portions, each addition followed by vigorous shaking for 2 to 3 min. The mixture was allowed to stand for a few minutes, and the lower organic layer was drained off. 4-(N-(Bromoacetyl)amino)benzenearsonic acid (BRAA) was precipitated by acidification of the solution to about pH 2-3 with the dropwise addition of 98% sulfuric acid, collected by vacuum filtration, and dried, giving BRAA as a white solid.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([N:24]=[N+]=[N-])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].Cl.[CH2:28]([O:30][CH2:31][CH3:32])C>C(O)C.[Pd]>[C:1]([O:4][CH:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:11]([NH:24][C:17](=[O:18])[C:12]2[CH:32]=[C:31]([O:30][CH3:28])[CH:5]=[C:6]([O:7][CH3:8])[CH:11]=2)[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])[C@H]1OC(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1cc(OC)cc(C(=O)N[C@H]2[C@@H](OC(C)=O)[C@@H](COC(C)=O)OC(OC(C)=O)[C@@H]2OC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
1,2,4,6-Tetra-O-acetyl-3-azido-3-deoxy-D-galactopyranose 1 (167 mg, 0.45 mmol) was suspended in ethanol (5 ml), and palladium (10% on carbon, 17 mg) and HCl (1 ml of a 1M solution in diethyl ether) were added. The mixture was degassed and stirred at room temperature under a hydrogen atmosphere. After 1 h, dichloromethane was added, and the mixture was filtered through Celite and concentrated in vacuo. Half of the residue was dissolved in dichloromethane (2 ml) and pyridine (0.5 ml). 3,5-Dimethoxybenzoyl chloride (168 mg) was added, and the mixture was stirred at room temperature. After 18 h, TLC (1:1, heptane:ethyl acetate) showed the presence of a single carbohydrate product (Rf 0.2). The reaction mixture was diluted with diethyl ether (30 ml) and washed with H2SO4 (30 ml of a 10% aqueous solution), NaHCO3 (30 ml of a saturated aqueous solution), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give 1,2,4,6-tetra-O-acetyl-3-deoxy-3-(3,5-dimethoxybenzamido)-D-galactopyranose 4 (50 mg, 44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:33][CH2:34][CH:35]([OH:38])[CH2:36][CH2:37]5)[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCC(O)CC2)CC1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCC(O)CC4)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 19.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.6 g) and 5-amino-2-[4-(4-hydroxypiperidin-1-yl) piperidin-1-yl]benzonitrile (0.6 g), the title compound (0.2 g) was obtained, melting point: 213° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1([N:20]([CH3:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][CH2:13][C:14]1([N:20]([CH3:28])[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6]
Reactant: CN(Cc1ccccc1)C1(CN)CCCCC1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Product: CN(Cc1ccccc1)C1(CNC(=O)c2ccc(Cl)c(Cl)c2)CCCCC1
Yield: 98.8 %

Procedure:
A solution of 3,4-dichlorobenzoyl chloride (2.095 g.) in benzene (50 ml) was added to a solution of 1 -aminomethyl-N-methyl-N-benzylcyclohexylamine (2.32 g.) in benzene (50 ml) and the mixture heated under reflux for 1 hr. The solution was allowed to cool, washed with 2N sodium hydroxide solution (3 × 50 ml), water (4 × 100 ml), dried (Na2SO4) and evaporated to give a white crystalline solid (4.0 g). Recrystallisation from cyclohexane afforded 1-[3,4-dichlorobenzoylaminomethyl]-N-methyl-N-benzylcyclohexylamine (110/39) as white prisms (3.589 g. 89%) m.p. 139°-145°.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[OH:8][C:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[NH:11][C:10]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].[OH-].[Na+]>O.C(O)(C)C>[OH:8][C:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:19])(=[O:20])[N:11]([CH3:5])[C:10]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1,425 ml (15 mol) of dimethyl sulfate are added at between 10° and 15° C. to a solution of 2,833 g (10 mol) of isopropyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide and 440 g (11 mol) of sodium hydroxide in 4 l of water and 11.3 l of isopropanol. The mixture is maintained with stirring for 4 hours at room temperature, diluted with 28 l of water and cooled to 0°-5° C. The precipitate obtained is centrifuged, washed with cold water and dried, 2.675 g (90%) of a white or slightly pink solid, m.p. 102°-3° C. (104°-5° C. from methanol), being obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C(OCC)(=O)C.O>[Cl:16][CH2:17][CH2:18][C:19]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:20]
Reactant: O=C(Cl)CCCl
Reactant: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cccc(C)c1NC(=O)CCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A mixture of 2,6-dimethylaniline (60.5 g) and potassium carbonate (45 g) is dissolved in a 3:1 mixture of ethyl acetate and water (1,200 ml). To the ice-cooled mixture, 100 ml of an ethyl acetate solution of 3-chloropropionyl chloride (52.5 ml) is added dropwise under agitation. The reaction mixture is stirred for 3 hours at room temperature and the aqueous layer is subsequently separated. The organic layer is washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and subsequently dried over Glauber's salt. Upon distilling off the solvent under vacuum, a colorless powder results. Recrystallization from ethanol provides a colorless needle in an amount of 96.5 g (yield: 90.8%). m.p. 131° C.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([C:16]4[N:20](CCC#N)[N:19]=[N:18][N:17]=4)[CH:15]=[C:10]3[N:9]=[C:8]2[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:33][C:34]1[CH:39]=[C:38]([C:40]([NH:42][CH3:43])=[O:41])[CH:37]=[CH:36][C:35]=1[C:44]1[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH3:43][NH:42][C:40]([C:38]1[CH:37]=[CH:36][C:35]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)=[C:34]([CH2:33][O:31][C:28]2[CH:29]=[CH:30][C:25]([C:8]3[N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:11]4=[N:12][CH:13]=[C:14]([C:16]5[NH:17][N:18]=[N:19][N:20]=5)[CH:15]=[C:10]4[N:9]=3)=[CH:26][CH:27]=2)[CH:39]=1)=[O:41]
Reactant: CNC(=O)c1ccc(-c2ccc(C#N)cc2)c(CBr)c1
Reactant: N#CCCn1nnnc1-c1cnc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(-c2ccc(C#N)cc2)c(COc2ccc(-c3nc4cc(-c5nnn[nH]5)cnc4n3C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
Intermediate 63 (50 mg, 0.12 mmol) in dimethylformamide was reacted with 2-(bromomethyl)-4′-cyano-N-methyl-1,1′-biphenyl-4-carboxamide (63a) (40 mg, 0.12 mmol), cesium carbonate (20 mg, 0.06 mmol) and the resulting suspension stirred under a nitrogen atmosphere at rt for 3h at which point ethyl acetate (30 mL) was added. The organic phase was washed with water (2×25 mL) and brine (1×), dried (Na2SO4), and concentrated on a rotary evaporator. The resulting residue was dissolved in 10% methanolic sodium hydroxide (5 mL) and water (2 mL) was added. The resulting solution was stirred at rt under a nitrogen atmosphere for 30 minutes at which point 10% hydrochloric acid was added until pH=2. This solution was extracted with ethyl acetate, dried (Na2SO4), and concentrated on a rotary evaporator and the residue purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product as a white solid (6 mg, 7%). 1H NMR (CD3OD) δ 9.16 (s, 1H), 8.7 (br s, 1H), 8.15 (d, 1H, J=1.46), 7.94 (dd, 1H, J=8.06, 1.83), 7.80 (d, 2H, J=8.42), 7.71 (br m, 2H), 7.65 (d, 2H, J=8.06), 7.49 (d, 1H, J=8.06), 7.17 (d, 2H, 6.59), 5.14 (s, 1H), 4.46 (br m, 1H), 2.96 (s, 3H), 2.83 (br m, 2H), 1.96 (br m, 4H), 1.75 (br m, 1H), 1.39 (br m, 3H); ESI-MS m/e 610.24 (M+H); HPLC purity (ELSD)>95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:19]([CH2:20][CH2:21]Cl)[C:18](=[O:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[CH2:24]([NH2:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:19]([CH2:20][CH2:21][NH:26][CH2:24][CH3:25])[C:18](=[O:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CCN
Reactant: COc1ccccc1Cc1nc2ccccc2c(=O)n1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCNCCn1c(Cc2ccccc2OC)nc2ccccc2c1=O
Reaction time: 8 h
Yield: 16 %

Procedure:
A mixture of 328 mg (1 mmol) of 2-(2-methoxyphenylmethyl) -3-(2-chloroethyl)-4(3H)-quinazolinone and a 70% aqueous ethylamine solution (0.6 ml) in ethanol (10 ml) was heated at 80 ° C. W for 8 hours in a sealed tube. The solvent was distilled off under reduced pressure and to the residue thus obtained there was added a 10 % aqueous potassium carbonate solution, followed by extraction with dichloromethane. The thus obtained dichloromethane solution was dried over magnesium sulfate and then concentrated. The resulting residue was purified by silica gel column chromatography (eluent: 1% ethanol-chloroform) to obtain 55 mg (16%) of 2-(2-methoxyphenylmethyl)-3-(2-ethylaminoethyl)-4(3H)-quinazolinone as an oily substance. Subsequently, the thus obtained quinazolinone was dissolved in ether (3 ml) and to the resulting solution was added a 10% HCl/ethanol solution. The precipitated crystals were collected by filtration to obtain the hydrochride of the captioned compound.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[CH3:25][O:26][C@@H:27]1[C@H:32]([O:33][CH3:34])[C@@H:31]([O:35][CH3:36])[C@H:30]([CH3:37])[O:29][C@H:28]1[O:38][NH2:39]>CCO>[CH3:25][O:26][C@@H:27]1[C@H:32]([O:33][CH3:34])[C@@H:31]([O:35][CH3:36])[C@H:30]([CH3:37])[O:29][C@H:28]1[O:38][N:39]=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([C:13]2[N:12]=[CH:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:23])([F:1])[F:24])=[CH:5][CH:6]=3)[CH:14]=2)=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(-c2cn(-c3ccc(OC(F)(F)F)cc3)cn2)cc1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON)[C@@H]1OC
Solvent: CCO
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON=Cc2ccc(-c3cn(-c4ccc(OC(F)(F)F)cc4)cn3)cc2)[C@@H]1OC
Yield: 43.6 %

Procedure:
A solution of 4-[1-(4-trifluoromethoxyphenyl)-1H-imidazol-4-yl]-benzaldehyde (50 mg, 0.15 mmol) and O-(2S,3R,4R,5S,6S)-(3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl)-hydroxylamine (45 mg, 0.20 mmol) were combined in 5 mL of dry EtOH, and the solution heated at reflux under a N2 atmosphere for 12 h. The resulting solution was concentrated in vacuo and purified by chromatography (Biotage, 1:1:1 Hexanes/EtOAc/DCM) to furnish 35 mg (44%) of Compound 26 as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.90 (s, 1H), 7.85 (d, J=6 Hz, 2H), 7.68 (d, J=6 Hz, 2H), 7.60 (s, 1H), 7.68 (s, 1H), 7.50 (d, J=6 Hz, 2H), 7.38 (d, J=6 Hz, 2H), 3.77 (dd, J=3.2, 2.0 Hz, 1H), 3.68 (dd, J=9.6, 6.2 Hz, 1H), 3.59 (s, 3H), 3.56 (s, 3H), 3.55 (s, 3H), 3.51 (m, 1H), 3.21 (t, J=9.3 Hz, 1H), 1.33 (d, J=6.1 Hz, 3H); MS 536.1 (M+H); mp 178° C. Anal. Calcd. for C16H10F3N3O2: C, 59.01; H, 5.50; N, 7.65. Found: C, 58.86; H, 5.58; N, 7.63.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]([O:33][C@H:34]([CH3:52])[CH2:35][N:36]1[C:40]([CH3:41])=[C:39]([C:42](O)=[O:43])[C:38](=[O:45])[N:37]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][CH2:30][C:31]([O:33][C@H:34]([CH3:52])[CH2:35][N:36]1[C:40]([CH3:41])=[C:39]([C:42](=[O:43])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:38](=[O:45])[N:37]1[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:32])=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: COc1ccc2c(Oc3ccc(N)cc3F)ccnc2c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Yield: 75.8 %

Procedure:
To a solution of 3-fluoro-4-(7-methoxyquinolin-4-yloxy)benzenamine (399 mg, 1.38 mmol), (R)-1-(2-(2-(tert-butoxycarbonylamino)acetoxy)propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (500 mg, 1.15 mmol) in dry CH2Cl2 (5 mL) was added EDCI (264 mg, 1.38 mmol) and HOAT (32 mg, 0.23 mmol). The mixture reaction was refluxed for 3 h. The reaction mixture was then concentrated in vacuo and the residue was purified by a silica gel column chromatography (100% EtOAc) to give the title compound as a white solid (610 mg, 76%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[N+:19]([CH3:22])([O-:21])=[O:20].Cl>CS(C)=O.O>[N+:19]([CH2:22][C:7]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([O-:21])=[O:20]
Reactant: CCOC(=O)C=C1CCCCC1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCCCC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
To a mixture of 64.72 g (0.469 mole) potassium carbonate suspended in 469.5 mL dimethyl sulphoxide is measured in, during the course of 1 to 2 hours at 95° C., a solution of 158 g, (0.939 mole) ethyl cyclohexylideneacetate and 85.94 g (1.408 mole) nitromethane. After completion of the addition, stirring is continued at 95° C. for 2 to 3 hours. Subsequently, with ice-water cooling, the reaction solution is acidified with about 150 mL concentrated hydrochloric acid and diluted with 1.5 L of water. The resultant phases are separated and the aqueous phase is extracted several times with petroleum ether. The combined organic phases are washed neutral with water and dried over anhydrous sodium sulphate. The solvent is subsequently distilled off in a vacuum. 190.3 g Ethyl 1-nitromethyl-cyclohexaneacetate in the form of an oil are obtained; yield 88.4% of theory. Composition according to HPLC: 90% of the desired product of Step 2 and 6% ethyl cyclohexylideneacetate (Step 1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[N:11]([CH3:12])[C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3Cl)[CH:14]=2)=[N:9][CH:8]=1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[OH:33].C([O-])(O)=O.[Na+]>O(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[N:11]([CH3:12])[C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:33][C:25]3[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=3[F:23])[CH:14]=2)=[N:9][CH:8]=1
Reactant: Cn1c(C2OCCCO2)cnc1-c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: Cn1c(C2OCCCO2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 180 °C
Yield: 31.2 %

Procedure:
A mixture of 40 (5.9 g, 17.57 mmol), 2-fluoro-4-nitrophenol (5.52 g, 35.1 mmol) and NaHCO3 (1.346 g, 16.02 mmol) in Ph2O (7 mL) was heated to 180° C. for 4 hours. The reaction mixture was cooled to RT and diluted with DCM, filtered and concentrated. Purification of the residue by column chromatography (eluent EtOAc) afforded 41 (2.5 g, 31% yield) as a yellow solid. MS (m/z): 457.1 (M+H).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[S:13]([N:11]1[CH2:10][CH2:9][N:8]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[C@@H:7]([CH2:6][N:37]2[CH2:38][CH2:39][NH:34][C:35](=[O:40])[CH2:36]2)[CH2:12]1)(=[O:14])=[O:15]
Reactant: O=C1CNCCN1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCNC(=O)C2)cc1)C(F)(F)F
Temperature: 130 °C
Yield: 44.7 %

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (100 mg, 0.189 mmol, Intermediate B) was combined with piperazin-2-one (18.9 mg, 0.189 mmol, Alfa-Aesar) and potassium carbonate (78 mg, 0.57 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (1.89 mL) and heated at 130° C. for 30 min. After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). After concentration of the filtrate, the crude residue was purified by silica gel chromatography (0 to 7% MeOH in CH2Cl2) followed by purification via reverse-phase HPLC (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient). The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3 and then the organic extracts were dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia in MeOH to give the title compound (45 mg) as a mixture of two isomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][NH:39]3)=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:43][CH2:44][CH2:45][OH:46]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([F:27])([F:29])[F:28])=[CH:16][CH:15]=2)[C@@H:10]([O:30][CH2:31][C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:44][CH2:45][OH:46])=[CH:34][CH:33]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3c(c2)NCCC3)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCCCOCC(F)(F)F)cc2)[C@@H](OCc2ccc3c(c2)N(CCCO)CCC3)C1

Procedure:
In analogy to the procedure described in example 4(a), the (3R,4R)-3-(1,2,3,4-tetrahydro-quinolin-7-ylmethoxy)-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was alkylated with 1-bromo-3-hydroxy-propane to yield the (3R,4R)-3-[1-(3-hydroxy-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2,2,2-trifluoro-ethoxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 637 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.COC(=O)CC[SH:23].[H-].[Na+].Cl>O.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][SH:23])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: COC(=O)CCS
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(CS)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.25 h

Procedure:
To the solution of 2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)oxirane (8.0 g) and 3-mercaptopropionic acid methyl ester (11.2 ml) in dimethylformaide (160 ml) was added 60% sodium hydride suspension in oil (4.0 g), and the mixture was stirred for 15 minutes. 1N aqueous hydrochloric acid solution (101 ml) was added dropwise to adjust pH to 7, and dimethylformamide and water were evaporated off under reduced pressure. To the residue was added 20 ml of water, followed by extraction with ethyl acetate (50 ml×3). The extract was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography (6.0×9.0 cm) and eluted with ethyl acetate-hexane (3:1). The desired fraction was concentrated, and to the residue was added diethyl ether, to give 2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (6.44 g) as colorless needles. mp. 112°-113° C.