Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18]=[N:19][NH:20][CH:21]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[C:31](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:22][CH:23]2[CH2:24][CH2:25]2)[CH2:13][CH2:12][N:11]([S:14]([C:17]2[N:18]=[N:19][N:20]([CH3:31])[CH:21]=2)(=[O:15])=[O:16])[CH2:10][CH2:9]1)=[O:5]
Reactant: O=C(NCC1(CC2CC2)CCN(S(=O)(=O)c2c[nH]nn2)CC1)c1ccc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(S(=O)(=O)N2CCC(CNC(=O)c3ccc(Cl)cc3Cl)(CC3CC3)CC2)nn1
Temperature: 25 °C

Procedure:
2,4-Dichloro-N-[4-(cyclopropylmethyl)-1-(1H-[1,2,3]triazole-4-sulfonyl)piperidin-4-ylmethyl]benzamide (472 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (276 mg, 2 mmol) and methyl iodide (81 μL, 1.3 mmol) were added and the mixture stirred at room temperature over night.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-].O>CCO.[Fe]>[NH2:27][C:25]1[CH:24]=[CH:23][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:26]=1
Reactant: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reaction time: 0.67 h
Yield: 77 %

Procedure:
To a mixture of 1-(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone (269) (358.2 mg, 0.87 mmol) and NH4Cl (39.4 mg, 0.74 mmol) in EtOH (8.7 mL)/water (4.3 mL) at 100° C. was added Fe (411.3 mg, 7.36 mmol) in one portion and the mixture heated to reflux with vigorous stirring for 40 min. The mixture was filtered through Celite®, the Celite® washed with EtOH and the combined organic solutions concentrated under reduced pressure. The residue was dissolved in DCM, extracted with water, dried aver anhydrous Na2SO4 and concentrated under reduced pressure affording 270 (256.5 mg, 0.67 mmol, 77% yield) as a white solid. MS (m/z): (M+1) 384.2 (100%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1.[CH2:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:16][CH3:17].C(N(CC)C(C)C)(C)C>ClC(Cl)C>[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:18]([CH2:15][CH2:16][CH3:17])(=[O:20])=[O:19])[CH:7]=1
Reactant: COC(=O)Cc1cccc(CN)c1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)NCc1cccc(CC(=O)OC)c1

Procedure:
Following the procedure described in Preparation 8, (3-aminomethyl-phenyl)-acetic acid methyl ester hydrochloride (603 mg, 2.80 mmol) was converted to the title sulfonamide by reaction with 1-propanesulfonyl chloride (0.375 mL) and N,N-diisopropylethylamine (2.0 mL) in dichloroethane (10 mL). 1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (m, 4H), 4.60 (bs, 1H), 4.29 (s, 2H), 3.70 (s, 3H), 3.63 (s, 2H), 2.92 (t, 2H), 1.79 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:34])([CH3:33])[CH2:23][CH2:24][O:25]CC3C=CC=CC=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:34])([CH3:33])[CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(O)(CCOCc1ccccc1)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(O)(CCO)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 55 °C
Reaction time: 9 h
Yield: 75.2 %

Procedure:
4-[4-(4-Benzyloxy-2-hydroxy-2-methylbutoxy)phenyl]piperazine-1-carboxylic acid tert-butyl ester (6.16 g, 13.1 mmol), palladium hydroxide on carbon (0.62 g) and ethanol (62 ml) were mixed and stirred at 50 to 60° C. under a hydrogen atmosphere for 9 hours. The mixture was filtered through Celite to remove the catalyst, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→0:100) to afford the title compound as a colorless powder (3.75 g).
Reaction SMILES: C(O)C.[OH:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][C:19]([C:21]([O:23]CC)=[O:22])=[CH:18][C:17]=3[CH:26]=2)=[CH:9][CH:8]=1)[CH3:6]>O1CCCC1>[OH:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18][C:17]=3[CH:26]=2)=[CH:11][CH:12]=1)[CH3:6]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)O)cc3)ccc2o1
Solvent: C1CCOC1
Solvent: CCO
Product: CC(O)c1ccc(-c2ccc3c(c2)CC(C(=O)O)O3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75 ml of ethanol was added to a solution of 23.9 g of 6B in 300 ml of tetrahydrofuran, then 195.7 g of 2.5% sodium/mercury amalgam was added in portions, at room temperature. The mixture was stirred at room temperature overnight. The mercury was separated, the solid was collected and dissolved in 300 ml of water. The solution was acidified to pH=1 with concentrated hydrochloric acid. The solid was collected, washed with water and dried (P2O5 ; reduced pressure, 45° C.). The product was dissolved in tetrahydrofuran, the solution was filtered and its volume reduced to 30 ml by evaporating the solvent under reduced pressure. The resulting solution was triturated with ether. The solid was collected and dried in a vacuum oven over P2O5 to give 2,3-dihydro-5-(4-(1-hydroxyethyl)phenyl)-2-benzofurancarboxylic acid (6C), mp: 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][CH3:14].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([N:13]([CH3:14])[CH3:12])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1cnc(Cl)cn1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cnc(Cl)cn1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
5-chloropyrazine-2-carbonyl chloride (2.13 gram, 12.05 mmol) and dimethylamine HCl salt (1.06 gram, 12.7 mmol) were suspended in dichloromethane (50 mL) with stirring. Triethylamine (5.04 mL, 36.2 mmol) in dichloromethane (25 mL) was added dropwise at 0° C. to the reaction mixture. The combined solution was warmed up to ambient temperature and stirred for 4 hours. The compound was diluted with dichloromethane, washed with 1N HCl, water, brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient of 30 to 80% ethyl acetate in heptane) to provide desired 5-chloro-N,N-dimethylpyrazine-2-carboxamide (SM-1: 2.24 g, 85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.74 (d, J=1.37 Hz, 1H) 8.53 (d, J=1.37 Hz, 1H) 3.15 (s, 3H) 3.12 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: C1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole), in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Then, under nitrogen atmosphere, piperidine (1.31 g, 0.015 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to give a solid which was triturated with water and dried under high vacuum over the weekend at 50° C. The solid was recrystallized from isopropyl alcohol and refrigerated overnight. The crystalline material was collected by filtration, washed with cold isopropyl alcohol, and dried under high vacuum at 50° C. overnight to give 2.95 g (59%) of title compound, mp 176°-178° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[C:11]1[N:16]2[CH:17]=[N:18][N:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1>>[N:19]1[N:18]=[CH:17][N:16]2[C:11]([O:8][C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=3)=[CH:12][CH:13]=[CH:14][C:15]=12
Reactant: Clc1cccc2nncn12
Reactant: Nc1ncc(Br)cc1O
Product: Nc1ncc(Br)cc1Oc1cccc2nncn12

Procedure:
Prepared according to Example 1, step A, using 2-amino-5-bromopyridin-3-ol and 5-chloro-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:23][CH:24]1[CH2:28][CH2:27][O:26][CH2:25]1>>[O:26]1[CH2:27][CH2:28][CH:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:25]1
Reactant: NC1CCOC1
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)n(C)n1
Product: CCCCc1noc(C)c1COc1cc(C(=O)NC2CCOC2)n(C)n1
Yield: 76 %

Procedure:
As described for example 86, 5-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (60 mg, 0.2 mmol) was converted, using rac-3-aminotetrahydrofuran instead of isopropylamine, to the title compound (54 mg, 76%) which was obtained as a colorless oil. MS: m/e=363.1 [M+H]+.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.[CH2:27]([NH2:29])[CH3:28]>>[CH2:27]([NH:29][C:8](=[O:9])[CH2:7][CH:6]([N:5]1[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]2[C:1]1=[O:26])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[CH3:28]
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC
Reactant: CCN
Product: CCNC(=O)CC(c1ccc(OC)c(OC)c1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 77 %

Procedure:
The procedure of Example 46 was followed utilizing 3-phthalimido-3-(3,4-dimethoxyphenyl)propionic acid and ethylamine (1.0 equiv). After the reaction mixture was concentrated, the residue was diluted with 20 mL of water and 1 mL of ether. The mixture was stirred for 1 hour to afford a slurry. The slurry was filtered and the solid dried in vacuo to afford 0.66 g (77%) of 3-phthalimido-3-(3,4-dimethoxyphenyl)propionic ethylamide compound as a white powder: mp 131.0-132.5° C.; 1H NMR (DMSO-d6, 250 MHz) δ8.08 (t, 1H, J=5 Hz), 7.78-7.95 (m, 4H), 7.03 (s, 1H), 6.85-7.00 (m, 2H), 5.69 (t, 1H, J=8 Hz), 3.74 (s, 3H), 3.72 (s, 3H), 3.18 (d, 2H, J=8 Hz), 2.98(m, 2H), 0.88 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ168.8, 167.7, 148.5, 148.2, 134.5, 131.6, 131.2, 123.1, 119.4, 111.6, 111.1, 55.5, 50.5, 37.3, 33.2, 14.5; Anal. Calcd. for C21H22N2O5. Theoretical: C, 65.96; H, 5.80; N, 7.33. Found: C, 65.85; H, 5.84; N, 7.24.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].CO.Cl.[C:17](=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1c(Cl)cc(C(=O)O)c(Cl)c1N
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(C)c(N)c1Cl

Procedure:
30 g of 3-amino-2,5-dichloro-4-methylbenzoic acid are initially introduced into 140 ml of MeOH. HCl gas is now passed in for 20 minutes and the mixture is then boiled under reflux for a further 5 hours. After cooling, the mixture is poured into water and rendered alkaline with sodium carbonate. The ester which has precipitated is isolated and dried. Yield: 30.8 g, melting point: 53°-55°.
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[C:16]2/[CH:20]=[C:21]1\[O:22][C:23]2[C:30]([CH2:31][N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[C:29]([OH:45])[CH:28]=[CH:27][C:24]=2[C:25]\1=[O:26])C)=O)(C)(C)C.[ClH:46]>C(Cl)Cl.O1CCOCC1>[ClH:46].[ClH:46].[ClH:46].[OH:45][C:29]1[CH:28]=[CH:27][C:24]2[C:25](=[O:26])/[C:21](=[CH:20]/[C:16]3[C:15]4[C:19](=[C:11]([CH2:10][NH:8][CH3:6])[CH:12]=[CH:13][CH:14]=4)[NH:18][CH:17]=3)/[O:22][C:23]=2[C:30]=1[CH2:31][N:32]1[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1
Reactant: CN(Cc1cccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c12)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCc1cccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCNCC4)C3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(7-{[tert-butoxycarbonyl(methyl)-amino]methyl}-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.044 g, 0.071 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 4 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of chloroform and methanol and thereby washed to obtain (Z)-6-hydroxy-2-({7-[(methylamino)methyl]-1H-indol-3-yl}methylene)-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.025 g, 72%).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH:15]=[C:16](Cl)[CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C>[NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)=Cc1cc(C)nc(Nc2ccccc2)n1
Solvent: CC#N
Product: CC#Cc1cc(C)nc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 6.7 %

Procedure:
Into a 50 ml round bottom flask, 0.52 g (0.02 mol) of 2-anilino-4-methyl-6-(2-chloropropen-1-yl)pyrimidine, 4.0 g of KF/alumina and 20 ml of anhydrous acetonitrile were charged, and the mixture was stirred at room temperature for 5 hours in the flask equipped with a calcium chloride tube. Then, the mixture was subjected to filtration to remove the solid content, and the solvent was distilled off. The residue was dissolved in toluene and washed with water. This toluene layer was washed with water and concentrated, and then it was subjected to column chromatography to obtain 0.3 g of 2-anilino-4-methyl-6(1-propynyl)pyrimidine having a melting point of from 125° to 126° C. The yield was 67%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1)=[O:4].[CH3:20][C:21]1([CH3:34])[CH2:30][CH2:29][C:28]([CH3:32])([CH3:31])[C:27]2[CH:26]=[C:25]([NH2:33])[CH:24]=[CH:23][C:22]1=2>N1C=CC=CC=1>[CH2:15]([N:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)[C:12]([NH:33][C:25]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:34])([CH3:20])[CH2:30][CH2:29][C:28]([CH3:32])([CH3:31])[C:27]=2[CH:26]=1)=[O:13])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Reactant: CCCCCN(C(=O)Cl)c1ccc(C(=O)OC)cc1
Solvent: c1ccncc1
Product: CCCCCN(C(=O)Nc1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C(=O)OC)cc1
Temperature: 40 °C
Reaction time: 15 h
Yield: 66.9 %

Procedure:
A solution of 4-methoxycarbonylphenyl-pentyl-carbamoyl chloride (45) (180 mg, 0.63 mmole) in 5 mL pyridine was treated with 130 mg of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1.05 eq.) and stirred at 40° C. for 15 hours. The reaction mixture was concentrated in vacuo to give an orange oil which was purified by flash chromatography (SiO2, 10%-20% ethyl acetate/hexanes) to provide 190 mg (67%) of methyl 4-[1-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (47) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)=[O:13])[C:9](=[O:23])[S:8][C:5]2=[N:6][CH:7]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:24](=[O:26])[CH3:25])[CH2:16][CH2:15]3)=[O:13])[C:9](=[O:23])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Cn1c(=O)sc2ncc(Cl)cc21)N1CCN(CCO)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCN1CCN(C(=O)Cn2c(=O)sc3ncc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To an ice-cooled solution of 6-chloro-2-oxo-1-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl]-1,2-dihydrothiazolo[5,4-b]pyridine (1.35 g) in dry pyridine (10 ml), acetic anhydride (0.73 g) was added dropwise and then the mixture was stirred at the temperature for 2 hours and at the room temperature for 4 hours. After removal of the solvent, the residual oil obtained was purified on an aluminum-oxide column chromatography using a mixture of chloroform and n-hexane (2:1). The fractions containing the objective compound were collected and evaporated to give crude crystals. The crude crystals were recrystallized from ethyl acetate to afford 6-chloro-2-oxo-1-{[4-(2-acetoxyethyl)-1-piperazinyl]carbonylmethyl}-1,2-dihydrothiazolo[5,4-b]pyridine (1,2 g).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:36]([F:39])([F:38])[F:37])[O:20][N:19]=[C:18]([C:21]3[CH:34]=[CH:33][C:24]([C:25]([NH:27][CH:28]4[CH2:32][O:31][NH:30][CH2:29]4)=[O:26])=[C:23]([CH3:35])[CH:22]=3)[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1.C(=O)C.[BH3-]C#N.[Na+]>CO>[Cl:15][C:13]1[CH:12]=[C:11]([C:16]2([C:36]([F:37])([F:39])[F:38])[O:20][N:19]=[C:18]([C:21]3[CH:34]=[CH:33][C:24]([C:25]([NH:27][CH:28]4[CH2:32][O:31][N:30]([CH2:2][CH3:3])[CH2:29]4)=[O:26])=[C:23]([CH3:35])[CH:22]=3)[CH2:17]2)[CH:10]=[C:9]([Cl:8])[CH:14]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CNOC1
Reactant: O=C(O)C(F)(F)F
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN1CC(NC(=O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2C)CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.1 %

Procedure:
Crude 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-isoxazolidin-4-yl-2-methyl-benzamide trifluoroacetic acid salt (0.16 mmol) was dissolved in MeOH (0.8 ml). Then acetaldehyde (0.090 ml, 10 equiv) was added at 0° C. under an argon atmosphere. After stirring for 1 hour at 0° C., NaBH3CN (20 mg, 2 equiv) was added. The reaction mixture was left to stir over the weekend. It was then evaporated. Flash column chromatography eluting with ethyl acetate/methanol (10/0 to 9/1) afforded 7.5 mg of the expected compound as a mixture of diastereomers. LCMS (Method E) 2.02 min, M+H 516/518. 1H-NMR (MeOD, 400 MHz): 7.70-7.53 (m, 5H), 7.52-7.37 (m, 1H), 4.92-4.85 (m, 1H), 4.40-4.22 (m, 2H), 4.00 (d, 1H), 3.83-3.62 (m, 1H), 3.29-2.52 (m, 4H), 2.43 (s, 3H), 1.16 (t, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.[I-]>[C:8]1([C:6]2[N:7]=[C:3]([CH2:2][O:20][C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[CH:24]=[O:25])[O:4][C:5]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.75 h
Yield: 78.3 %

Procedure:
A mixture of 2-bromomethyl-4,5-diphenyloxazole (26.72 g, 85 mmol) obtained according to D. L. Aldous, et al., J. Org. Chem. 2, 228-334 (1937), 3-hydroxybenzaldehyde (9.34 g, 76 mmol), potassium carbonate (12.92 g, 93 mmol), potasssium iodide (0.5 g) and dimethylformamide (250 mL) was stirred at 110° C. After 45 minutes, the mixture was cooled, diluted with water and extracted with diethyl ether (3×). The combined extracts were washed with water (3×), dried over sodium sulfate and concentrated in vacuo to give an oil which was chromatographed on a column of silica gel. Elution with a mixture of hexanes and diethyl ether (2:1) afforded 3-[(4,5-diphenyl-2-oxazolyl)methoxy]benzaldehyde (21.16 g, 70%). An analytical sample was recrystallized from a mixture of CH2Cl2 and hexanes and had mp 72°-75° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20]C)=[O:19])=[CH:16][C:3]1=2.[OH-].[Na+].O.Cl>CO>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)Cc1ccccc1C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1ccccc1C2
Yield: 86.3 %

Procedure:
In 2 ml of methanol was dissolved 0.1 g of methyl 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-2-acetate obtained in Example 16, and 6 ml of a 10% aqueous solution of sodium hydroxide was added. The mixture was heated under reflux for 2 hours with stirring. After the reaction, the reaction mixture was cooled, and water was added. The mixture was acidified with 10% hydrochloric acid, and the precipitated solid was extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The ether was distilled off. Recrystallization of the residue from a mixture of ether and n-hexane afforded 0.082 g of 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-2-acetic acid as colorless needle-like crystals having a melting point of 171° to 173° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([N:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[CH3:16].[CH3:34][S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([N:27]2[CH2:32][CH2:31][CH:30]([N:41]3[CH2:42][CH2:43][N:38]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:39][CH2:40]3)[CH2:29][CH2:28]2)[CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[CH3:16]
Reactant: CCOc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
Sodiumtriacetoxyborohydride (2.59 g, 12.2 mmol) was added to a stirring suspension of 1-[3-(ethyloxy)-4-nitrophenyl]-4-piperidinone (2.15 g, 8.14 mmol), 1-(methylsulfonyl)piperazine (2.67 g, 16.3 mmol), acetic acid (0.70 mL, 12.2 mmol), and TEA (1.13 mL, 8.14 mmol) in 1,2-DCE (100 mL). The reaction was stirred at rt overnight then poured into saturated NaHCO3 (aq). The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were then dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford 1-{1-[3-(ethyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.50 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.86 (d, J=9.4 Hz, 1H), 6.58 (dd, J=9.5, 2.4 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.99-4.08 (m, 2H), 3.04-3.12 (m, 4H), 2.90-2.99 (m, 2H), 2.86 (s, 3H), 2.55-2.61 (m, 4H), 1.77-1.88 (m, 2H), 1.39-1.50 (m, 2H), 1.35 (t, J=6.9 Hz, 3H).