Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].Cl.[CH3:19][NH2:20]>CCO>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:20][CH3:19])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CN
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NC)c([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 99.3 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.125 g, 0.521 mmol), methylamine hydrochloride (0.035 g, 0.521 mmol) in 80% aq. EtOH (3 mL) was heated at 85° C. for 4 hours. Usual work-up provided the title compound (0.130 g, 100%) which was used without further purification. MS (ESI) (M+H)+=252.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:4][CH:3]=1.[CH3:17][C:18]([OH:22])([C:20]#[CH:21])[CH3:19].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]#[C:20][C:18]([CH3:19])([OH:22])[CH3:17])=[CH:3][CH:4]=1
Reactant: C#CC(C)(C)O
Reactant: COCCCCCCOc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COCCCCCCOc1ccc(C#CC(C)(C)O)cc1

Procedure:
Under a nitrogen atmosphere, to a mixture of 1-bromo-4-(6-methoxyhexyloxy)benzene (3.68 g), 2-methyl-3-butyn-2-ol (1.86 ml) and triethylamine (18 ml) in pyridine (7.4 ml) was added triphenylphosphine (67.2 mg), copper(I) iodide (24.4 mg) and dichlorobis(triphenylphosphine)palladium(II) (18.0 mg), and refluxed overnight. After cooling, insoluble material was filtered off and washed with isopropyl ether. The filtrate was evaporated under reduced pressure. To the residue was added isopropyl ether and the mixture was washed with 0.1N-hydrochloric acid, water and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude yellow oil. The crude yellow oil was purified by silica gel chromatography (10:1-2:1 hexane-ethyl acetate) to give 4-[4-(6-methoxyhexyloxy)phenyl]-2-methyl-3-butyn-2-ol (3.17 g) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:15][CH:16]([CH3:20])[C:17](Cl)=[O:18]>C1C=CC=CC=1>[Cl:15][CH:16]([CH3:20])[C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:18]
Reactant: CC(Cl)C(=O)Cl
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: c1ccccc1
Product: CC(Cl)C(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Yield: 92.7 %

Procedure:
47.2 g (0.25 mole) of 6-(p-aminophenyl)-4,5-dihydropyridaz-3-one and 35.6 g (0.28 mole) of 2-chloropropionyl chloride in 250 ml of absolute benzene are refluxed for 2 hours. The product is filtered off at 10° C., washed first with benzene and then with water and dried under reduced pressure at 100° C. 64.8 g (93% of theory) of 6-[p-(2-chloropropionylamino)-phenyl]-4,5-dihydropyridaz-3-one are obtained as a beige solid which, after recrystallization from propanol, melts, with decomposition, at 243°-244° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][N:7]=1)=[O:5])[CH3:2]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NCCc2cc(OC)c(OC)cc21
Agent: [Pd]
Product: CCOC(=O)c1nccc2cc(OC)c(OC)cc12
Yield: 95.7 %

Procedure:
To a refluxing solution of 2.0 g (8.0 mmol) of 6,7-dimethoxy-3,4-dihydro-isoquinoline-1-carboxylic acid ethyl ester was added to 2.0 g of 10% Pd—C. After 12 h at reflux, the reaction mixture was cooled, filtered through celite, and evaporated under reduced pressure to provide 2.0 g (98%) of 6,7-dimethoxy-isoquinoline-1-carboxylic acid ethyl ester. LCMS: 262 (M+1)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C@H:12]3[OH:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@@H:22]4[O:30][C@@H:23]4[CH2:24]3)[CH2:19][CH2:18]5)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C@H:12]3[OH:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@H:22]([OH:30])[C@@H:23]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH2:24]3)[CH2:19][CH2:18]5)[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Product: C[C@]12C[C@H](N3CCCCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Yield: 87.5 %

Procedure:
16β-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-2α,3α-epoxy-5α-androstane-17β-ol is reacted with piperidine as described in Example 3 to give the title compound in a yield of 87.5%, m.p.: 183°-185° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:28])([F:27])[N:18]1[CH:23]=[C:22]([CH:24]=[CH2:25])[CH:21]=[CH:20][C:19]1=[O:26].[OH-].[K+]>CN1C(=O)CCC1>[F:27][C:17]([F:16])([F:28])[N:18]1[CH:23]=[C:22]([CH2:24][CH2:25][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:21]=[CH:20][C:19]1=[O:26]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(=O)n(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(=O)n(C(F)(F)F)c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 1-(trifluoromethyl)-5-vinylpyridin-2(1H)-one and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH:10]([NH:12][NH2:13])[CH2:9][CH2:8][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.O.CN(C)[CH:25]=[O:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:25](=[O:26])[NH:13][N:12]=[C:10]3[CH2:9][CH2:8][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: NNC1CCC(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: CN(C)C=O
Solvent: O
Product: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)CC2
Reaction time: 20 h

Procedure:
15.0 g of 7-chloro-5-(2-fluorophenyl)-2-hydrazino-4,5-dihydro-2H-1-benzazepine are dissolved in 200 ml of dimethylformamide. After adding 18 g of N,N'-carbonyl-diimidazole, the mixture is stirred at 52° for 20 hours, poured into 2 l of water and extracted with ethyl acetate. The organic extracts are washed with water, dried and evaporated. The residue is chromatographed on 800 g of silica gel. By elution with chloroform which contains 2% ethanol and crystallization from ether there is obtained 8-chloro-6-(2-fluorophenyl)-2,4,5,6-tetrahydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 236°-238°.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7](=O)[CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:3].C(O)(C)(C)C.[C:23]([S-:25])#[N:24].[K+]>O>[CH2:2]([O:4][C:5](=[O:17])[CH2:6][C:7]1[NH:24][C:23](=[S:25])[N:9]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=1)[CH3:3]
Reactant: N#C[S-]
Reactant: CCOC(=O)CC(=O)CNC1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)Cc1cn(C2CCCCC2)c(=S)[nH]1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
200 g (0.758 mol) 4-Cyclohexylamino-3-oxo-butyric acid ethyl ester hydrochloride were dissolved in 360 ml water and 120 ml tert-butanol and were heated to 90° C. Then 88.4 g (0.91 mol) KSCN were added and the mixture was heated for 20 s, thereby a phase separation occurred. After cooling to RT, the phases were separated and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with Brine, dried with MgSO4 and concentrated. The solid was digested in MTBE and filtered to yield 192 g (0.715 mol, 94%) of (1-Cyclohexyl-2-thioxo-2,3-dihydro-1H-imidazol-4-yl)-acetic acid ethyl ester as a beige solid. HPLC: tR=1.16 min (YMC J′ sphere ODS H 80 20×2.1 mm, 4 μm, A: H2O+0.05% TFA, B: MeCN, 4%→95% B in 2 min, 1 ml/min, 30° C.); Mass (ES+) (C13H20N2O2S): calculated. 268. found 269 [M+H]+.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1ccnc(COc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(OCc3cc(C(CC(=O)O)C4CC4)ccn3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-(((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)oxy)methyl)pyridin-4-yl)propanoate (140 mg) in THF (2.0 mL) and methanol (1.0 mL) was added 1N aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid (2.0 mL) at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate and hexane to give the title compound (123 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([CH2:32][C:33](Cl)=[O:34])[CH:31]=1>ClCCl>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:36])=[C:30]([CH2:32][C:33]([NH:1][C:2]2([C:14]([O:16][CH3:17])=[O:15])[CH2:3][CH2:4][C:5]([O:12][CH3:13])([C:8]([F:11])([F:10])[F:9])[CH2:6][CH2:7]2)=[O:34])[CH:31]=1
Reactant: COC(=O)C1(N)CCC(OC)(C(F)(F)F)CC1
Reactant: Cc1ccc(Br)cc1CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)Cc2cc(Br)ccc2C)CCC(OC)(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.00 g (11.75 mmol) of methyl 1-amino-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Example 22A) and 1.19 g (11.75 mmol) of triethylamine were dissolved in 40 ml of dichloromethane. 2.65 g (10.69 mmol) of (5-bromo-2-methylphenyl)acetyl chloride (Example 3A), dissolved in 40 ml of dichloromethane, were added dropwise to this solution, and the reaction mixture was stirred at room temperature overnight. For work-up, the mixture was diluted with dichloromethane and the organic phase was washed with aqueous saturated sodium bicarbonate solution and with aqueous 1% strength citric acid. After drying over sodium sulphate, the organic phase was concentrated and the product was dried. This gave 4.79 g (87% of theory) of the title compound as a beige powder.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:18])=[CH:5][C:6]([OH:17])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[CH3:2].Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25]>>[C:8]([C:7]1[C:6]([OH:17])=[CH:5][C:4]([O:18][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[C:3]([CH2:1][CH3:2])[CH:16]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CCCCCBr
Reactant: CCc1cc(C(=O)c2ccccc2)c(O)cc1O
Product: CCc1cc(C(=O)c2ccccc2)c(O)cc1OCCCCC#N
Yield: 38.2 %

Procedure:
Following the procedure of Example 16, 0.726 g of 5-ethyl-2,4-dihydroxybenzophenone and 0.53 g of 5-bromopentanenitrile were allowed to react and provided 0.37 g of the desired title product, m.p. =42°-44° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[C:16]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([N+:29]([O-])=O)=[C:24]([F:32])[CH:23]=2)([CH3:19])([CH3:18])[CH3:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:29][C:25]4[CH:26]=[C:27]5[C:22](=[CH:23][C:24]=4[F:32])[N:21]([CH2:6][C@H:5]([OH:1])[CH2:4][OH:3])[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:28]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)c(F)cc2n1C[C@H](O)CO

Procedure:
(S)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(2,3-dihydroxypropyl)-6-fluoro-1H-indol-5-yl)cyclopropanecarboxamide was prepared using an experimental procedure similar to Example 72 from 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid and 2-tert-butyl-6-fluoro-5-nitro-1H-indole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[CH2:6][CH2:5]2.IC.[C:15](=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[OH:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:12])=[CH:3][C:2]=1[O:1][CH3:15]
Reactant: O=C1CCc2cc(O)c(O)cc21
Reactant: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2c(cc1O)C(=O)CC2

Procedure:
A mixture of Example 63 (2.0 g, 12 mmol), iodomethane (1.9 mL, 30 mmol), and lithium carbonate (2.2 g, 30 mmol) in N,N-dimethylformamide (40 mL) was heated to 55° C. for 24 hours. The solution was concentrated under vacuum and was diluted with a 2% solution of hydrochloric acid in water. The precipitate was collected by filtration and was dried under high vacuum to provide the desired product. 1H NMR (500 MHz, CD3OD): δ 2.63 (t, J=6 Hz, 6H), 3.05 (t, J=6 Hz, 6H), 3.98 (s, 3H), 7.05 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][N:5]([CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:21])[C:6](=[O:17])[CH2:7][N:8]1[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]1=[O:10].Cl>[OH-].[Na+].CO.O>[C:22]([N:20]([CH3:21])[CH2:19][CH2:18][N:5]([C:6](=[O:17])[CH2:7][N:8]1[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]1=[O:10])[CH2:4][C:3]([OH:29])=[O:2])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: COC(=O)CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cn(CC(=O)N(CCN(C)C(=O)OC(C)(C)C)CC(=O)O)c(=O)[nH]c1=O

Procedure:
N-[(N-Boc)(N-methyl)-2-aminoethyl]-N-[(1-thyminyl)acetyl] glycine methyl ester was dissolved in 1N NaOH in MeOH/H2O 1:1 for 2 hours. The pH was adjusted to 2 with 2N HCl and extracted with ethyl acetate (50 ml). The organic phase was dried with Na2SO4 and evaporated to dryness. The yield of the title compound was 77%.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[O:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: Oc1ccccn1
Product: CN(C(=O)Oc1ccc(Cn2ccccc2=O)cc1)c1ccccc1
Yield: 66 %

Procedure:
The title compound was prepared in 66% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 2-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.12 (s, 2H), 6.13 (t, 1H), 6.60 (d, 1H), 7.10 (br s, 2H), 7.22–7.41 (m, 9H); HPLC-MS: m/z=335.2 (M+1); Rt=2.97 min.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[C:13]([C:25]([O:27]CC)=[O:26])[C:12]2=[O:30])=[CH:2]1.[OH-].[K+]>C(O)C.O.Cl>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[C:13]([C:25]([OH:27])=[O:26])[C:12]2=[O:30])=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(F)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1=C(Nc2ccc(F)cc2F)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 95 °C
Reaction time: 3 h
Yield: 110.2 %

Procedure:
To a solution of the compound (0.20 g, 0.45 mmol) of Example 53 in ethanol (2.0 mL), aqueous 50% w/v potassium hydroxide solution (0.5 mL) was added at ambient temperature. The mixture was stirred at 95° C. for 3 h. Cooled to ambient temperature, diluted with water and conc. hydrochloric acid was added dropwise to neutralize. The precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.19 g, y. 98%).
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]([F:35])([F:34])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.IC.[C:38](=O)([O-])[O-].[K+].[K+]>O>[OH:1][C:2]1([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:38])=[C:26]([O:31][C:32]([F:34])([F:35])[F:33])[CH:25]=2)[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1ccc(C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)C2(O)CCCCC2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
A solution of tert-butyl 4-{(1-hydroxycyclohexyl)[4-hydroxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate (0.35 g 0.72 mmol) (See Example 400, step 1) and iodomethane (0.16 g, 1.08 mmol) in N-N′-dimethylformamide (5 mL) was treated with potassium carbonate (0.12 g, 0.86 mmol), and the solution was stirred at room temperature for 16 hours. The reaction was then poured into water and extracted 3 times with ethyl acetate. The combined extracts were washed twice with water, then dried over magnesium sulfate and concentrated to afford 0.31 g of tert-butyl 4-[(1-hydroxycyclohexyl)[4-methoxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate). The product was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[CH:8]=2)[N:3]=1.[NH2:22][C:23]([CH2:28][CH3:29])([CH2:26][OH:27])[CH2:24][OH:25].O>CN1C(=O)CCC1>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][C:23]([CH2:28][CH3:29])([CH2:26][OH:27])[CH2:24][OH:25])[N:11]=[CH:10]2
Reactant: CCC(N)(CO)CO
Reactant: Nc1nc(Cl)nc2ccc(Oc3ccc(F)cc3F)cc12
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(CO)(CO)Nc1ncc2cc(Oc3ccc(F)cc3F)ccc2n1
Temperature: 25 °C
Yield: 47 %

Procedure:
Compound (1G) (250 mg, 0.85 mmol) and 2-amino-2-ethyl-1,3-propanediol (298 mg, 2.5 mmol) in NMP (0.25 mL) were stirred at 120° C. for 4 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc (2×25 mL). The combined organic layers were dried over sodium sulfate and evaporated in vacuo. The crude product was purified by chromatography (silica gel, CH2Cl2:MeOH, 95:5) to afford 150 mg of the above-titled compound (Example 1). Mp=110-112.9° C. MW (M+H)+=376.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCCC>[Br:18][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCBr)CC1
Reaction time: 20 h

Procedure:
tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5.76 g, 25.0 mmol) was dissolved in dry tetrahydrofuran (100 mL) and carbon tetrabromide (9.12 g, 27.5 mmol). A solution of triphenyl phosphine (6.62 g, 25.3 mmol) in dry tetrahydrofuran (25 mL) was added dropwise, and the mixture was stirred for 20 hours. The reaction was diluted with n-hexane (100 mL) and washed with a saturated NaHCO3 solution, water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes 1:4 gave the title compound. MS (DCI) m/z 295 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH:11]([OH:14])[CH2:12][CH3:13].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH:11]([O:14][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:12][CH3:13]
Reactant: CCC(O)c1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: CCC(Oc1ccc([N+](=O)[O-])cc1)c1c(Cl)cccc1Cl

Procedure:
1,3-Dichloro-2-[1-(4-nitrophenoxy)propyl]benzene was prepared according to the method described in Example 20f but from 0.236 g of sodium hydride (at 60% in the oil), 1.1 g of 1-(2,6-dichlorophenyl)propan-1-ol and 0.832 g of 1-fluoro-4-nitrobenzene. We thus obtain 1.18 g of 1,3-dichloro-2-[1-(4-nitrophenoxy)propyl]benzene in the form of a colorless oil which crystallizes, having the following characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.3 h
Yield: 76 %

Procedure:
A solution of (3R)-N-tert-butyloxycarbonylpyrrolidin-3-ol (2.25 g, 12.0 mmol), in anhydrous THF (10 ml) was added portionwise to a slurry of sodium hydride (60% dispersion in oil, 0.63 g, 13.8 mmol) in THF (35 ml) and the mixture stirred for 0.3 h at 0° C. A solution of benzyl bromide (2.37 g, 13.8 mmol) in dry THF (2 ml) was added and the mixture warmed to room temperature and stirred for 18 h. Water (70 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine, dried (MgSO4) and evaporated. The crude product was chromatographed on silica gel eluting with CH2Cl2 /MeOH (100:0→97:3) to give the desired product (2.53 g, 76%), δ (250 MHz, CDCl3) 1.46 (9H, s, OC(Me)3), 1.87-2.11 (2H, m, CH2), 3.42-3.50 (4H, m, 2 of CH2), 4.10-4.16 (1H, m, CH--OBn), 4.53 (2H, s, OCH2Ar), 7.26-7.39 (5H, m, Ar).