Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21](C(O)=O)=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:37][N:38](C)[CH:39]=[O:40]>O1CCCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:39]([NH:38][C:37]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)=[O:40])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2)CCN3CC(C)C)cc1
Reaction time: 1.5 h

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (2 g) was dissolved in tetrahydrofuran (25 ml), and to the solution were added thionyl chloride (0.5 ml) and N,N-dimethylformamide (catalytic amount) at room temperature under ice-cooling, and the mixture was stirred for 1.5 hours. The solvent was distilled off, the residue was dissolved in tetrahydrofuran (50 ml), and the solution was added dropwise to a solution of p-aminophenol (0.55 g) and triethylamine (2 ml) in tetrahydrofuran (25 ml) under ice-cooling. The mixture was stirred for 3 hours under nitrogen atmosphere at room temperature, and the solvent was distilled off. To the residue was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-(4-hydroxyphenyl)-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (2 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH3:10][CH:11]([OH:15])[CH2:12][C:13]#[CH:14].C(N(CC)CC)C>C(OCC)C>[OH:15][CH:11]([CH3:10])[CH2:12][C:13]1[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:14]=1
Reactant: C#CCC(C)O
Reactant: CCOC(=O)/C(Cl)=N\O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)c1cc(CC(C)O)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl chlorooximidoacetate (4 g, 26.4 mmol) and 4-pentyn-2-ol (10.00 ml, 107 mmol) were dissolved in diethyl ether (30 ml). A solution of triethylamine (3.68 ml, 26.4 mmol) in diethylether (20 ml) was added dropwise to the reaction mixture. After 1 h of stirring at RT the reaction mixture was washed with brine and water, dried with MgSO4 and evaporated to dryness. The residue was purified with flash chromatography using a gradient of methanol in methylene chloride affording 2.51 g (48%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ, 1.11 (d, 3H), 1.31 (t, 3H), 2.82-2.94 (m, 2H), 3.93-4.03 (m, 1H) 4.35 (q, 2H), 4.89 (d, 1H), 6.67 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH2:18]1[O:26][C:25]2[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=2[O:19]1>>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:23]3[CH:22]=[CH:21][C:20]4[O:19][CH2:18][O:26][C:25]=4[CH:24]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: Cc1cc(NS(=O)(=O)c2ccc(-c3ccc4c(c3)OCO4)cc2)on1
Yield: 67 %

Procedure:
N-(3-methyl-5-isoxazolyl)-4-(3,4-methylenedioxyphenyl)benzenesulfonamide was prepared in the same manner as described in Example 14b, using N-(3-methyl-5-isoxazolyl)-4-bromobenzenesulfonamide and 3,4-methylenedioxyphenylboronic acid resulting in a 67% yield of final product.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]([CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+]([O-])=O)[CH:14]=1)(=[O:12])=[O:11].[CH:31]1[C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=[C:33]([OH:40])[CH:32]=1.[H-].[Na+]>CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]([CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:40][C:33]2[CH:32]=[CH:31][C:36]([N+:37]([O-:39])=[O:38])=[CH:35][CH:34]=2)[CH:14]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)N(CCC2CCCCO2)CCC2CCCCO2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cc(S(=O)(=O)N(CCC3CCCCO3)CCC3CCCCO3)ccc2Cl)cc1
Reaction time: 19 h

Procedure:
To a solution of the chloro derivative from Step 2 (6.5 g, 13.2 mmol) and p-nitrophenol (1.95 g, 14.0 mmol) in dimethylformamide (75 mL) was added 60% sodium hydride mineral oil suspension (0.56 g, 14.0 mmol). The resulting solution was stirred at 60° under nitrogen for 19 hours. After concentrating under reduced pressure at 60° , the residue was partitioned between ethyl acetate and brine. The organic extract was dried (Na2SO4) filtered and concentrated. The residue was flash chromatographed over silica gel and 6.8 g of pure product was eluted with 15% ethyl acetate - 85% n-butylchloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][Si:10]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(N)CN>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:2]1([NH:1][CH2:9][Si:10]([O:11][CH2:12][CH3:13])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO[Si](CCl)(OCC)OCC
Solvent: Nc1ccccc1
Solvent: NCCN
Product: CCO[Si](CNc1ccccc1)(OCC)OCC
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
In a 500 ml four-necked flask having a reflux condenser, KPG stirrer and thermometer, 65.7 g of dry aniline (pKb 9.4) were heated to 120° C. and 60 g of chloromethyltriethoxysilane were added in the course of 180 min with stirring and stirring was effected for a further 60 min. Thereafter, the temperature was reduced to 105° C. and 42.4 g of ethylenediamine (pKb 4.07) were added to the mixture in the course of 10 min with stirring, phase separation occurring. At constant temperature, stirring was effected for a further 30 min, cooling to 70° C. being effected during this procedure and the heavier ethylenediamine hydrochloride phase then being separated off. The upper phase was subjected to fractional distillation without a distillation column. 18.3 g of aniline having a purity of 84.8%, 14.4 g of aniline having a purity of 97.8% (45% recovery) and 47.8 g (yield 62.9%) of N-phenylaminomethyltriethoxysilane were obtained, the purity of which was determined as 88.9%. The chloride value of the product was 88 ppm.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1)#[N:2].[CH3:13][Mg]Br.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[C:1]([C:3]1[C:8]([CH3:9])=[C:7]([CH3:13])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1cc([N+](=O)[O-])cnc1C#N
Reactant: C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])cnc(C#N)c1C
Temperature: -70 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
2-Cyano-3-methyl-5-nitropyridine (0.33 g, 2 mmol) was dissolved in 10 mL of THF and cooled in a dry ice/acetone bath under nitrogen. Methylmagnesium bromide (1.33 mL, 4 mmol) was added via syringe over five mins. The reaction was stirred for 2 h at −70° C. DDQ (0.068 g, 3 mmol) in 7 mL of THF was added and the mixture warmed to 25° C. The solvent was removed in vacuo and the residue was purified by silica gel chromatography using CH2Cl2 as the eluent to give compound 773A (0.15 g, 42%) as a red oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=O)#[N:2].C1(P(=[CH:31][CH:32]=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=[CH:31][CH:32]=[O:33])#[N:2]
Reactant: N#Cc1ccc(O)c(C=O)c1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(O)c(C=CC=O)c1
Yield: 45.4 %

Procedure:
A solution of 5-cyano-2-hydroxybenzaldehyde (4.3 g) and (triphenylphosphoranylidene)acetaldehyde (9.4 g) in toluene (150 ml) was stirred at 70° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/ethyl acetate=3/1 as an eluant to give the desired compound (2.3 g, yield 44%) as a colorless solid.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br.C([O-])C.[Na+]>C(O)C>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Oc1ccc(I)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Fc1cccc(COc2ccc(I)cc2)c1

Procedure:
A solution of 3.0 g (15.9 mmol) of 4-iodophenol and 3.49 g (15.9 mmol) of 3-fluorobenzyl bromide in 30 ml ethanol is treated dropwise at RT with 20 ml of a 1 molar solution of sodium ethanolate in ethanol. The reaction mixture is refluxed for 4 h and the precipitated sodium bromide is filtered off. The filtrate is evaporated to dryness, treated with 100 ml of water, acidified by addition of citric acid and extracted three times with dichloromethane. After drying and evaporation, the residue is subjected to chromatography on silica gel (hexane/ethyl acetate 9:1). This yields 4.23 g (81%) of a colorless solid. mp=48° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=1[CH:10]=[O:11].Cl[CH2:18][C:19]1[CH2:20][CH2:21][N:22]([C:31](=[O:33])[CH3:32])[CH2:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[C:31]([N:22]1[CH2:23][C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:19]([CH2:18][O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[CH:10]=[O:11])[CH2:20][CH2:21]1)(=[O:33])[CH3:32]
Reactant: O=Cc1c(O)cccc1O
Reactant: CC(=O)N1CCC(CCl)=C(c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(COc2cccc(O)c2C=O)=C(c2ccccc2)C1
Temperature: 50 °C
Yield: 34.6 %

Procedure:
To a suspension of K2CO3 (40 mg, 0.28 mmol) and 2,6-dihydroxybenzaldehyde (40 mg, 0.28 mmol) in DMF (1 mL) was added a solution of 1-(4-(chloromethyl)-5-phenyl-3,6-dihydropyridin-1(2H)-yl)ethan-1-one (35 mg, 0.14 mmol) in DMF (1 mL), the mixture was heated at 50° C. for 3 h, cooled to room temperature, and was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO3, brine, dried over Na2SO4, and was concentrated to give crude oil, which was purified by column (DCM/MeOH=90:10) to give 2-((1-acetyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)-6-hydroxybenzaldehyde (17 mg). 1H NMR (400 MHz, CDCl3, NMR shows rotamer exist, only one set of signal was reported) □ (ppm) 11.93 (s, 1H), 10.36 (s, 1H), 7.34 (m, 5H), 7.22 (m, 1H), 6.49 (d, J=8.8 Hz, 1H), 6.10 (d, J=8.8 Hz, 1H), 4.47 (s, 2H), 4.32 (s, 2H), 3.68 (t, J=6.0 Hz, 2H), 2.47 (m, 2H), 2.18 (s, 3H); MS (ESI) m/z 352.5 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]OS(C)(=O)=O)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:20]1[C:24]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][NH:22][C:21]1=[O:30]>C(#N)C.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:22]2[CH2:23][C:24]3([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[O:20][C:21]2=[O:30])=[N:6][CH:7]=1
Reactant: O=C1NCC2(CCCCC2)O1
Reactant: CS(=O)(=O)OCc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(Br)cn1
Temperature: 70 °C
Yield: 57.8 %

Procedure:
Methanesulfonic acid 5-bromo-pyridin-2-ylmethyl ester (85 mg, 0.319 mmol), cesium carbonate (312 mg, 0.957 mmol) and 1-oxa-3-aza-spiro[4.5]decan-2-one (49.5 mg, 0.319 mmol) were mixed in acetonitrile (2 mL). The reaction mixture was heated at 70° C. for 5 hours and then diluted with dichloromethane (8 mL). The mixture was washed with water (3 mL) and brine (3 mL). The combined organic phase was dried over sodium sulfate and concentrated. The residue was purified on silica gel eluting with 10 to 20% ethyl acetate in hexanes to give the product as an off-white solid (60 mg, 58%). 1H NMR (300 MHz, CDCl3): δ 8.6 (d, 1H), 7.81 (dd, 1H), 7.23 (d, 1H), 4.49 (s, 2H), 3.27 (s, 2H), 1.79 (m, 4H), 1.47 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:36][C:35]=1[C:46]1[N:51]=[CH:50][N:49]=[C:48]([NH:52][CH:53]([C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([F:64])([F:63])[F:62])[CH:56]=2)[CH3:54])[CH:47]=1>ClCCl.CN(C)C1C=CN=CC=1>[N:40]1([C:37]2[CH:38]=[CH:39][C:34]([NH:33][C:14]([C:13]3[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=3)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])=[C:35]([C:46]3[CH:47]=[C:48]([NH:52][CH:53]([C:55]4[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([F:64])([F:62])[F:63])[CH:56]=4)[CH3:54])[N:49]=[CH:50][N:51]=3)[CH:36]=2)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1
Reactant: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2N)ncn1)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(Nc1cc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)ncn1)c1cccc(C(F)(F)F)c1
Temperature: 30 °C
Reaction time: 3 h
Yield: 30.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (147 mg, 0.50 mmol, 1.10 equiv) in dichloromethane (5 mL), EDC.HCl (143 mg, 0.74 mmol, 1.50 equiv), 4-dimethylaminopyridine (92 mg, 0.71 mmol, 1.50 equiv), and 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(1-(3-(trifluoromethyl)phenyl)ethyl)pyrimidin-4-amine (200 mg, 0.45 mmol, 1.00 equiv). The resulting solution was stirred for 3 h at 30° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (5:1). The product was obtained as 100 mg (31%) of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[N:17]1([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:31][CH:30]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCOCC4)cc3)cc2)cc1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 302 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-morpholinylbenzoate. [M+H]+ calcd for C35H35N4O5: 591.26; found: 591.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:5][C:6]([CH:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=1.[CH:31](=O)[CH2:32][CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[CH:5][C:6]([CH:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:21])([CH3:22])[CH2:20]2)=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([CH2:31][CH2:32][CH3:33])[CH2:13][CH2:14]2)[CH:8]=1
Reactant: CCC=O
Reactant: COc1cc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)cc1N1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN1CCN(c2cc(OC)c(N3CCCCC3)cc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 1-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (5 mg, 0.0121 mmol) produced in Example (72b), propionaldehyde (1.4 mg, 0.0242 mmol) and tetrahydrofuran (0.3 mL) was added sodium triacetoxyborohydride (5 mg, 0.0242 mmol), followed by stirring for 1 hour and 10 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The solvent was distilled off nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]-4-propylpiperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was distilled of by nitrogen stream. Heptane was added to the obtained residue to produce a solid, which was then triturated by sonication. The supernatant heptane solution was removed and the resulting solid was dried to give 6.1 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@H](O)C1
Temperature: 25 °C
Yield: 148.3 %

Procedure:
Heat a mixture of (3R,4R)-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.02 mol, 6.0 g), 5-bromo-2-fluoronitrobenzene (0.03 mol, 6.71 g) and triethyl amine (0.058 mol, 5.88 mL) in ethyl acetate (180 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (12.35 g, crude). 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.50-1.51 (m, 1H), 2.08-2.12 (m, 1H), 2.93 (dd, 1H), 3.01 (br s, 1H), 3.55-3.61 (m, 1H), 3.62-3.68 (m, 1H), 3.68 (br s, 1H), 4.13-4.18 (m, 1H), 6.97 (d, 1H), 7.48 (dd, 1H), 8.08 (d, 1H), 8.30 (d, 1H). ES-MS m/z 316 [M−Boc]+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)(C(C)(C)C)(C)C.Cl.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[CH3:32][O:31][CH2:30][CH2:29][O:28][C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[N:20][N:21]=[C:22]2[CH:27]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
To a solution of 8-(tert-butyldimethylsilyloxy)-2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinoline (0.070 g, 0.155 mmol) in THF (8 mL) was added 1M HCl (1.5 mL, 1.50 mmol). After stirring at ambient temperature for 2 hours, 1 M HCl (5 mL) was added and the reaction mixture stirred for an additional 16 hours. The mixture was neutralized with 1M NaOH and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 40 mg (77%) of desired product. MS APCI (+) m/z 337.3 (M+1) detected.
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].[F:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH:16]=O)[CH:11]=[C:12]([F:14])[CH:13]=1>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:16]=[C:15]([C:10]2[CH:9]=[C:8]([F:7])[CH:13]=[C:12]([F:14])[CH:11]=2)[N:4]=1
Reactant: CSC(=N)NN
Reactant: O=CC(=O)c1cc(F)cc(F)c1
Product: CSc1nncc(-c2cc(F)cc(F)c2)n1
Yield: 79.6 %

Procedure:
3-(methylsulfanyl)-5-(3,5-difluorophenyl)-1,2,4-triazine (28 g, 80.0%) was prepared from methyl hydrazine carbimidothioate (20.68 g, 197.4 mmol) and 2-(3,5-difluorophenyl)-2-oxoacetaldehyde (25 g, 147.0 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Br[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][C:12]=1[O:21][CH3:22]>>[CH3:22][O:21][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:11]=1[CH2:10][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:15]([OH:17])=[O:16]
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(C(=O)O)ccc1COCC(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of 2,2,2-trifluoroethanol (874 μL, 12.0 mmol) at 0° C. was added NaH (60%, 520 mg, 13.0 mmol) and the mixture was stirred at this temp for 10 min, then at room temperature for 10 min. The mixture was cooled to 0° C. before methyl 4-(bromomethyl)-3-methoxybenzoate (2.59 g, 10.0 mmol) was added. The cooling bath was removed and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water and extracted with EtOAc (3×). The organics were combined, washed with water, brine, dried (MgSO4) and evaporated to dryness. Crushed NaOH was added to the residue, followed by water (4 mL) and MeOH (20 mL). The mixture was stirred at room temperature for 1 hour. The MeOH was evaporated and the residue was taken up in 1N NaOH (30 ml) and the pH was adjusted to pH 2 with conc HCl. The precipitate was filtered, washed with water (2×) then hexanes (2×) and desiccated to give 3-methoxy-4-((2,2,2-trifluoroethoxy)methyl)benzoic acid. 1H NMR (400 MHz, CDCl3) δ 7.79 (dd, J=7.8, 1.4 Hz, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 4.80 (s, 2H), 4.00-3.91 (m, 5H).
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30]I>>[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([F:15])[F:1])=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13]
Reactant: ClCCCCI
Reactant: O=C(O)Cc1ccc(OCC(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: O=C(O)C(CCCCCl)c1ccc(OCC(F)F)cc1
Yield: 77.3 %

Procedure:
Step AX (2): 2-(4-(2,2-Difluoroethoxy)phenyl)acetic acid (6.00 g, 27.8 mmol) was deprotonated with NaHMDS (2.0 M in THF, 41.6 mL, 83 mmol) and reacted with 1-chloro-4-iodobutane (9.10 g, 41.6 mmol) using a procedure analogous to Step AC (1) to afford 6-chloro-2-(4-(2,2-difluoroethoxy)phenyl)hexanoic acid (6.94 g, 21.5 mmol, 77% yield) as a viscous oil that slowly solidified at rt to afford an off-white solid. LC-MS (M−H)− 305.21. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24 (d, J=8.9 Hz, 2 H), 6.87 (d, J=8.5 Hz, 2 H), 5.88-6.23 (m, 1 H), 4.15 (td, J=13.0, 4.1 Hz, 2 H), 3.44-3.53 (m, 3 H), 1.99-2.12 (m, 1 H), 1.70-1.86 (m, 3 H), 1.31-1.50 (m, 2 H).