Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][O:15][CH2:16][C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[C@@H:18]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C@@H:19]([OH:21])[CH3:20])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][O:15][CH2:16][C@H:17]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)[C@@H:18]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[C@@H:19]([OH:21])[CH3:20])[C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@H](COC[C@H](Cc1ccc(C)cc1)[C@@H](OCC(C)C)[C@H](C)O)NC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C[C@@H](COC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](OCC(C)C)[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(((2S,3R,4S)-4-hydroxy-3-isobutoxy-2-(4-methylbenzyl)pentyl)oxy)propanoate (2.06 g, 4.28 mmol) in aqueous THF (16 THF:5H2O; 21 mL total volume) was added LiOH—H2O (0.54 g, 12.83 mmol) and the reaction was stirred for 4 h at room temperature. The reaction was diluted with H2O (50 mL) and the majority of the THF was removed on the rotovap. The aqueous residue was acidified with 2 N HCl and extracted with CH2Cl2 (6×50 mL) until the aqueous phase was nearly clear. The combined organic extracts were washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated to a colorless oil (1.96 g). The oil was purified by RP flash chromatography (C18; 0→85% CH3CN/H2O) to give (S)-2-((tert-butoxycarbonyl)amino)-3-(((2S,3R,4S)-4-hydroxy-3-isobutoxy-2-(4-methyl-benzyl)pentyl)oxy)-propanoic acid (1.71 g, 85%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 4H), 6.57 (s, 2H), 5.47 (d, J=8.1 Hz, 1H), 4.44 (m, 1H), 3.92 (m, 1H), 3.77 (m, 1H), 3.58 (m, 1H), 3.41 (d, J=7.2 Hz, 1H), 3.24 (m, 4H), 2.91 (dd, J=13.7, 4.0 Hz, 1H), 2.46 (dd, J=13.7, 10.8 Hz, 1H), 2.31 (s, 3H), 2.10 (dd, J=6.8, 3.3 Hz, 1H), 1.81 (dp, J=13.2, 6.6 Hz, 1H), 1.44 (s, 9H), 1.25 (d, J=6.2 Hz, 3H), 0.91 (dd, J=6.7, 2.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.72, 153.71, 135.81, 133.44, 127.15, 127.02, 81.61, 78.33, 76.81, 69.13, 68.31, 67.08, 51.93, 40.98, 31.48, 27.16, 26.42, 19.12, 17.65, 17.58, 17.38; ESIMS m/z 491 ([M+Na]+).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:39])[F:38])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:40]C(OC(Cl)C)=O>C(Cl)Cl>[ClH:40].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH:37]([F:38])[F:39])=[CH:32][CH:31]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: FC(F)Oc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Solvent: ClCCl
Product: Cl
Product: FC(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-benzhydryl-3-[2-(trifluoromethyl)-4′-(difluoro-methoxy)benzhydryloxy]azetidine (174) (2.73 g from previous step-assumed 4.7 mmol) in DCM (40 mL), cooled in ice-water bath, was added 1-chloroethyl chloroformate (1 mL, 9.4 mmol). After 1 h, the mixture was allowed to warm to ambient temperature. After a further 5.5 h, the mixture was concentrated under reduced pressure, methanol (40 mL) was added, and the mixture was stirred for 16 h. The mixture was concentrated under reduced pressure, then dissolved in iso-hexane (4 mL)-DIPE (30 mL)-MeOH (2 mL). Upon stirring, a precipitate formed. The mixture was cooled in ice-water bath for 15 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24](O)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH2:30]([N:32]([CH2:38][CH3:39])[CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)[CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24]([N:35]4[CH2:36][CH2:37][CH:33]([N:32]([CH2:38][CH3:39])[CH2:30][CH3:31])[CH2:34]4)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)C1CCNC1
Reactant: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)O
Product: CCN(CC)C1CCN(C(=O)c2c(COC)nn(-c3cccc(/C=C/c4ccc(Cl)cc4)c3)c2COC)C1

Procedure:
In analogy to the procedure described for example 1, 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and [rac]-diethyl-pyrrolidin-3-yl-amine gave the title compound as brown solid. MS: 537.3 (MH+, 1 Cl).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[C:14]([CH3:18])=[C:15]([CH3:17])[NH:16][C:9]=12)[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[ClH:23].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:16]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6][C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[O:3][CH2:1][CH3:2])[C:14]([CH3:18])=[C:15]1[CH3:17]
Reactant: Clc1cccc(CBr)c1
Reactant: CCOc1ccccc1COc1ccnc2c(C)c(C)[nH]c12
Product: CCOc1ccccc1COc1ccnc2c(C)c(C)n(Cc3cccc(Cl)c3)c12
Product: Cl
Yield: 79.8 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 33, except for using 7-(2-ethoxybenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine prepared in Step 2 and 3-chlorobenzyl bromide, the titled compound was obtained as a white solid. (Yield: 79.8%)
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:20][CH3:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:1][CH2:2][C:3]1([CH2:20][CH3:21])[CH:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][C:11]=32)[CH2:6][CH2:5][CH2:4]1)(=[O:24])[CH3:23]
Reactant: CCC1(CO)CCCN2CCc3c([nH]c4ccccc34)C21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC1(COC(C)=O)CCCN2CCc3c([nH]c4ccccc34)C21
Reaction time: 72 h
Yield: 61.2 %

Procedure:
2.50 g. (8.82 mmoles) of 1-hydroxymethyl-1-ethyl-1,2,3,4,6,7,12,12b-octahydro-indolo[2,3-a] quinolizine are dissolved in 15 ml. of absolute pyridine. 15 ml. of acetic anhydride are added to the solution, and the mixture is allowed to stand at room temperature for three days. Thereafter the solution is evaporated in vacuo, and the oily residue is stirred with a 5% sodium hydrocarbonate solution. The separated solid substance is filtered off, washed with water, dried, and recrystallized first from aqueous methanol and then from methanol. 1.75 g. (61.2%) of the title compound are obtained in the form of shiny crystals melting at 96°-97° C.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[C:7](B(O)O)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[C:22]1[CH:33]=[CH:32][C:25]([CH2:26][N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:24][CH:23]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[C:7]([C:22]2[CH:33]=[CH:32][C:25]([CH2:26][N:27]3[CH:31]=[N:30][N:29]=[N:28]3)=[CH:24][CH:23]=2)[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: Brc1ccc(Cn2cnnn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)Cc1cc(-c2ccc(Cn3cnnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Yield: 61.5 %

Procedure:
5-iso-Butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (401.0 mg, 1.256 mmol, see Example 1(c) above), 1-(4-bromobenzyl)-1H-tetrazole (199.4 mg, 0.834 mmol, see step (a) above), toluene (20 mL), ethanol (3.0 mL), NaOH (1.0M, 5.0 mL, 5.0 mmol) and Pd(PPh3)4 (29.0 mg, 0.25 mmol) were mixed under N2. The mixture was warmed to reflux for 2 hours. The mixture was diluted with EtOAc (20 mL), washed with water and brine, and dried over MgSO4. The solvent was removed and the residue was separated by column chromatography using CHCl3:MeOH (40:1) as eluent to give 222.4 mg of the sub-title compound (yield: 62%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.CN(C=O)C.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30]>O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: O=C1CCc2cc(N3CCN(C(=O)c4ccc([N+](=O)[O-])cc4)CC3)ccc2N1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 2 ml of pyridine were added to 40 ml of DMF. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.7 g of 4-nitrobenzoyl chloride. After completion of addition, the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 2.4 g of 6-[4-(4-nitrobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 235.5°-236.5° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][N:6]([CH3:30])[CH:7]([CH2:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:8]=O.C([BH3-])#N.[Na+].O>CO>[NH2:3][CH2:2][CH2:1][NH:4][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([OH:17])[C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][CH:7]([N:6]([CH3:30])[CH3:5])[CH3:8]
Reactant: CCCCC(=O)C(CC(C=O)N(C)C)(c1ccccc1)c1ccccc1
Reactant: NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(CC(c1ccccc1)(c1ccccc1)C(O)CCCCNCCN)N(C)C
Temperature: 25 °C

Procedure:
Ethylenediamine was added to a solution of 2-dimethylamino-4,4-diphenyl-5-oxononanal (12 mg), as prepared in Example 1, in methanol (0.5 ml). After the mixture was stirred at room temperature, sodium cyanoborohydride (10 mg) was added. The mixture was stirred at room temperature for 18 hours, water was added, and the aqueous mixture was extracted with chloroform. The combined extracts were washed with brine and dried (MgSO4). Rotary evaporation gave a crude product which was further dried in vacuo to yield 4 mg of N-(2-aminoethyl)-8-dimethylamino-6,6-diphenyl-5-hydroxynonylamine.
Reaction SMILES: CS([O:5][CH:6]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]2=[O:25])[CH2:7]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=1>C(#N)C>[O:25]=[C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][N:19]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][CH:6]([O:5][C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[CH2:7]1
Reactant: N#Cc1ccc(O)cc1
Reactant: CS(=O)(=O)OC1CCN(CCc2ccccc2N2CCCCC2=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(OC2CCN(CCc3ccccc3N3CCCCC3=O)C2)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of 1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl methanesulfonate a10-2 (0.183 g, 0.5 mmol, 1 eq) in acetonitrile (4 ml) is added K2CO3 (0.138 g, 1 mmol, 2 eq) and 4-hydroxybenzonitrile (0.060 g, 0.5 mmol, 1 eq). The solution is stirred overnight at 85° C. After filtration and solvent removal, the residue is purified by basic reverse phase chromatography on silicagel (gradient: CH3CN/H2O/NH4OH from 40/60/0.1 to 70/30/0.1) to give 85 mg of pure 4-[(1-{2-[2-(2-oxopiperidin-1-yl)phenyl]ethyl}pyrrolidin-3-yl)oxy]benzonitrile 50.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:34][CH2:35][O:36][CH3:37])=[CH:6][C:7]([O:30][CH2:31][O:32][CH3:33])=[C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12](=[S:15])[NH:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].[C:38](=O)([O-])[O-].[K+].[K+].C(O)C.CI>C(OCC)C>[CH:1]([C:4]1[C:5]([O:34][CH2:35][O:36][CH3:37])=[CH:6][C:7]([O:30][CH2:31][O:32][CH3:33])=[C:8]([C:10]2[N:11]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[CH:20][CH:21]=3)[C:12]([S:15][CH3:38])=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1-c1ccc(CN2CCN(C)CC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Solvent: CI
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SC)n1-c1ccc(CN2CCN(C)CC2)cc1
Yield: 63.1 %

Procedure:
5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-2,4-dihydro-[1,2,4]triazol-3-thione (F652-06, 3.17 g, 6.01 mmol) and potassium carbonate (829 mg, 6.00 mmol) were weighed and placed in a reaction vessel. After adding ethanol (30 mL), methyl iodide (0.374 mL, 6.01 mmol) was added to the mixture. After heating for 1 hour under reflux, the temperature was returned to room temperature, and the solvent was distilled off under reduced pressure. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and then filtered to remove sodium sulfate, and the solvent was distilled off under reduced pressure to obtain pale yellow foam. Diethyl ether was added to the foam and the insoluble material was removed by filtration. After washing with water, the filtrate was washed with saturated sodium chloride solution. The extract was dried with sodium sulfate, and sodium sulfate was removed by filtration. The solvent was distilled off under reduced pressure to obtain 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-5-methylsulfanyl-[1,2,4]triazole (F652-07, pale yellow foam, 2.05 g, 63%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH2:25])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:33][CH:34]([S:36]([Cl:39])(=[O:38])=[O:37])[CH3:35]>C(Cl)Cl.CO>[ClH:39].[ClH:39].[CH2:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([O:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][NH:25][S:36]([CH:34]([CH3:35])[CH3:33])(=[O:38])=[O:37])[CH2:18][CH2:17]3)[CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCCCc1cc(OC2CCN(CCCN)CC2)c2ncccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCc1cc(OC2CCN(CCCNS(=O)(=O)C(C)C)CC2)c2ncccc2c1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3-{4-[(6-Butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)amine (for example, as prepared for Intermediate 36) (30 mg, 0.09 mmol) was dissolved in DCM (1 ml), and treated with triethylamine (38 μl, 0.27 mmol), and 2-propanesulfonyl chloride (commercially available, for example, from Aldrich) (20 μl, 0.18 mmol). The mixture was stirred in a stoppered vial at room temperature for 1 h, then left to stand at room temperature overnight. LCMS analysis indicated that reaction was not complete. Further triethylamine (38 μl, 0.27 mmol), and 2-propanesulfonyl chloride (17 μl, 0.18 mmol) were added and the mixture stirred at room temperature for 1.5 h. LCMS analysis indicated that reaction was still not complete. Further triethylamine (19 μl, 0.14 mmol), and 2-propanesulfonyl chloride (10 μl, 0.09 mmol) were added and the mixture stirred at room temperature overnight. The mixture was diluted with methanol and applied to an SCX-2 cartridge (5 g) eluting with methanol, followed by 10% aqueous 0.88 s.g. ammonia in methanol. The relevant fractions were concentrated, and the residue was purified by MDAP. The appropriate fractions were combined and concentrated, but the product was found to contain an impurity, thought to be (3-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}propyl)sulfamic acid. The material was dissolved in methanol and applied to an aminopropyl cartridge (5 g) eluting with methanol. The relevant fractions were combined and concentrated to give the title compound as the free base: LCMS RT=2.68 min, ES+ve m/z 448 (M+H)+. The material was dissolved in methanol and treated with 1.25 M hydrogen chloride in methanol (0.5 ml, excess). The volatiles were removed under a stream of nitrogen to give the title compound (13 mg, 27%): LCMS RT=2.80 min, ES+ve m/z 448 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][CH3:11])(=[O:9])[CH:7]=[CH2:8].COC1C=C(O)C=CC=1O>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:8][CH2:7][C:6]([O:10][CH3:11])=[O:9])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: CCNCC
Agent: COc1cc(O)ccc1O
Product: CCN(CC)CCC(=O)OC
Yield: 98.9 %

Procedure:
Diethylamine (350 g; 4.8 moles) was added to 344 g (4 moles) of methyl acrylate containing 500 ppm of methoxyhydroquinone and the mixture was made to react at 70°-80° C. for 15 hours, so that the addition to the double bond was completed. After completion of the reaction, the unreacted diethylamine was removed by distillation to give 630 grams of methyl beta-diethylaminopropionate. The yield was 99%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][N:37]=[CH:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:36]=[N:37][N:38]=[CH:39]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2cnnc2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cnnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (383 mg, 1.2 mmol) and 3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionic acid ethyl ester [CAS-No. 335255-97-5 ] (259 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow solid (290 mg).
Reaction SMILES: [OH-:1].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4]>C(OCC)(=O)C.CCCCCC>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:4])=[O:1])=[CH:7][CH:8]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 73.6 %

Procedure:
Using N-Boc-L-tHyp(Tosyloxy)-OMe (5g, 10.5 mmol), powdered KOH (1.75 g, 26.5 mmol) and 4-nitrophenol (3.66 g, 26.3 mmol) after 4 days at reflux, 2.52 g (65%) of the corresponding 4-nitrophenyl ether was obtained by column chromatography (silica ge, ethyl acetate/hexane mixtures) and crystallization of the appropriate fractions from ethyl acetate/hexane (1:1). An alternate method is to triturate the oily crude and pentane several times [hexane doesn't work] and then add a very, small amount of ethyl acetate to solidify the product. The filtered, solid product may than be crystallized as above. Elemental analysis for C17H22N2O7 (366.324 g/mmol): Calculated C, 55.74; H, 6.05; N, 7.65. Found C, 55.71; H, 6.05; N, 7.65.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16](C=O)[CH:15]=[N:14]1.C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21].[C:42]1([CH3:48])C=CC=C[CH:43]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[N:17]=[C:16]([CH2:43][CH:42]([OH:21])[CH3:48])[CH:15]=[N:14]1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Reactant: O=Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Product: CC(O)Cc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole-4-carboxaldehyde (2 g) and formylmethylene triphenylphosphorane (1.9 g) were heated under reflux in toluene for 4 hours. After removal of the solvent at reduced pressure the resulting residue was purified by column chromatography to give 3-[(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazol-4-yl]-2-propanol, m.p. 68°-69°. This compound (1.8 g) was than stirred with diaminomaleonitrile (0.6 g) in methanol containing a trace of p-toluenesulphonic acid for 4 hours. Removal of the solvent at reduced pressure and column chromatography gave 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[3-(2-amino-1,2-dicyanoethenylimino)-2-propenyl]-2H-1,2,3-triazole, m.p. 207°-209°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=[O:6].C(Cl)CCl.C1C=CC2N(O)N=[N:22][C:20]=2C=1.Cl.CN>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([NH:22][CH3:20])=[O:6]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(O)c(Br)c1
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CNC(=O)c1ccc(O)c(Br)c1
Reaction time: 16 h

Procedure:
To a stirred solution of 3-bromo-4-hydroxybenzoic acid (Commercial eg Aldrich) (2.0 g), EDC (2.65 g), HOBT (1.41 g) and TEA (6.2 ml) in DCM (60 ml) was added methylamine hydrochloride (1.87 g). This was stirred at 25-30 C for 16 h. The solvent was removed under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The organics were dried (sodium sulphate) and concentrated in vacuo to yield the title compound, 0.57 g
Reaction SMILES: [CH:1]1(CN)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19])([O-])=O.[N:22]1C=CC=C[CH:23]=1>C(OCC)(=O)C>[NH2:9][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:22]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH3:23])(=[O:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: c1ccncc1
Reactant: NCC1CCCCC1
Solvent: CCOC(C)=O
Product: CN(C1CCCCC1)S(=O)(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a stirred solution of cyclohexylmethylamine (0.57 g, 5 mmol) in pyridine (8 ml) was added slowly at 0° C. 2-nitrobenzenesulfonyl chloride (1.10 g, 5 mmol) and the reaction mixture was allowed to warm to room temperature and stirred overnight. The pyridine was removed under reduced pressure and the crude mixture obtained was diluted with ethyl acetate and washed with hydrochloric acid solution (25 ml), water (25 ml), brine (25 ml) and dried over sodium sulphate. The solvent was removed under reduced pressure and the resulting crude oil (1.40 g) was dissolved in ethanol and hydrogenated in the presence of a catalytic amount of Raney-Ni®. The catalyst was removed by filtration through Celite® and the solvent was eliminated under reduced pressure to yield a yellow solid (0.80 g, 60%).