Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([CH3:18])[N:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])[C@@H:5]([C:13]([O:15]CC)=[O:14])[CH2:4][CH2:3]1>FC(F)(F)C(O)=O>[CH2:10]([O:9][C:7]([N:6]1[CH:2]([CH3:18])[CH2:3][CH2:4][C@@H:5]1[C:13]([OH:15])=[O:14])=[O:8])[CH:11]=[CH2:12]
Reactant: C=CCOC(=O)N1[C@@H](C(=O)OCC)CCC1(C)O
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)N1C(C)CC[C@@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(R)-1-Allyl 2-ethyl 5-hydroxy-5-methylpyrrolidine-1,2-dicarboxylate (3.0g, 12 mmol) was dissolved in trifluoroacetic acid (20 mL) and cooled to 0° C. before borane-pyridine complex (2.9 mL, 23 mmol) was added. The reaction mixture was heated to 90° C. for 3 h, then concentrated in vacuo and NaOH—about 5N (30 mL) was added. The mixture was stirred for 2 h at 60° C., then cooled, washed with EtOAc (30 mL) and acidified to ˜pH 5 with conc HCl. The mixture was extracted into dichloromethane, which was separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound. Found MS (ES+): 214 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[CH3:5][N:6]([CH3:15])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([NH2:14])=[CH:9][N:8]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:14]([C:10]1[C:11]([CH3:13])=[CH:12][C:7]([N:6]([CH3:15])[CH3:5])=[N:8][CH:9]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(N(C)C)ncc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)ncc1N=C=S
Temperature: 0 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
Thiophosgene (9.3 mL, 125 mmol) was added dropwise to a stirred mixture of N2,N2,4-trimethylpyridine-2,5-diamine (15.7 g) in tetrahydrofuran (100 mL) and saturated aqueous sodium hydrogen carbonate (150 mL) at 0° C., and the mixture was stirred at 0° C. for 2 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with n-hexane to give the title compound as a colorless powder (14.1 g, 73.0 mmol, 70% in 2 steps).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:28]([CH3:31])([CH3:30])O)[CH:5]=[C:6]([O:26][CH3:27])[C:7]=1[O:8][C:9]1[C:10]2[N:18]=[N:17][N:16]([CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[C:11]=2[N:12]=[C:13]([CH3:15])[N:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:28]([CH3:31])=[CH2:30])[CH:5]=[C:6]([O:26][CH3:27])[C:7]=1[O:8][C:9]1[C:10]2[N:18]=[N:17][N:16]([CH:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])[C:11]=2[N:12]=[C:13]([CH3:15])[N:14]=1
Reactant: CCCC(CCC)n1nnc2c(Oc3c(Br)cc(C(C)(C)O)cc3OC)nc(C)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C=C(C)c1cc(Br)c(Oc2nc(C)nc3c2nnn3C(CCC)CCC)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-5-methoxy-α,α-dimethyl-4-[(5-methyl-3-(1-propylbutyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-yl)-oxy]benzenemethanol (0.59 g) in 35 mL of benzene, a small quantity of p-toluene sulfonic acid was added. The solution was refluxed under azeotropic conditions for 1.5 hours. Once cooled to room temperature, the solution was washed with saturated NaHCO3 followed by water. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was chromatographed silica gel using a mixture of 1:1 ethyl acetate and hexane to yield the title compound as a colorless solid, mp 110-115° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH3:16])[CH3:15]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1([CH3:16])[CH3:15]
Reactant: [H][H]
Reactant: CC1(C)CN(Cc2ccccc2)CCC1N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CNCCC1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.3 g) and 4-amino-1-benzyl-3,3-dimethylpiperidine (1.6 g, 7.33 mmol) in methanol (25 ml) was stirred in hydrogen atmosphere (1 atm.) at 30° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3,3-dimethylpiperidine. Yield 0.7 g (75%), C7H16N2, m/z 129 (M+1), PMR (CDCl3): 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs, 2H, D2O exchangeable), 2.26-2.68 (m, 4H), 3.06 (m, 1H), 3.52 (bs, 1H, D2O exchangeable).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CI.[H-].[Na+].[C:23](OCC)(=O)C>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:23])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1ccc(OCCCCCn2ccnc2)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(OCCCCCn2ccnc2)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 1.87 g p-[5-(1-imidazolyl)pentyloxy]phenol and 0.46 ml methyl iodide in 18 ml anhydrous N,N-dimethylformamide, was added under ice cooling and with stirring 290 mg of 60% sodium hydride in oil, and stirring was continued at room temperature for five minutes. Ethyl acetate was added to the reaction mixture, the precipitate which separated out was filtered off, and the filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography [chloroform/methanol/28% ammonia water (50:1:0.1)], affording 2.0 g of 1-[5-(1-imidazolyl)pentyloxy]-4-methoxybenzene as oil.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[O:19]1[C:23]2[CH:24]=[CH:25][C:26](N)=[CH:27][C:22]=2[CH2:21][CH2:20]1.[K+].[Br-]>CCOC(C)=O>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)=[CH:27][C:22]=2[CH2:21][CH2:20]1
Reactant: Nc1ccc2c(c1)CCO2
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4)CCO5)c3c2s1
Yield: 95 %

Procedure:
Prepared from VII and 2,3-dihydro-1-benzofuran-5-amine. Flash chromatography eluent (EtOAc). Yield: 95%; yellow solid; mp 216° C.; IR (KBr) νmax/cm−1 2894, 2853, 2228, 1643, 1609, 1579, 1484, 1467, 1376, 1353, 1306, 1269, 1219, 1192, 1164, 1123, 978, 941, 881, 814; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=8.7 Hz), 8.10 (s, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.22 (m, 1H), 7.04 (s, 1H), 6.78 (m, 1H), 4.53 (t, 2H, J=8.7 Hz), 3.20 (t, 1H, J=8.7 Hz); HRMS calcd for C18H12N5OS (M+H+): 346.0763, found 346.0762.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](C(OOCC)=O)=[O:13])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[CH:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[C:22]([OH:27])[CH:21]=1>>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:13])[NH:26][C:25]1[CH:20]=[CH:21][C:22]([OH:27])=[CH:23][CH:24]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: Nc1ccc(O)cc1
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCS1
Product: CC(C)OC(=O)C(C(=O)Nc1ccc(O)cc1)=C1SCS1

Procedure:
Following the procedure of Example 18, the titled compound was prepared as a white solid (66%) from isopropyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate and p-aminophenol.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33](=[N:42][C:43]#[N:44])OOC3C=CC=CC=3)[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:45]1([NH2:51])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>C(O)(C)C>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[CH:27]=[C:28]([NH:32][C:33]([NH:51][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[N:42][C:43]#[N:44])[CH:29]=[C:30]([CH3:31])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(NC(=NC#N)OOc3ccccc3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: NC1CCCCC1
Solvent: CC(C)O
Product: CCCc1nc2c(C)cc(NC(=NC#N)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 1c from 4'-[[2-n-propyl-4-methyl-6-(2-phenoxy-3-cyano-isoureido)-1H-benzimidazol-1-yl] -methyl]-2-(1H-tetrazol-5-yl)-biphenyl and cyclohexylamine in boiling isopropanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[N:14]=2)=[CH:5][CH:4]=1)[CH3:2].[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH:19][C:27](=[O:28])[CH2:26][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCc1ccc(Nc2nc3cc(N)ccc3o2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(Nc2nc3cc(NC(=O)Cc4ccccc4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The compound 1 prepared in Example 1 (1 mmol, 1 eq) was dissolved with DMF (dimethylformamide, 3 mL), and 2-phenylacetyl chloride (1 mmol, 1 eq) and N,N-diisopropylethylamine (1 mmol, 1 eq) were added together thereto. The mixture was then stirred at room temperature for 16 hours. To the reaction solution was added 10% aqueous HCl solution, and the mixture was extracted with 30 mL of EtOAc. The organic layer was washed with 10% aqueous HCl solution, and then two times with saturated NaHCO3 solution and two times with saturated aqueous NaCl solution. After drying with anhydrous MgSO4 and filtering under reduced pressure, the organic solvent was removed under reduced pressure to prepare the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[CH3:17]N.[Cl-].[Na+]>CO>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:17])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCCCC(=O)O
Reactant: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)CCCCCNC(C)=O
Temperature: 25 °C

Procedure:
Methyl 6-acetamidohexanoate was prepared as a low-melting solid by sequential treatment of 6-acetamido hexanoic acid with thionyl chloride and methanol. Five grams of this compound, (27 mmol) was dissolved in an excess of 40% aqueous methylamine solution, and the resulting mixture was stirred for sixteen hours at room temperature. The reaction mixture was saturated with sodium chloride and extracted several times with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was removed in vauo to yield a crude residue. Recrystallization from THF yielded 4.5 grams (90%) of pure product, melting point 99°-100° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.C(=S)=S>>[Br:10][C:11]1[S:12][C:13]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:14][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Brc1cccs1
Solvent: S=C=S
Product: O=C(c1ccccc1)c1ccc(Br)s1
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
To a mixture of benzoyl chloride (2.81 g, 20.0 mmol) and 2-bromothiophene (3.42 g, 21.0 mmol) in carbon disulfide (120 mL) aluminum chloride (5.34 g, 40.0 mmol), was added in portions over 10 min with vigorous magnetic stirring. The reaction was next allowed to stir for 2.5 h before being quenched with 100 mL 1 M HCl (aq). The organics were separated, the aqueous layer extracted with carbon disulfide (3×50 mL), and the combined organics washed with water (3×100 mL) and dried over MgSO4. After filtration, the organics were concentrated in vacuo and the residue chromatographed on a silica gel column (hexane:ether=9:1) to yield 5.14 g (96%) of yellow crystals. mp 41-43° C.; 1H NMR (CDCl3): δ 7.84 (d, 2H, 3J=8.0 Hz), 7.62 (t, 1H, 3J=7.2 Hz), 7.52 (t, 2H, 3J=7.5 Hz), 7.40 (d, 2H, 3J=3.5 Hz), 7.15 (d, 2H, 3J=4.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][C@@H:15]([C:20]2[S:21][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][C:17](O)=[O:18])=[O:13])[C:7]1=[O:34].[CH3:39][N:40](C)[CH:41]=O.CNC.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>O1CCCC1>[CH3:39][N:40]([CH3:41])[C:17]([CH2:16][C@@H:15]([NH:14][C:12]([C:8]1[C:7](=[O:34])[N:6]([CH2:5][C:4]2[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:20]1[S:21][C:22]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:18]
Reactant: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CN(C)C(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reaction time: 2 h

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-propionic acid (0.026 g, 0.000049 mol;) was dissolved in N,N-Dimethylformamide (2 mL, 0.03 mol;) and 2.0 M of Dimethylamine in Tetrahydrofuran (0.243 mL) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.024 g, 0.000063 mol;) was added. The reaction was allowed to stir for 2 hours and LC-MS showed disappearance of starting material and appearance of product at 1.28 562.10. The reaction was purified by Gilson Preparative HPLC and the pure fractions were concentrated. ES (+) MS m/e=562.10; NMR (400 MHz, DMSO-d6) δ ppm 2.79 (s, 3H), 3.00 (s, 3H), 3.06 (d, 2H, J=7 Hz), 5.22 (d, 2H, J=5 Hz), 5.7 (m, 1H), 6.60 (t, 1H, J=8 Hz), 7.00 (d, 1H, J=3 Hz), 7.14-7.21 (m, 3H), 7.38-7.49 (m, 2H), 7.54 (t, 1H, J=8 Hz), 7.79 (m, 1H), 8.2-8.25 (m, 2H), 8.29 (m, 1H), 8.4 (dd. 1H), 10.29 (d, 1H)
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O[C:67]1[CH:74]=[CH:73][C:70]([CH:71]=[O:72])=[C:69]([O:75][CH3:76])[CH:68]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH3:76][O:75][C:69]1[CH:68]=[C:67]([O:65][CH2:64][CH:22]2[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]2)[CH:74]=[CH:73][C:70]=1[CH:71]=[O:72]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: COc1cc(O)ccc1C=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C=O)c(OC)c2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 5.5 h
Yield: 100 %

Procedure:
3,4,5-Tris(octadecyloxy)cyclohexylmethyl alcohol (238 mg, 0.26 mmol), 4-hydroxy-2-methoxybenzaldehyde (79 mg, 0.52 mmol) and triphenylphosphine (149 mg, 0.57 mmol) were dissolved in THF (6 ml), diisopropyl azodicarboxylate (115 mg, 0.57 mmol) was added, and the mixture was stirred for 5.5 hr. Water (1 ml) was added to the reaction mixture and the mixture was concentrated. The residue was precipitated with acetonitrile (2.5 ml) to give 2-methoxy-4-[3′,4′,5′-tris(octadecyloxy)cyclohexylmethyloxy]benzaldehyde (272 mg, 0.26 mmol, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:26]1[CH:31]=[C:30]([OH:32])[CH:29]=[C:28]([CH:33]([OH:36])[CH2:34][NH2:35])[CH:27]=1>>[OH:36][CH:33]([C:28]1[CH:27]=[CH:26][CH:31]=[C:30]([OH:32])[CH:29]=1)[CH2:34][NH:35][CH:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: NCC(O)c1cccc(O)c1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4cccc(O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 218) and DL-norphenylephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.25–1.60 (m, 2 H), 2.00–2.15 (m, 2 H), 2.50–3.10 (m, 5 H), 3.60–3.70 (m, 2 H), 3.79 (s, 3 H), 4.80–4.90 (m, 1 H), 6.05 (brs, 1 H), 6.70–6.80 (m, 1 H), 6.80–6.85 (m, 4 H), 6.90 (d, J=9.0 Hz, 2 H), 7.02 (d, J=9.0 Hz, 2 H), 7.16 (t, J=7.7 Hz, 1 H), 7.60 (d, J=9.0 Hz, 2 H), 9.45 (s, 1 H), 9.70 (s, 1 H); MS (ES) m/z: 498.5 (MH+); HRMS Calcd. for C26H31N3O5S(M+): 497.1984. Found: 497.1961.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([CH3:23])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH3:5].[OH-].[Na+]>C1COCC1.CO>[CH3:23][C:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=1)([CH3:5])[C:3]([OH:24])=[O:2]
Reactant: COC(=O)C(C)(C)Oc1ccccc1Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(Oc1ccccc1Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.8 %

Procedure:
To a solution of 433A (5.05 g, 15.2 mmol) in a mixed solvent of THF/MeOH (45 ml, 2/1) was added 2N NaOH (15.2 ml, 30.4 mmol). The mixture was stirred at rt for 2.5 h, concentrated. The residue was purified by flash chromatography on silica gel (2%-5% MeOH—CH2Cl2) gave 433B (4.38 g, 91%) as a light yellow solid.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]([CH3:43])([CH2:41][CH3:42])[CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([C:14]1([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O>C(OCC)(=O)C.O>[CH3:6][C:7]([CH3:43])([CH2:41][CH3:42])[CH2:8][C:9]1[N:5]=[C:12]([C:14]2([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=4)=[CH:29][CH:28]=3)[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[NH:11][CH:10]=1
Reactant: [NH4+]
Reactant: CCC(C)(C)CC(=O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CCCN1C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CCCN2C(=O)OC(C)(C)C)n1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
Ammonium acetate (1.47 g, 19 mmol) was added to an ambient temperature solution of tert-butyl 2-{[(4,4-dimethyl-2-oxohexyl)amino]carbonyl}-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate (200 mg, 0.38 mmol) in xylenes (10 mL). After stirring at 160° C. in a sealed tube overnight, the reaction mixture was diluted with ethyl acetate and water. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane followed by high pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded tert-butyl 2-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.[F:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](F)[CH:27]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:26]3[CH:25]=[N:24][CH:23]=[C:22]([F:21])[CH:27]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Reactant: Fc1cncc(F)c1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cncc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example, step using 3,5-Difluoropyridine instead of 3-bromopyridineto yield the final compound as a off-white solid, MS (ISP): m/e=371.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:5][NH:6][CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:14].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[S:34][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:32][CH:31]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:5][N:6]([CH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]1=[O:14])[S:35]([C:33]1[S:34][C:30]([Cl:29])=[CH:31][CH:32]=1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: COc1ccc(CNC2CCCCNC2=O)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(Cl)s2)cc1F
Reaction time: 8 h

Procedure:
rac-3-(3-Fluoro-4-methoxy-benzylamino)-azepan-2-one (213 mg, 0.80 mmol) was dissolved in CH2Cl2 (7.7 ml) and treated with DMAP (30 mg, 0.24 mmol), Hünig's base (0.30 ml, 1.76 mmol) and ⅛ of the cooled (0° C.) reaction mixture was reacted with 5-chloro-thiophene-2-sulfonyl chloride (48 mg, 0.22 mmol) and shaken overnight in a parallel reaction block. Solvent was removed under reduced pressure and the residue dissolved in aqueous acetonitrile solution and purified using high throughput preparative RP(C18) chromatography: lyophilisate 13 mg;
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH3:14]>>[CH3:14][C:10]1[N:9]([CH2:8][CH2:7][CH2:6][NH:1][C:2]([NH2:4])=[O:3])[CH2:13][CH2:12][N:11]=1
Reactant: Cc1nccn1CCCN
Reactant: NC(N)=O
Product: CC1=NCCN1CCCNC(N)=O
Yield: 95.7 %

Procedure:
60.0 g of urea was added to 139.2 g of 1-(3′-aminopropyl)-2-methylimidazole and reacted at 160° C. for 10 hours, and after the reaction, a volatile component was removed to obtain 176.1 g of a 1-{3′-(2″-methylimidazolinyl)propyl}urea composition. 117.4 g of dipropylene glycol was added thereto to prepare a solution containing 60% of a 1-{3′-(2″-methylimidazolinyl)propyl}urea composition (IZUM), which was subjected to the following foaming test. The composition of the solution is shown in Table 17.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:13]=1.[Br:14]Br.O>C(O)(=O)C>[Br:14][CH:8]1[C:7](=[O:12])[C:6]2[CH:13]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:11][CH2:10][CH2:9]1
Reactant: O=C1CCCSc2ccc(F)cc21
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cc(F)ccc2SCCC1Br
Reaction time: 4 h

Procedure:
7-Fluoro-2,3,4,5-tetrahydro-1-benzothiepin-5-one (1 equivalent) was also dissolved in glacial acetic acid and stirring continued at room temperature. Bromine (2.5 equivalents) was added dropwise and stirring continued at room temperature for 4 hours. Water was added to the reaction mixture was then extracted with 2×25 ml ethyl acetate. The combined ethyl acetate extracts were washed with water, saturated sodium bicarbonate, and water. The combined extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a solid which was recrystallized from the ethyl acetate/hexane 1:1 v/v to afford 4-bromo-7-fluoro-2,3,4,5-tetrahydro-1-benzothiepin-5-one: 1H NMR (CDCl3) δ 7.55 (dd, 1H, J=2.7, 9.0 Hz), 7.44 (dd, 1H, J=8.7, 5.1 Hz), 7.11 (Apparent dt, 1H, J=2.7, 4.8 Hz), 5.34 (dd, 1H, J=5.7, 10.2 Hz), 3.20-2.50 (m, 4H).