Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C)(C)C.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]/[CH:19]=[CH:20]/[C@@H:21]([OH:26])[C@@H:22]([NH2:25])[CH2:23][OH:24].Cl.[CH:28]1([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1.CN1CCOCC1>O1CCCC1>[OH:24][CH2:23][C@H:22]([NH:25][C:34]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:35])[C@H:21]([OH:26])/[CH:20]=[CH:19]/[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6]
Reactant: O=C(O)C1CCCCC1
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: CN1CCOCC1
Product: CCCCCCCCCCCCC/C=C/[C@@H](O)[C@H](CO)NC(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.5 %

Procedure:
N-((2S,3R,E)-1,3-dihydroxyoctadec-4-en-2-yl)cyclohexanecarboxamide (Compound I-1) was synthesized by adding 40 mg (0.29 mmol) of tert-butyl alcohol (HOBt) and 100 mg (0.29 mmol) of D-sphingosine/HCl at 0° C. to the solution of 38 mg (0.29 mmol) of cyclohexanecarboxylic acid in 25 mL of anhydrous tetrahydrofuran (THF). After 5 min, 67 mg (0.33 mmol) of dicyclohexylcarbodiimide (DCC) was added, and the pH of the solution was adjusted to 8 with 4-methylmorpholine. The reaction mixture was stirred at 0° C. for 2 h and at room temperature overnight. On evaporation the residue was dissolved in 100 mL of ethyl acetate. The solution was washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, and saturated sodium chloride, and the organic phase was separated and dried over anhydrous magnesium sulfate for 2 h. After filtration and evaporation under reduced pressure, the crude product was recrystallized in ethyl ether to obtain 60 mg (51%) of N-((2S,3R,E)-1,3-dihydroxyoctadec-4-en-2-yl)cyclohexanecarboxamide as colorless powder. GC/MS (m/e): 391 [M+H2O]+. 1H NMR (d6-DMSO, 300 MHz) δ/ppm=7.224 (d, J=8.4 Hz, 1H), 5.513 (dt, J=15.3 Hz, J=6.6 Hz, 1H), 5.345 (dd, J=15.3 Hz, J=6.6 Hz, 1H), 4.789 (d, J=5.1 Hz, 1H), 4.422 (t, J=5.4 Hz, 1H), 3.872 (q, J=6.0 Hz, 1H), 3.636 (m, 1H), 3.446 (m, 2H), 2.088 (m, 1H), 1.917 (m, 2H), 1.652 (m, 6H), 1.225-1.157 (m, 26H), 0.843 (t, J=6.6 Hz, 3H). 13C NMR (d6-DMSO, 75 MHz) δ/ppm=132.083, 131.506, 72.063, 61.298, 55.665, 44.657, 32.358, 31.979, 30.172, 29.732, 29.656, 29.382, 29.246, 26.194, 26.042, 22.778, 14.624. Anal. Calcd for C25H47NO3: C, 73.30; H, 11.56; N, 3.42; O, 11.72. Found: C, 72.99; H, 11.64; N, 3.74; O, 11.91.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH3:15][CH:16]([O:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27]O)[CH2:17][CH3:18]>>[CH3:15][CH:16]([O:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[CH2:17][CH3:18]
Reactant: CCC(C)Oc1cc(Cl)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCC(C)Oc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-butan-2-yloxy-4-chlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C20H19ClN4O2, 383; Found, 383.
Reaction SMILES: C[O:2][C:3](=[O:50])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:19]3[N:20]=[N:21][N:22]([CH3:24])[N:23]=3)[C:13]3[CH:40]=[C:41]([CH3:49])[C:42]([C:45]([F:48])([F:47])[F:46])=[C:43]([CH3:44])[C:12]2=3)=[CH:6][CH:5]=1.[OH-].[Na+]>CO.O.Cl>[F:34][C:32]([F:33])([F:35])[C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=1)[CH2:25][N:18]([C:19]1[N:20]=[N:21][N:22]([CH3:24])[N:23]=1)[C@H:14]1[CH2:15][CH2:16][CH2:17][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:50])=[O:2])=[CH:5][CH:6]=2)[C:12]2[C:43]([CH3:44])=[C:42]([C:45]([F:46])([F:47])[F:48])[C:41]([CH3:49])=[CH:40][C:13]1=2
Reactant: COC(=O)c1ccc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)c(C)c32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(Cc1ccc(C(=O)O)cc1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7,9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-benzoic acid methyl ester (0.1 mmol) in methanol (1 mL), add 4N sodium hydroxide (0.5 mL). Heat the mixture at 60° C. for 3 h. Dilute the cooled mixture with water and 1N HCl to bring the pH to 6-7 and extract with CH2Cl2 (3×15 mL). Combine the organic layers, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by chromatography (elution with 5% methanol in EtOAc) to afford the title compound. MS (ES+): 701 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18](=O)([O-])[O-].[Na+].[Na+].CI.O>CN(C=O)C>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:15])([F:16])[F:17])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: Cc1c(C(=O)O)cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 94.8 %

Procedure:
To stirred solution of 2-methyl-3-nitro-5-(trifluoromethyl)benzoic acid (1 g, 4.01 mmol) in DMF (3 mL) was added sodium carbonate (0.63 g, 6.02 mmol) and methyl iodide (1.14 g, 8.03 mmol). The resulting mixture was heated at 60° C. for 4 h. On completion, water was added to the reaction, and the product extracted using DCM. Combined organic layers were dried, concentrated under reduced pressure and purified by column chromatography over silica to give methyl 2-methyl-3-nitro-5-(trifluoromethyl)benzoate (1 g, 95.2%).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([N+:12]([O-])=O)[CH:7]=[CH:6]C=1C#N.[H][H].[C:17]([OH:20])(=[O:19])[CH3:18]>OS(O)(=O)=O.O.CO>[NH2:12][C:8]1[CH:7]=[CH:6][C:18]([C:17]([OH:20])=[O:19])=[C:2]([F:1])[C:9]=1[O:10][CH3:11]
Reactant: COc1c([N+](=O)[O-])ccc(C#N)c1F
Reactant: [H][H]
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COc1c(N)ccc(C(=O)O)c1F

Procedure:
A solution of 2-fluoro-3-methoxy-4-nitrobenzonitrile (170 mg) in H2SO4 and H2O (0.5 mL/0.5 mL) was heated at 100° C. for 18 h. After which, it was separated between ethyl acetate and water. Organic extract was dried and concentrated to give a residue, which was then dissolved in a mixture of methanol and acetic acid (2 mL/2 mL) and was hydrogenated using hydrogen balloon overnight. The solution was filtered through celite, and the filtrate concentrated to give a read solid as the product. [M+H] calc'd for C8H8FNO3, 186. found 186.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2.[H-].[Na+].[H][H].[CH3:18]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH3:18])[C:10](=[O:13])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1NC(=O)CC2
Reactant: [H][H]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1N(C)C(=O)CC2
Temperature: 0 °C
Yield: 96 %

Procedure:
8-Methoxy-3,4-dihydro-1H-quinolin-2-one (15 g) was dissolved in DMF (150 ml), and 3.6 g of sodium hydride (60% in oil) was added under ice cooling. After the addition, stirring was carried out at room temperature until the generation of hydrogen stopped. The resulting mixture was cooled with ice water again, and 5.8 ml of methyl iodide was added dropwise, followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to thereby obtain 16.7 g (yield: 96%) of 8-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+].[Na]>CO>[NH2:1][C:2]1[C:7]([O:11][CH3:10])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(N)c(Br)n1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1nc(C)cnc1N
Temperature: 25 °C
Yield: 75 %

Procedure:
2-Amino-3-bromo-5-methylpyrazine (0.374 g) was added to a freshly prepared solution of sodium methoxide in methanol (made by addition of sodium (0.115 g) to methanol (6 ml). The reaction mixture was heated under reflux for 18 hours, cooled to ambient temperature and the solvent removed by evaporation. Water (5 ml) was added to the residue and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give 2-amino-3-methoxy-5-methylpyrazine as a white crystalline solid (0.208 g, 75%), m.p. 67°-69° C.; mass spectrum (+ve CI): 140 (M+H)+.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.[N:14]([CH:17]1[CH:20](CCO)[NH:19][C:18]1=[O:24])=[N+:15]=[N-:16].N1C=CC=CC=1>C(Cl)Cl>[N:14]([CH:17]1[CH:20]([CH2:2][CH2:3][O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[NH:19][C:18]1=[O:24])=[N+:15]=[N-:16]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [N-]=[N+]=NC1C(=O)NC1CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: [N-]=[N+]=NC1C(=O)NC1CCOC(=O)C(F)(F)F
Temperature: 0 °C

Procedure:
Trifluoroacetic anhydride (0.2 mol) is added dropwise to an ice-cold, stirred solution of 3-azido-4-(2-hydroxyethyl)-azetidin-2-one (0.2 mol) and pyridine (0.21 mol) in methylene chloride (200 ml). The solution is stirred for 15 more min. at room temperature, then washed with water, dried with magnesium sulfate, and filtered. Evaporation of the methylene chloride under vacuum leaves 3-azido-4-(2-trifluoroacetoxyethyl)-azetidin-2-one.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:36][CH2:37][OH:38].N([O-])=O.[Na+].[BrH:43]>CC#N.O.[Cu]Br>[Br:43][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH2:36][CH2:37][OH:38]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(CCO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(CCO)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 6-(N-(4-amino-3-(2-hydroxyethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (250 mg, 0.465 mmol) in MeCN (1 mL) maintained at 0° C. was added sodium nitrite (80 mg, 1.16 mmol) dissolved in water (0.50 mL). followed by 48% aqueous HBr (0.25 mL). The resulting mixture was treated with copper(I) bromide (133 mg, 0.930 mmol) in 48% aqueous HBr (0.30 mL). After stirring at 60° C. for 1 hour the reaction mixture was cooled to RT, diluted with water and extracted with EtOAc. The organic solution was washed with water, dried over sodium sulfate, and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica gel, hexane/EtOAc) to afford the title compound in 65% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.36-8.51 (m, 1H) 8.05 (s, 1H) 7.92 (dd, J=8.89, 5.37 Hz, 2H) 7.49-7.62 (m, 1H) 7.31-7.49 (m, 3H) 7.09-7.26 (m, 2H) 4.69 (t, J=5.28 Hz, 1H) 3.46-3.60 (m, 2H) 3.30-3.40 (m, 3H) 2.72-2.87 (m, 5H) 2.04-2.22 (m, 1H) 0.70-1.06 (m, 3H) 0.41 (br. s., 1H).). LCMS (m/z, ES+)=601,603 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:22](I)[CH3:23]>CN(C)C=O.C(OCC)C.O>[CH2:22]([O:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1)[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-hydroxy-3-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (10 g, 38 mmol) in dimethylformamide (70 mL) was added sodium hydride (60% dispersion in oil, 1.5 g) and the resulting mixture stirred for 0.5 h. Ethyl iodide (3.6 mL, 45 mmol) was added and the mixture stirred for 12 h at 70° C. The mixture was cooled to room temperature and diluted with diethyl ether (200 mL) and water (200 mL), the layers were separated and the aqueous portion extracted with diethyl ether (200 mL). The combined organic extracts were washed with brine (200 mL) and sodium hydroxide solution (2N, 200 mL) and then evaporated to give a yellow oil.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44].O>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:42][C:43]([O:45][CH3:46])=[O:44])[C:26]=1[C:32](=[O:34])[CH3:33])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1C(C)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6′-hydroxyacetophenone (0.6 g) in N,N-dimethylformamide (5 mL) were added potassium carbonate (0.26 g) and methyl bromoacetate (0.13 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (0.62 g).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:16]([C:17](O)=[O:18])[CH2:15][C:14]2([CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].C1C2(OCCCO2)C[C@@H](C2NC=C([C:42]3[CH:47]=[CH:46][C:45]([C:48]4[CH:53]=[CH:52][C:51]([C:54]5[N:55]=[C:56]([C@@H:59]6[CH2:63][CH2:62][CH2:61][N:60]6[C:64]([C@@H:66]([NH:70][C:71](=[O:74])[O:72][CH3:73])[CH:67]([CH3:69])[CH3:68])=[O:65])[NH:57][CH:58]=5)=[CH:50][CH:49]=4)=[CH:44][CH:43]=3)N=2)N1>>[CH3:68][CH:67]([CH3:69])[C@H:66]([NH:70][C:71](=[O:74])[O:72][CH3:73])[C:64]([N:60]1[CH2:61][CH2:62][CH2:63][C@H:59]1[C:56]1[NH:57][CH:58]=[C:54]([C:51]2[CH:50]=[CH:49][C:48]([C:45]3[CH:44]=[CH:43][C:42]([C:10](=[O:11])[CH2:6][NH:5][C:17]([CH:16]4[CH2:15][C:14]5([CH2:20][CH2:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24]5)[CH2:13][N:12]4[C:10](=[O:11])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([CH3:9])[CH3:8])=[O:18])=[CH:47][CH:46]=3)=[CH:53][CH:52]=2)[N:55]=1)=[O:65]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CC6(CN5)OCCCO6)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1C(=O)O)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CC2(CCS(=O)(=O)CC2)CC1C(=O)NCC(=O)c1ccc(-c2ccc(-c3c[nH]c([C@@H]4CCCN4C(=O)[C@@H](NC(=O)OC)C(C)C)n3)cc2)cc1)C(C)C
Yield: 49 %

Procedure:
Prepared in 49% yield from 2-{N-[(methyloxy)carbonyl]-L-valyl}-8-thia-2-azaspiro[4.5]decane-3-carboxylic acid 8,8-dioxide (107) (100 mg, 0.26 mmol) and methyl {(1S)-1-[((2S)-2-{4-[4′-(aminoacetyl)-4-biphenylyl]-1H-imidazol-2-yl}-1-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate dihydrochloride (1) (148 mg, 0.26 mmol), in an analogous fashion as described in Example 15.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.OO.C(O)(=O)C.[CH:18](=[O:22])[CH2:19][CH2:20]C>C1(C)C=CC=CC=1.Cl[Cu]>[CH2:18]([O:22][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:19][CH3:20]
Reactant: CCCC=O
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: Cl[Cu]
Agent: OO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C

Procedure:
1.8 g 2,2,6,6-tetramethyl-piperidin-4-ol (intermediate product of Ciba Specialty Chemicals Inc.) are suspended in 7 ml of toluene. 3.6 ml of a 30% aqueous hydrogen peroxide solution and 0.41 g acetic acid are added at 5° C. and the solution is stirred at room temperature over night. 4.2 ml butanal and, after 15 min., 50 mg CuCl are added. The reaction mixture is stirred for 18 h at room temperature. The two phases are separated and the organic one is washed with 0.05M hydrochloric acid, sodium bisulfite solution, water, diluted sodium hydroxide solution, water and finally saturated sodium chloride solution. The organic phase is dried over sodium sulfate and finally evaporated to complete dryness under vacuum to afford 0.38 g product.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])=[CH:10][CH:9]=1>CN(C=O)C.CCOC(C)=O>[N:1]([CH2:6][CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH:16]([CH3:17])[CH3:18])=[O:14])=[CH:10][CH:9]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)OC(=O)c1ccc(CCBr)s1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)c1ccc(CCN=[N+]=[N-])s1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
Sodium azide (697 mg, 10.7 mmol) was added to a solution of the bromide from step 2 (2.7 g, 9.7 mmol) in DMF (39 mL) at room temperature. After 18 h at room temperature, the reaction mixture was diluted with EtOAc (300 mL) and washed with water (3×100 mL) and brine (50 mL). The organic phases was dried (Na2SO4), filtered and concentrated in vacuo to afford 2.24 g (96%) of isopropyl 5-(2-azidoethyl)thiophene-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[CH2:9]([N:11]([CH2:15][CH3:16])[CH2:12][CH2:13][NH2:14])[CH3:10].O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:14][CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:9][CH3:10])[CH:3]=1
Reactant: Clc1cc(Br)ccn1
Reactant: CCN(CC)CCN
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCNc1cc(Br)ccn1

Procedure:
In a microwave vial, 4-Bromo-2-chloro-pyridine (0.3 g, 1.56 mmol) and N,N-diethylethylenediamine (0.9 g, 7.8 mmol) were heated under microwave irradiations (180° C., 30 min). Water and Ethyl acetate were then added and the layers separated. The aqueous layer was extracted with ethyl acetate and the organics combined, washed twice with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude was used without further purification. Yield: 0.31 g, 71%. LCMS method: 2, RT: 0.47 min; MI: 272-274 [M+1].
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[CH:4]=1.P(Cl)(Cl)([Cl:14])=O.N1C2C(=CC=CC=2)C=CC=1>C1(C)C=CC=CC=1.O>[Cl:14][C:5]1[CH:4]=[C:3]([C:2]([F:11])([F:10])[F:1])[N:8]=[CH:7][N:6]=1
Reactant: Oc1cc(C(F)(F)F)ncn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(Cl)ncn1
Yield: 21.6 %

Procedure:
A solution of 6-(trifluoromethyl)pyrimidin-4-ol (5.0 g, 30.5 mmol), phosphoryl chloride (3.41 mL, 36.6 mmol), and quinoline (2.16 mL, 18.3 mmol) in toluene (50 mL) was stirred at 100° C. for 5 h. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (10% EtOAc/Hexane) to yield the desired product (1.20 g, 21.6%). 1H NMR (400 Mflz, CDCl3): 9.21 ppm (1H, s), 7.78 (1H, s).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8]O)=[CH:6][N:5]=[CH:4]1)[CH3:2].S(Cl)([Cl:12])=O>>[ClH:12].[Cl:12][CH2:8][C:7]1[N:3]([CH2:1][CH3:2])[CH:4]=[N:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CCn1cncc1CO
Product: CCn1cncc1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 1-ethyl-5-hydroxymethylimidazole (9.5 g), thionyl chloride (50 ml) was added by portions at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate, to give 5-chloromethyl-1-ethylimidazole hydrochloride (12.4 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>C(O)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([N:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:5])[CH:20]=[CH:19][N:18]=1
Reactant: Nc1ccccc1C(=O)N1CCCCC1
Reactant: Cc1cc(Cl)ccn1
Solvent: CC(=O)O
Product: Cc1cc(Nc2ccccc2C(=O)N2CCCCC2)ccn1
Reaction time: 8 h
Yield: 9.8 %

Procedure:
A mixture of 18.2 g of 1-(2-aminobenzoyl)piperidine and 12.2 g of 2-methyl-4-chloropyridine in 5.0 ml of acetic acid was heated at reflux for six hours and then kept at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue treated with dilute acid to pH 2 and extracted with methylene dichloride. The aqueous layer was made basic with potassium carbonate and extracted with chloroform. Further work-up of this solution afforded 2.58 g of 1-[2-(2-methyl-4-pyridinylamino)benzoyl]piperidine, m.p. 93°-95° C. when recrystallized from ethyl acetate--ether--hexane.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH2:18])[CH3:14].[CH2:21]([NH:28][CH2:29][CH2:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:13]([N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][NH:18][C:1](=[O:2])[N:28]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:29][CH2:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH3:14]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CCN
Reactant: O=S(=O)(CCNCc1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)N(CCS(=O)(=O)c1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.98 %

Procedure:
A mixture of 3.89 (0.024 mole) of 1,1'-carbonyldiimidazole and 2.55 g (0.022 mole) of N,N-diethylethylenediamine in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 5.70 g (0.0183 mole) of N-benzyl-2-phenylsulfonylethanamine in 50 ml of tetrahydrofuran was added, and the mixture was refluxed for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and water. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. Flash chromatography on silica gel (methanol) gave 5.35 g (69.98%) of oil: 1H NMR (CDCl3) δ7.45-8.00 (m, 5, C6H5SO2), 7.05-7.40 (m, 5, C6H5CH2), 5.65 (br s, 1, NH), 4.2 (s, C6H5CH2), 3.0-3.84 (m, 6, SO2CH2CH2 and NHCH2) 2.2-2.65 (m, 6, CH2N(CH2CH3)2), 0.90 (t, 6, CH3).