Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([N+:25]([O-:27])=[O:26])=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Isopropoxy-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:20]1([C:24](=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][C:27]=2[CH3:33])[CH2:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:20]1([C:24](=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:19][CH2:18][CH2:17][C@@H:15]3[CH2:16][C@@H:14]3[CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=4)[CH2:9][CH2:10]3)=[CH:28][C:27]=2[CH3:33])[CH2:23][CH2:22][CH2:21]1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Reactant: Cc1cc(O)ccc1CC(=O)N1CCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (50 mg, 0.177 mmol) was dissolved in toluene (1 ml) and 1-(azetidin-1-yl)-2-(4-hydroxy-2-methylphenyl)ethanone (36.4 mg, 0.177 mmol), triphenylphosphine (55.8 mg, 0.213 mmol), and DIAD (41.4 μl, 0.213 mmol) added and the mixture stirred at RT overnight. The mixture was diluted with ethyl acetate (20 mL), washed with brine (10 ml), dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica gel, Biotage 25M, eluting with a gradient eluant of 0-100% EtOAc/Hexane to afford afford the title compound. LC/MS (m/z): 469 (M+H)+. GPR119 Human EC50: 0.73 nM.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C-:13]#[N:14].[Na+].CS(C)=O>O>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:13]#[N:14])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Cc1ccc(CC#N)cc1
Yield: 73.4 %

Procedure:
527 g of 4-isobutylbenzyl chloride, 153 g of sodium cyanide and 720 ml of dimethylsulfoxide are agitated for 6 hours at 40° C. The mixture is cooled and then diluted with water. An oily layer separates and is extracted with ether. The ether solution is subjected to fractionation and yields 367 g of 4-isobutylphenyl acetonitrile.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][C:32]([CH3:36])(O)[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>C(Cl)Cl>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][C:32]([CH3:36])([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: CC1(O)CCN(c2nnc3ccc(F)cn23)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Yield: 96.3 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (550 mg, 1.81 mmol) was added to a solution of Intermediate 79c (150 mg, 0.60 mmol) and Et3N (242 mg, 2.40 mmol) in a DCM (5 mL) and the mixture stirred at reflux for 1 h. The reaction mixture was diluted with DCM (30 mL), washed with water (2×), brine, dried (MgSO4), and then concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound (235 mg, 96%). 1H NMR (400 MHz, CDCl3): 1.00-1.20 (21H, m), 1.40 (3H, s), 1.76-1.93 (4H, m), 3.18-3.29 (2H, m), 3.44-3.58 (2H, m), 7.03-7.12 (1H, m), 7.58-7.69 (2H, m).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[NH:5][C:4]1=[O:20].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30](Cl)=[O:31]>C(Cl)Cl>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30]([N:2]([CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[NH:5][C:4]1=[O:20])[CH3:1])=[O:31]
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: CNC1N=C(c2ccccc2)c2ccccc2NC1=O
Solvent: ClCCl
Product: CN(C(=O)c1cc2ccccc2[nH]1)C1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,3-Dihydro-3-(RS)-methylamino-5-phenyl-2H-1,4-benzodiazepin-2-one (130 mg, 0.49 mmol) and indole-2-carbonyl chloride (88 mg, 0.49 mmol) were combined in CH2Cl2 (5 ml) and stirred 2 hours at 25° C. The reaction was concentrated and chromatographed on silica gel (3% MeOH in CH2Cl2) to give the title compound as a white solid from CH2Cl2 : (m.p. 287°-288.5°).
Reaction SMILES: CN(C)C=O.[OH:6][CH:7]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=1)[CH:8]([O:11][CH3:12])[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(OCC)(=O)C>[OH:6][CH:7]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:15]([CH3:21])[CH:14]=1)[CH:8]([O:9][CH3:10])[O:11][CH3:12]
Reactant: CCOC(=O)CCl
Reactant: COC(OC)C(O)c1cc(C)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(C)c(C(O)C(OC)OC)cc1C
Yield: 77.1 %

Procedure:
To N,N-dimethylformamide (81 g) were added 4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol (20.0 g), potassium carbonate (15.8 g) and ethyl chloroacetate (12.4 g) at room temperature with stirring. The mixture was stirred at room temperature for an hour, and then stirred at 71° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and a mixture of ethyl acetate and hexane was added to the residue. The precipitated crystals were collected by filtration to give ethyl 2-[4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (21.3 g).
Reaction SMILES: Br[O-:2].[Na+].[C:4]([C:7]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]2[C:13]([CH3:20])([CH3:19])[CH2:12][CH2:11][C:10]([CH3:22])([CH3:21])[C:9]=2[C:8]=1[O:23][CH3:24])(=[O:6])C>O1CCOCC1.O>[CH3:24][O:23][C:8]1[C:9]2[C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][C:13]([CH3:20])([CH3:19])[C:14]=2[C:15]([O:17][CH3:18])=[CH:16][C:7]=1[C:4]([OH:6])=[O:2]
Reactant: [O-]Br
Reactant: COc1cc(C(C)=O)c(OC)c2c1C(C)(C)CCC2(C)C
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(=O)O)c(OC)c2c1C(C)(C)CCC2(C)C
Reaction time: 8 h

Procedure:
In a second stage, this hypobromite solution is slowly added to a stirred solution, cooled to about 5° C., of 43 g of 2-acetyl-1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene, obtained in stage (b) above, in 500 cm3 of dioxane. The rate of introduction is such that the temperature does not exceed 15° C. The reaction mixture is then left to stand overnight, diluted with 300 cm3 of water, then, at a temperature lower than 20° C., the excess sodium hypobromite is destroyed by the slow addition of a 25% aqueous solution of sodium bisulfite. The expected acid is then precipitated by acidifying the mixture by the addition of 380 cm3 of 6N HCl. The precipitate is filtered, washed with water and dried under reduced pressure. 40.8 g of 1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalene carboxylic acid are obtained in the form of a white solid having a melting point of 187° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([CH2:17][CH2:18][CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][Cl:24].C(N(CC)CC)C>C(#N)C>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:21][CH2:22][CH2:23][Cl:24])[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH2:17][CH2:18][CH3:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCCBr
Reactant: CCCc1cc(N2CCNCC2)nc(C(C)(C)C)n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc(N2CCN(CCCCl)CC2)nc(C(C)(C)C)n1

Procedure:
15 g of 2-tert-butyl-4-piperazin-1-yl-6-propyl-pyrimidine (57.2 mmol), 9 g of 1-bromo-3-chloropropane (57.2 mmol), 8.7 g of triethylamine (86.2 mmol) in 200 ml of acetonitrile were heated to reflux for 3 h. The precipitate was filtered off and the remaining filtrate evaporated to dryness. The thus obtained crude product was purified by chromatography on silica gel with dichloromethane/methanol (0-5%). Yield: 6 g (31%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[N:8]1.Cl[CH:18]([F:20])[F:19].O>CN(C)C=O>[F:19][CH:18]([F:20])[N:7]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[N:8]1
Reactant: FC(F)Cl
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(C(F)F)c1
Temperature: 135 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
6.0 g (43.5 mmoles) of anhydrous potassium carbonate was added to a solution of 3.0 g (21.4 mmoles) of ethyl 1H-pyrazole-4-carboxylate dissolved in 100 ml of N,N-dimethylformamide. Thereinto was blown chlorodifluoromethane. The resulting mixture was stirred at 130 to 140° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 1.67 g (yield: 41.0%) of ethyl 1-difluoromethyl-1H-pyrazole-4-carboxylate as a colorless transparent oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:26][CH2:25][CH2:24][NH:23][C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22].O=[CH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCCC(C)C>ClCCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:12]2=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22]
Reactant: CCOC(=O)CCCCCC=O
Reactant: Fc1ccc(-c2nc3c(nc2-c2ccc(F)cc2F)NCCC3)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCCC(C)C
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(F)cc3F)c(-c3ccc(F)cc3F)nc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture comprising 2,3-bis(2,4-difluorophenyl)-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate CC) (310 mg, 0.863 mmol) in 1,2-dichloroethane (10 ml) was added to ethyl 7-oxoheptanoate (446 mg, 2.59 mmol) and stirred at RT for 15 mins. Sodium triacetoxyborohydride (914 mg, 4.31 mmol) was added and stirring continued at RT for 3 days. The mixture was heated to 60° C. for 3 h and allowed to cool to RT. The resulting mixture was applied to a pre-wet (iso-hexane) Isolute® cartridge (silica) and eluted with 20-33% EtOAc in iso-hexane to afford the titled compound;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[N:10]([CH2:17][CH:18]([OH:34])[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[CH2:22][CH2:21]3)[N:9]=2)=[CH:4][C:3]=1[CH3:35].Cl[C:37](=[O:42])[C:38]([O:40][CH3:41])=[O:39].CO.C(Cl)Cl>C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[C:37]([N:14]1[CH2:15][CH2:16][C:11]2[N:10]([CH2:17][CH:18]([OH:34])[CH2:19][N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[CH2:22][CH2:21]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:35])[CH:4]=3)[C:12]=2[CH2:13]1)=[O:42]
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1cc(-c2nn(CC(O)CN3CCN(c4ccccc4C#N)CC3)c3c2CNCC3)ccc1Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(=O)N1CCc2c(c(-c3ccc(Cl)c(C)c3)nn2CC(O)CN2CCN(c3ccccc3C#N)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
2-(4-{3-[3-(4-Chloro-3-methyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-2-hydroxy-propyl}-piperazin-1-yl)-benzonitrile (58 mg, 0.118 mmol) was dissolved in CH2Cl2 (0.59 mL) and treated with methyl chlorooxoacetate (16 mg, 0.129 mmol). The reaction mixture was allowed to stir for 18 h at room temperature. Column chromatography (silica, 2-10% MeOH/CH2Cl2) gave (3-(4-chloro-3-methyl-phenyl)-1-{3-[4-(2-cyano-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl)-oxo-acetic acid methyl ester (54 mg, 79%) as a white solid. MS (electrospray): m/z 577.3 (577.2, calculated for C30H33ClN6O4, [M+H]+). 1H NMR (400 MHz, CDCl3): 7.32-7.62 (m, 5H), 7.14 (t, J=7.6 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 4.59-4.80 (m, 3H), 4.12-4.28 (m, 2H), 3.92 (s, 3H), 3.78-3.86 (m, 2H), 3.44-3.60 (m, 5H), 3.15-3.40 (m, 4H), 2.83-3.05 (m, 2H), 2.41 (s, 3H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)(=[O:4])=[O:3].[NH2:21][C:22]1[O:26][N:25]=[C:24]([CH3:27])[C:23]=1[Br:28]>>[Br:28][C:23]1[C:24]([CH3:27])=[N:25][O:26][C:22]=1[NH:21][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[CH:13]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccsc1CCc1ccc2c(c1)OCO2
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccsc2CCc2ccc3c(c2)OCO3)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]-thiophene-3-sulfonamide was prepared in the same manner as described in Example 10. By reacting 3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene with 5-amino-4-bromo-3-methylisoxazole and purifying the crude product by HPLC, N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide was obtained in a 30% yield, m.p. 180° (dec.).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)(=[O:20])=[O:19])[CH2:14][C:15]([OH:17])=O.[CH2:36]([N:38]1CCOCC1)[CH3:37].ClC(OCC)=O.C(N)C>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)(=[O:19])=[O:20])[CH2:14][C:15]([NH:38][CH2:36][CH3:37])=[O:17]
Reactant: CCN1CCOCC1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)c2c(Cc3c(F)cccc3F)cccc2OC)cc1OC
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)CN(c1c(Cc2c(F)cccc2F)cccc1OC)S(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 0.25 h

Procedure:
To 1.8 g of N-[2-(2,6-difluorobenzyl)-6-methoxyphenyl]-N-[(3,4-dimethoxyphenyl)sulfonyl]glycine dissolved in 30 ml of tetrahydrofuran at 0° C. are introduced 0.5 ml of N-ethylmorpholine and 0.38 ml of ethyl chloroformate. After 15 minutes at 10° C., 0.8 g of ethylamine dissolved in tetrahydrofuran is added and the mixture is left at room temperature for 30 minutes. The medium is taken up in ethyl acetate and washed with water, and the organic phase is dried over anhydrous sodium sulfate and concentrated to give 1.4 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1>>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:12][C:11]=13)=[O:19])[CH2:24]2
Reactant: O=C(O)c1cccc2oc(-c3ccc(Cl)cc3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccc(Cl)cc4)nc13)C2
Yield: 16 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-chlorophenyl)benzoxazole-4-carboxamide was prepared from 2-(4-chlorophenyl)benzoxazole-4-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 16% yield as a white solid: mp 185-187° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.72 (d, J=7.7 Hz, 1H), 8.27 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.1 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.56 (t, J=8.0 Hz, 1H), 4.01 (m, 1H), 3.02 (m, 2H), 2.44 (s, 3H), 2.41 (m, 2H), 2.09 (m, 1H), 1.97 (m, 2H), 1.47 (m, 3H), 1.00 (m, 2H); MS (ESI) m/z 410 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])(=[O:21])[CH3:20].[Na+].C(Cl)(=O)C>C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][O:15][C:19](=[O:21])[CH3:20])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CC(=O)OCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 67.1 %

Procedure:
1.27 g (5 mmol) of N-benzyloxycarbonyl-L-homoserine are dissolved in 5 ml of acetic acid, and 0.41 g (5 mmol) of sodium acetate is added. 1.19 g (15 mmol) of acetyl chloride are then added and stirring is carried out for one hour. The acetic acid and the excess acetyl chloride are removed in vacuo, the residue is taken up in 30 ml of methyl isobutyl ketone and 30 ml of water, and the pH is adjusted to 8 using 50% sodium hydroxide solution. The aqueous phase is separated off, adjusted to pH=2 using hydrochloric acid and extracted using 30 ml of methyl iso-butyl ketone. Concentration of the organic phase in vacuo yields 0.99 g (67%) of N-benzyloxycarbonyl-O-acetyl-L-homoserine in the form of a colourless oil.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[NH2:13][C:14]([NH:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1[C:26]([NH2:28])=[O:27])=[CH:23][CH:22]=[C:21]([CH2:29][OH:30])[CH:20]=2)=[O:15].O>CS(C)=O>[NH2:13][C:14]([NH:16][C:17]1[NH:18][C:19]2[C:24]([C:25]=1[C:26]([NH2:28])=[O:27])=[CH:23][CH:22]=[C:21]([CH:29]=[O:30])[CH:20]=2)=[O:15]
Reactant: NC(=O)Nc1[nH]c2cc(CO)ccc2c1C(N)=O
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)Nc1[nH]c2cc(C=O)ccc2c1C(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
2-Iodoxybenzoic acid (1.8 g, 6.4 mmol) was added to a solution of 2-aminocarbonylamino-6-hydroxymethylindole-3-carboxamide (Compound 16-1, 1.4 g, 5.8 mmol) in dimethyl sulfoxide (100 mL), and the mixture was stirred at room temperature for 30 minutes. Water (100 mL) was added to the reaction mixture under ice-cooling, and the precipitated solid was separated by filtration. The resultant solid was washed with 0.25 N sodium hydroxide aqueous solution-(5 mL) and water (5 mL) and dried under reduced pressure to give the title compound (1.1 g) as a brown solid (yield 74%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:17])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[Br:44][C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][C:46]=1[O:52][CH3:53]>>[Br:44][C:45]1[C:46]([O:52][CH3:53])=[CH:47][C:48]([OH:51])=[C:49]([C:4]2([OH:17])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][CH:2]=3)[N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[O:16])[CH:50]=1
Reactant: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: COc1cc(O)ccc1Br
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(Br)c(OC)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-bromo-3-methoxyphenol, the title compound was obtained (48%): 1H NMR (300 MHz, CDCl3) δ 9.85 (s, 1H), 7.52-7.38 (m, 2H), 7.22 (td, 1H), 6.94 (d, 1H), 6.89 (s, 1H), 6.63 (s, 1H), 4.13-4.03 (br, 1H)3.86(s, 3H), 3.80-3.57 (m, 2H), 1.75-1.63 (m, 2H), 1.40-1.25 (m, 4H), 0.88 (t, 3H); MS (ES+) m/z 402 (M−17), 404 (M−17), 442 (M+23), 444 (M+23).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:28][O:27][C:20](=[O:26])[CH2:21][C:22]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:23]=1[CH3:25]
Reactant: COC(=O)CCC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1ccc(F)cc1)CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(F)cc1)CCCC3
Yield: 81.7 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-fluorophenyl)methanone (0.275 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.302 g (82%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C@@H:7]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C@H:8]1[OH:9])=[O:5])[CH3:2].[N:18]([O-])=[O:19].[Na+]>O.C(O)(=O)C>[CH2:1]([N:3]([N:18]=[O:19])[C:4]([NH:6][C@@H:7]1[O:15][C@H:14]([CH2:16][OH:17])[C@@H:12]([OH:13])[C@H:10]([OH:11])[C@H:8]1[OH:9])=[O:5])[CH3:2]
Reactant: O=N[O-]
Reactant: CCNC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN(N=O)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 96.4 %

Procedure:
1-ethyl-3-(β-D-glucopyranosyl)urea (930 mg) was dissolved in a mixture of water (4.3 ml) and acetic acid (4.3 ml), and to the solution was added 370 mg (1.5 mol. equivalents) of sodium nitrite in small portions under stirring. The mixture was stirred overnight at ambient temperature to complete the nitrosation. The reaction mixture was then treated with 4 ml of a cation-exchange resin, Amberlite IR-120 (H+ form), to remove the sodium ion therefrom. The reaction mixture was subsequently freeze-dried, affording 1.0 g of the titled compound as an amorphous substance of pale yellow color. [α]D26 -2° (c 1.0, H2O). This substance gave a single spot at Rf 0.82 in a thin layer chromatography on silica gel using chloroform-methanol (3:2 by volume) as eluent.