Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(OCC)C>[Cl:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:11])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: NCCN1CCOCC1
Solvent: CCOCC
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.2 G. of p-chlorobenzoic acid methyl ester and 6.25 g. of N-(2-aminoethyl)-morpholine are stirred together for 6 hours at 120° C. The mixture is then cooled to room temperature and 40 ml. of diethyl ether are added. Thereafter, the mixture is allowed to stand overnight in the refrigerator. The crystalline product is removed by filtration, washed with diethyl ether and recrystallized from isopropanol, and 2.6 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16]>C(O)(C(F)(F)F)=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[C:4](=[O:14])[C:3]=1[C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccccc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccccc21
Reaction time: 0.5 h
Yield: 95 %

Procedure:
1,1-Dimethylethyl N-((4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (270 mg, 782 μmol) was dissolved in TFA (2 mL) at ambient temperature. The mixture was then stirred for 30 minutes. The reaction mixture was concentrated, suspended in hexanes, filtered, washed with hexanes, and dried in a vacuum oven to give the title compound (215 mg) as a white solid. MS (m/z)=290 (M+H)+. Calculated for C15H15NO5 289.1.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:17]([OH:22])(=[O:21])[C:18]([CH3:20])=O.[OH-].[Na+]>O>[N:12]1([C:6]2[CH:11]=[CH:10][C:9]([C:18]([C:9]3[CH:8]=[CH:7][C:6]([N:12]4[CH2:13][CH2:14][CH2:15][CH2:16]4)=[CH:11][CH:10]=3)([CH3:20])[C:17]([OH:22])=[O:21])=[CH:8][CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: c1ccc(N2CCCC2)cc1
Reactant: CC(=O)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)(c1ccc(N2CCCC2)cc1)c1ccc(N2CCCC2)cc1
Yield: 74.7 %

Procedure:
Into 40 ml of 20% aqueous solution of sulfuric acid was dissolved 20 g of N-phenylpyrrolidine. To the solution was added 7.2 g of pyruvic acid and the mixture was heated with reflux for 16 hours. The reaction mixture was, after cooled, diluted with 300 ml of water and adjusted to pH 6 with addition of 20% aqueous solution of sodium hydroxide. The precipitated crystal was collected by filtration. The crystal was recrystallized from benzene to obtain 18.5 g (yielded 75%) of 2,2-bis(4-pyrrolidinophenyl)propionic acid as white crystal, having a melting point of 174°~176° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>CO.C(OCC)C>[CH2:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(NCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: c1ccc(CNc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 117.1 %

Procedure:
To the product from step 1 (148 mg, 0.387 mmol) in methanol (3 mL) was added 1M HCl in diethyl ether (6 mL) and the resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo to obtain the title product as a solid (128 mg, 93%); MS; m/z 283 (M+H): LCMS (UV) 97%: Elemental analysis Calc C, 60.85; H, 6.81; N, 7.88; Found C, 57.26; H, 7.21; N, 7.24. 1H NMR (400 MHz, DMSO-d6) δ 1.60-1.73 (m, 1H), 1.87-2.12 (m, 3H), 3.17-3.21 (m, 2H), 3.84-3.87 (m, 2H), 4.19-4.23 (dd, 1H J1=3.6 Hz, J2=10.8 Hz), 4.11-4.16 (m, 1H), 4.44 (s, 2H), 7.0 (d, 2H J=8.8 Hz), 7.29-7.38 (m, 5H); 7.48-7.49 (m, 2H) 9.1 (s, 1H), 9.8 (s, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.[CH3:25][N:26]([CH3:28])O.[OH-].[Na+]>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:26]([CH3:28])[CH3:25])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: CN(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN(C)C)n1-2

Procedure:
In the manner given in Example 15, 8-methylthio-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with a cold mixture of N,N-dimethylhydroxylamine and sodium hydroxide in dimethylformamide to give 8-methylthio-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 oxide.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH2:13][Br:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[P:15]([O:20]C)([O:18][CH3:19])[O:16][CH3:17]>C1(C)C=CC=CC=1>[Br:14][CH2:13][C:12]1[C:3]([CH2:2][P:15]([O:18][CH3:19])([O:16][CH3:17])=[O:20])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COP(OC)OC
Reactant: BrCc1cc2ccccc2nc1CBr
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1nc2ccccc2cc1CBr)OC
Yield: 72.6 %

Procedure:
A mixture of 2,3-di(bromomethyl)quinoline (0.50 g, 1.4 mmol) and trimethyl phosphite (0.18 ml, 1.4 mmol) was refluxed in toluene for 4 hours. The reaction mixture was then concentrated in vacuo and the residue was flash chromatographed on silica gel. Elution with ethyl acetate afforded 0.35 g of 3-bromomethyl-2-(dimethylphosphonomethyl)quinoline.
Reaction SMILES: N1CCCN2CCCCCC=12.[C:12]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]3[N:24]=[C:25](S(C)(=O)=O)[N:26](COCC[Si](C)(C)C)[C:21]3=[CH:20][C:19]=2[Cl:39])=[CH:14][CH:13]=1.[Si]([O:53][C@H:54]1[C@H:58]2[O:59][CH2:60][CH:61]([CH2:62][CH2:63][OH:64])[C@H:57]2[O:56][CH2:55]1)(C(C)(C)C)(C)C.O>CN(C=O)C>[C:12]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]3[N:24]=[C:25]([O:64][CH2:63][CH2:62][CH:61]4[C@H:57]5[O:56][CH2:55][C@@H:54]([OH:53])[C@H:58]5[O:59][CH2:60]4)[NH:26][C:21]3=[CH:20][C:19]=2[Cl:39])=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(CCO)CO[C@@H]21
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: O[C@@H]1CO[C@@H]2C(CCOc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.019 ml, 0.128 mmol) was added to a stirred mixture of 5-([1,1′-biphenyl]-4-yl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (52.6 mg, 0.102 mmol) and 2-((3aR,6R,6aS)-6-((tert-butyldimethylsilyl)-oxy)hexahydro-furo[3,2-b]furan-3-yl)ethanol (38.4 mg, 0.133 mmol) in DMF (1 ml) and the mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative TLC, eluting with EtOAc/isohexane (1:1) to give the title compound. LC-MS: calculated for C38H52ClN3O5Si2 721.31 observed m/e: 722.39 (M+H)+ (Rt 1.58/2 min)
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.CN(C=O)C.[OH-].[K+]>O>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])=[CH:19][CH:18]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Reactant: COc1ccc(N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(NCC(=O)Nc2ccccc2C(=O)O)cc1
Yield: 81.9 %

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol) , para-methoxyaniline (9.55 g, 77.5 mmol) and DMF (80 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature, and filtered. The filter cake was rinsed with cold water (100 mL) and dried under high vacuum at 45° C. to yield 7.62 g (85%) of the title compound as a white solid; 1H NMR (DMSO-d6) δ 13.5 (broad s, 1H), 12.04 (s, 1H), 8.73 (dd, J=8.4, J=1.0, 1H), 7.93 (dd, J=7.8, J=1.8, 1H), 7.59 (td, J=8.0, J=1.8, 1H), 7.13 (td, J=7.6, J=1.2, 1H), 6.73 (dt, J=8.8, J=2.2, 2H), 6.54 (dt, J=9.2, J=2.4, 2H), 6.2 (broad s, 1H), 3.77 (s, 2H), 3.62 (s, 3H); 13C NMR (DMSO-d6) δ 171.18, 168.95, 151.53, 142.2, 140.58, 134.12, 131.12, 122.62, 119.42, 116.03, 114.57, 113.42, 55.20, 49.76; MS (EI, m/z) 300 (M+).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[N:28][CH:29]=1)[CH2:6][CH2:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][NH:16][C:15]=2[N:14]=1)C.[OH-].[Na+]>C(O)C>[CH3:30][C:27]1[N:28]=[CH:29][C:24]([CH:5]([CH2:6][CH2:7][C:8](=[O:23])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]=3[N:14]=2)[C:4]([OH:31])=[O:3])=[CH:25][N:26]=1
Reactant: CCOC(=O)C(CCC(=O)CCCCc1ccc2c(n1)NCCC2)c1cnc(C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ncc(C(CCC(=O)CCCCc2ccc3c(n2)NCCC3)C(=O)O)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 1-10a (0.15 g, 0.353 mmol) in ethanol (1 mL) was added NaOH (0.39 rnL of 1N solution in water, 0.39 mmol). After 30 minutes, the mixture was concentrated, and the residue chromatographed on silica gel (20:10:1:1 to 10:10:1:1 ethyl acetate/ethanol/NH4OH/water) to give 1-11a as a white solid.
Reaction SMILES: C([O:4][CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[CH:19]=[C:20]([CH2:22][CH3:23])[S:21][C:8]=2[N:7]2[N:24]=[C:25]([C:27]([NH2:29])=[O:28])[N:26]=[C:6]12)(=O)C.CO.[OH-].[Na+].Cl>O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:9]2[CH:19]=[C:20]([CH2:22][CH3:23])[S:21][C:8]=2[N:7]2[N:24]=[C:25]([C:27]([NH2:29])=[O:28])[N:26]=[C:6]2[CH:5]([OH:4])[N:11]=1
Reactant: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(OC(C)=O)N=C2c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCc1cc2c(s1)-n1nc(C(N)=O)nc1C(O)N=C2c1ccccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 0.86 g. of 4-acetoxy-6-(2-chlorophenyl)-8-ethyl-4H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]-diazepine-2-carboxamide in 5 ml. of methanol is added dropwise 2 ml. of a 1N-aqueous sodium hydroxide solution with stirring and ice-cooling. After 5 minutes, to the resulting mixture is added 2 ml. of a 1N-aqueous hydrochloric acid solution and then water. The resulting precipitate is collected by filtration and then washed with water to give 6-(2-chlorophenyl)-8-ethyl-4-hydroxy-4H-thieno[3,2-f]-s-triazolo[1,5-a]-[1,4]diazepine-2-carboxamide as crystals. Recrystallization from ethanol gives colorless prisms melting at 228° to 231° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:22]=[CH:21][C:20]=2[N+:31]([O-:33])=[O:32])[CH:14]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:24]=[C:23]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)[CH:22]=[CH:21][C:20]=3[N+:31]([O-:33])=[O:32])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(F)ccn1
Reactant: Cc1ccc(N)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2ccnc(-c3cc(N4CCCCC4)ccc3[N+](=O)[O-])c2)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
Into a 100-mL 3-necked round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3,4-dimethylbenzenamine (2 g, 16.53 mmol, 4.98 equiv) in N,N-dimethylformamide (50 mL), and sodium hydride (660 mg, 16.50 mmol, 4.97 equiv, 60%). The resulting solution was stirred for 1 h at room temperature. To this was added 4-fluoro-2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridine (1 g, 3.32 mmol, 1.00 equiv). The resulting solution stirred for an additional 1 h at 50-80° C. in an oil bath. The reaction mixture was cooled. The reaction was then quenched with 150 mL of H2O. The resulting solution was extracted with 3×60 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×60 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate:petroleum ether (1:1). The product was obtained as 500 mg (37%) of a yellow solid.
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.Cl.C(O)(=[O:32])C>O>[NH2:4][C@:5]1([C:22]([OH:23])=[O:32])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][NH:7][CH2:6]1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: N[C@@]1(C(=O)O)CNC[C@@H]1CCCB(O)O
Temperature: 130 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
A solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (198 mg, 0.5 mmol) in 2:1:1 concentrated HCl:glacial acetic acid:water (8 mL) in a pressure bottle was stirred for 2 h at 60° C., then capped and stirred for 18 h at 130° C., cooled to room temperature, and uncapped. The solution was diluted with water (20 mL), then extracted with methylene chloride (20 mL) and concentrated. The residue was treated with water (20 mL) and concentrated three times to remove excess HCl, then dissolved in water (40 mL) and treated with DOWEX® 550A-OH resin (3 g) which had been rinsed with methanol. The mixture was stirred for 40 min, then filtered and the resin washed successively with water, methanol, methylene chloride, water, methanol, and methylene chloride. The resin was then stirred four times with 1N HCl (15 mL) and filtered, and the combined filtrates were concentrated. The residue was treated with water (20 mL) and concentrated three times to remove excess HCl, then dissolved in 1.5-2.0 mL water and subjected to HPLC gradient purification as follows: 0-25% B with A=0.1% trifluoroacetic acid/water and B=0.1% trifluoroacetic acid/acetonitrile. The appropriate fractions were concentrated, treated three times with 1 N HCl (10 mL) and concentrated, treated three times with water (10 mL) and concentrated, then dissolved in water (10 mL), frozen, and lyophilized overnight to afford (3R,4S)-3-amino-4-(3-boronopropyl)pyrrolidine-3-carboxylic acid (114 mg, 79%) as a pale amber glass. NMR (D2O) δ 3.90 (d, J=13 Hz, 1 H), 3.71 (dd, J1=11.5 Hz, J2=8.5Hz, 1 H), 3.46 (d, J=13Hz, 1H), 3.21 (t, J=12 Hz, 1 H), 2.50-2.65 (m, 1 H), 1.5-1.65 (m, 1 H), 1.10-1.40 (m, 3 H), 0.60-0.75 (m, 2 H). MS (m+1): 217.3; MS (m−H2O+1): 199.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N:8]=[C:9]=[S:10])[CH:5]=[CH:6][CH:7]=1.[NH3:17]>C(O)C>[CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([NH:8][C:9]([NH2:17])=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: Cc1cccc(N=C=S)c1N1CCOCC1
Solvent: CCO
Product: Cc1cccc(NC(N)=S)c1N1CCOCC1

Procedure:
React on of 3-methyl-2-morpholinophenyl isothiocyanate (8 g) in ethanol (5 ml) with a saturated solution of ammonia in ethanol (60 ml) at room temperature for 4 hours gave 1-(3-methyl-2-morpholinophenyl)thiourea (m.p. 178°-179° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+:13].Br[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>O.C(O)(C)C>[CH:17]1([CH2:16][CH2:15][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.[Na+:13]
Reactant: O=S(=O)(O)c1ccc(O)cc1
Reactant: BrCCC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=S(=O)([O-])c1ccc(OCCC2CCCC2)cc1

Procedure:
A solution of 4-hydroxybenzenesulfonic acid (6.5 grams, 28.2 mmole) and sodium hydroxide (2.2 grams, 55 mmole) in water (15 mL) was mixed with a solution of 2-(bromoethyl)cyclopentane (15.0 grams, 84.7 mmole) in isopropanol (40 mL) and the resulting mixture was heated at reflux for 2 days. The isopropanol was removed by evaporation under vacuum. The titled compound, 4.7 grams (57%), was collected by filtration and washed with isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([CH2:17]O)=[CH:5]2.[CH3:19][S:20]([C:23]1[C:31]2[C:26](=[CH:27][N:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)(=[O:22])=[O:21].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([CH2:17][N:25]1[C:26]3=[CH:27][N:28]=[CH:29][CH:30]=[C:31]3[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])=[N:24]1)=[CH:5]2
Reactant: CS(=O)(=O)CCn1c(CO)cc2cc(Cl)ccc21
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)CCn1c(Cn2nc(S(C)(=O)=O)c3ccncc32)cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.9 %

Procedure:
To a solution of [5-chloro-1-(2-methanesulfonyl-ethyl)-1H-indol-2-yl]-methanol (287 mg, 1.0 mmol), 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine (197 mg, 1.0 mmol) and PPh3 (786 mg, 3 mmol) in THF (50 mL) was added DIAD (606 mg, 3 mmol) dropwise in an ice-water bath under N2 protection. The mixture then stirred at RT overnight. The reaction was purified by preparative-HPLC to give the title product (13.5 mg, 2.8%).
Reaction SMILES: N1C=CC=CC=1.[OH-].[K+].[CH3:9][C:10]1[CH:11]=[C:12]([S:16](Cl)(=[O:18])=[O:17])[CH:13]=[CH:14][CH:15]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([CH3:35])[C:27]=1[S:28]([CH2:31][N+:32]([O-:34])=[O:33])(=[O:30])=[O:29])[NH2:24].Cl>O1CCCC1.O>[CH3:35][C:26]1[CH:25]=[C:23]([NH:24][S:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH3:9])[CH:11]=2)(=[O:18])=[O:17])[CH:22]=[C:21]([CH3:20])[C:27]=1[S:28]([CH2:31][N+:32]([O-:34])=[O:33])(=[O:30])=[O:29]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cccc(S(=O)(=O)Nc2cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.5 %

Procedure:
1.3 ml (16.1 mmol) of pyridine, dried over potassium hydroxide, and 2.3 g (12.1 mmol) of 3-methylbenzenesulphonyl chloride are successively added to a solution, maintained under a nitrogen atmosphere, of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl]sulphonyl]aniline in 50 ml of anhydrous tetrahydrofuran. The reaction medium is stirred for 24 h at room temperature and then maintained at 40° C. for 1 h, after which it is poured into a mixture of 100 ml of water and 100 g of ice. This mixture is acidified to pH 3 by addition of 1N hydrochloric acid and is extracted with 3 times 100 ml of methylene chloride. The combined organic extracts are washed with 100 ml of water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) to give 2.3 g (71%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-3-methylbenzenesulphonamide.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCOCC1>[CH2:2]([N:9]1[CH2:10][CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
6 M HCl (100 mL, aqueous) was added to a solution of 1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol (12.31 g, 41.36 mmol) in dioxane (50 mL), and the reaction was heated to strong reflux (110° C.). After 2 hours, the reaction was not complete. The heat was turned off and the reaction was left to stir at ambient temperature for 2 days. The reaction had progressed but was not complete so it was heated to 110° C. After 1 hour, the reaction was cooled and the volume was reduced by approximately one third. The solution was then cooled in an ice bath and neutralized with NaOH pellets. The thick suspension was filtered. The precipitate was rinsed with water and then dried under vacuum at 70° C. to afford 6.2 g (47%) of the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 2.74-2.62 (m, 1H), 3.30-3.06 (m, 2H), 3.50 (d, J=18.5, 1H), 3.67-3.56 (m, 1H), 3.82 (s, 3H), 4.03-3.90 (m, 1H), 4.21 (dd, J=5.7, 13.0, 1H), 4.34 (dd, J=5.1, 13.0, 1H), 5.88 (s, 1H), 6.88 (d, J=8.7, 2H), 7.32 (d, J=8.7, 2H), 7.51-7.43 (m, 3H), 7.71 (dd, J=2.7, 6.3, 2H), 12.85 (s, 1H); MS (ESI) m/z 280 (M+H)+; MS (DCI) m/z 280 (M+H)+.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=3)=[C:16]([CH3:29])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[I-].[Na+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1.O>CN(C)C=O>[CH:34]1([CH2:33][N:15]2[C:16]([CH3:29])=[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:21][CH:20]=3)[C:13]([O:12][C@@H:1]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]3[OH:3])=[N:14]2)[CH2:36][CH2:35]1
Reactant: BrCC1CC1
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(OC(C)C)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccc(OC(C)C)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1CC1CC1
Reaction time: 72 h
Yield: 60 %

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.050 g) cesium carbonate (0.20 g) and a catalytic amount of sodium iodide in N,N-dimethylformamide (1 mL) was added bromomethylcyclopropane (0.050 g) at 50° C., and the mixture was stirred for 3 days. Water was added to the reaction mixture, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol), and successively by column chromatography on silica gel (eluent: dichloromethane/methanol=8/1) to give 1-(cyclopropylmethyl)-3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole (0.034 g).