Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:20]C(=O)OC(C)(C)C)[CH2:8][N:9]([CH3:19])[C:10]([O:12][CH2:13][CH2:14][Si](C)(C)C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:20][C@@H:7]([CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH2:8][N:9]([CH3:19])[C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:4]=[CH:5][CH:1]=[CH:2][CH:3]=1
Reactant: CN(C[C@H](CC1CCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@@H](N)CC1CCCC1)C(=O)OCc1ccccc1
Yield: 210.7 %

Procedure:
A solution of (S)-tert-butyl 1-cyclopentyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-ylcarbamate (550 mg) in TFA/CH2Cl2 (10 mL, 20% v/v) was stirred for 2 hrs at 5° C. The reaction was neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×30 mL). The combined extracts were washed with saturated brine (30 mL), dried over Na2SO4, and evaporated to give (S)-benzyl 2-amino-3-cyclopentylpropyl(methyl)carbamate (420 mg) that was used without further purification.
Reaction SMILES: [F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][OH:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[F:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][O:4][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CCCCCCC(F)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.9 %

Procedure:
To a solution of 6.7 g of 2-fluorooctanol in 25 ml of pyridine, a solution of 10.4 g of p-toluenesulfonyl chloride in 40 ml of pyridine was added dropwise in 20 minutes below 0° C. on an ice water bath, followed by stirring for 7 hours at room temperature. After the reaction, the reaction mixture was poured into 200 ml of ice water and acidified with 6N-hydrochloric acid aqueous solution, followed by extraction with methylene chloride. The organic layer was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to precipitate a crystal. The crystal was purified by silica gel column chromatography to obtain 12.7 g of 2-fluorooctyl-p-toluenesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[NH2:27][CH2:28][CH:29]([OH:37])[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:27][CH2:28][CH:29]([OH:37])[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: NCC(O)CN1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(CCCNCC(O)CN2CCOCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 45 °C
Yield: 45.6 %

Procedure:
5-(3-methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1g (1.13 g, 2.9 mmol) was dissolved in 5.6 ml of dichloromethane under stirring, and 1-amino-3-morpholin-4-yl-propan-2-ol 53c (0.93 g, 5.8 mmol) was added to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight and heated for 14 hours at 45° C. in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with saturated brine (15 ml), exacted with dichloromethane (20 ml×3). The combined organic extracts were concentrated under reduced pressure, purified by silica gel column chromatography to obtain the title compound 5-[3-(2-hydroxy-3-morpholin-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 53d (600 mg, yield 72.5%) as a colorless oil.
Reaction SMILES: ClC1C=CC=CC=1Cl.[Cl:9][C:10]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:11]=1[NH2:12].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:9][C:10]1[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:13][C:11]=1[NH:12][S:32]([C:23]1[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:22]=1[Cl:21])(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Cl
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Solvent: Clc1ccccc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(C(F)(F)F)cc1Cl)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 400 ml flask, 200 ml of o-dichlorobenzene, 1 ml of pyridine and 2.0 g (0.01 mole) of 2-chloro-4-trifluoromethylaniline were charged. While stirring the contents, 2.8 g (0.01 mole) of 2-chloro-5-trifluoromethylbenzenesulfonylchloride was added dropwise at room temperature over 5 minutes. Thereafter, the reaction mixture was heated and stirred for 8 hours under reflux (175°-180° C.). After cooling the reaction mixture to room temperature, it was thoroughly washed first with dilute hydrochloric acid and then with water. Subsequent to its dehydration with anhydrous sodium sulfate, o-dichlorobenzene was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent: benzene) to isolate the intended Compound 2. m.p. 122°-123° C., yield 2.2 g (50%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH:22]1[CH2:24][CH2:23]1)[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([C:45]2[C:46]([CH2:51]OS(C)(=O)=O)=[N:47][CH:48]=[CH:49][CH:50]=2)([CH3:44])[CH3:43])=[CH:38][CH:37]=1>CC#N>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:51][C:46]1[C:45]([C:42]([C:39]2[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][CH:40]=2)([CH3:44])[CH3:43])=[CH:50][CH:49]=[CH:48][N:47]=1)[CH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][N:15]=1)[CH:22]1[CH2:23][CH2:24]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(CNCCCCN(C(=O)OC(C)(C)C)C2CC2)c(C)c1
Reactant: CC(C)(c1ccc(Cl)cc1)c1cccnc1COS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cnc(CN(CCCCN(C(=O)OC(C)(C)C)C2CC2)Cc2ncccc2C(C)(C)c2ccc(Cl)cc2)c(C)c1

Procedure:
Using General Procedure A: Reaction of cyclopropyl-{4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester and DIPEA in CH3CN with methanesulfonic acid 3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl ester gave {4-[{3-[1-(4-chloro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-cyclopropyl-carbamic acid tert-butyl ester as an oil. 1H.NMR (CDCl3) δ 0.51-0.54 (m, 2H), 0.64-0.70 (m, 2H), 1.21-1.28 (m, 4H), 1.42 (s, 9H), 1.63 (s, 6H), 2.14 (s, 3H), 2.28 (s, 3H), 2.33-2.40 (m, 3H), 3.00-3.04 (m, 2H), 3.27 (s, 2H), 2.62 (s, 2H), 6.90 (d, 2H, J=8.6 Hz), 7.14 (d, 2H, J=8.5 Hz), 7.20-7.22 (m, 2H), 7.84 (d, 1H, J=7.4 Hz), 8.12 (s, 1H), 8.53 (d, 1H, J=3.3 Hz).
Reaction SMILES: C([NH:11][C@H:12]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[C@H:26]1[O:55][C@H:54]([CH2:56][O:57]CC2C=CC=CC=2)[C@@H:45]([O:46]CC2C=CC=CC=2)[C@H:36]([O:37]CC2C=CC=CC=2)[C@@H:27]1[O:28]CC1C=CC=CC=1)[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[H][H]>C(O)C.[OH-].[Pd+2].[OH-].[C]>[NH2:11][C@H:12]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[C@H:26]1[O:55][C@H:54]([CH2:56][OH:57])[C@@H:45]([OH:46])[C@H:36]([OH:37])[C@@H:27]1[OH:28])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: O=C(N[C@H](Cc1c([C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N[C@H](Cc1c([C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[nH]c2ccccc12)C(=O)O
Yield: 62.4 %

Procedure:
To a solution of (2R*)-2-[N-(carbobenzyloxy)amino]-3-[2-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)indole-3-yl]propionic acid [compound (XII-1) wherein R1 to R4 are benzyl and Ar is phenyl](181 mg (0.210 mmol)) in ethanol (45 ml) was added 20% palladium hydroxide-carbon catalyst (150 mg) and the mixture was stirred at about 60° C. for about 11 hours under atmospheric pressure in the presence of hydrogen. The reacted solution was filtrated on Celite and the filtrate was concentrated. The residue was fractionated by high performance liquid chromatography [column: YMC-Pack ODS-AM SH-365-10AM, 500×30 mm, S-10, 120 Å; temperature: room temperature; migrating layer: 5% acetonitrile-water; flow rate: 40 ml/min.; detection: 278 nm (UV)] and then freeze-dried to give 48 mg (yield 62%) of (2R*)-2-amino-3-[2-(α-mannopyranosyl)indole-3-yl]propionic acid [compound (XIII-1)].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:9][CH2:10]2)(=[O:24])=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Fc1ccccc1N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)N1CCN(c2ccccc2F)CC1
Yield: 85.8 %

Procedure:
Sulfonylation of 1-(2-fluorophenyl)piperazine.HCl (325 mg, 1.5 mmol) with 3,4-dichlorobenzene-1-sulfonyl chloride (368.3 mg, 1.5 mmol) was carried out according to a similar procedure described for step 1A using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (0.575 mL, 3.3 mmol) as base. 1-[(3,4-dichlorophenyl)sulfonyl]-4-(2-fluorophenyl)piperazine was obtained in 85.8% yield (501 mg) as white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH:12]=O)[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].[OH-].[Na+].Cl>CO.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH:12]=[CH:17][N+:14]([O-:16])=[O:15])[CH3:2]
Reactant: CCc1c(C=O)[nH]c2ccccc12
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1c(C=C[N+](=O)[O-])[nH]c2ccccc12
Temperature: 25 °C

Procedure:
To a solution of 3-ethyl-2-indolecarbaldehyde (4.0 g) and nitromethane (4.93 g) in methanol (80 ml) was added dropwise 50% aqueous sodium hydroxide solution at 0~-5° C. for an hour. After being stirred at the same temperature for an hour and at room temperature an hour. The mixture was poured into a mixture of chilled water and 12N hydrochloric acid (4:1, 500 ml). The precipitates were collected, washed with water and dried to give 3-ethyl-2-(2-nitrovinyl)indole.
Reaction SMILES: Br.Br[CH2:3][CH2:4][C:5]1[C:14](=[O:15])[N:13]2[C:8]([S:9][CH2:10][CH2:11][CH2:12]2)=[N:7][C:6]=1[CH3:16].[CH3:17][C:18]1[C:26]2[O:25][N:24]=[C:23]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:22]=2[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:16][C:6]1[N:7]=[C:8]2[N:13]([C:14](=[O:15])[C:5]=1[CH2:4][CH2:3][N:30]1[CH2:31][CH2:32][N:27]([C:23]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:17])[C:26]=4[O:25][N:24]=3)[CH2:28][CH2:29]1)[CH2:12][CH2:11][CH2:10][S:9]2
Reactant: Cc1nc2n(c(=O)c1CCBr)CCCS2
Reactant: Cc1cccc2c(N3CCNCC3)noc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2n(c(=O)c1CCN1CCN(c3noc4c(C)cccc34)CC1)CCCS2
Temperature: 90 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A mixture of 7.4 parts of 7-(2-bromoethyl)-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one monohydrobromide, 4.4 parts of 7-methyl-3-(1-piperazinyl)-1,2-benzisoxazole, 10 parts of sodium carbonate and 94 parts of N,N-dimethylformamide was stirred overnight at 90° C. After cooling, the reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 3.8 parts (44.6%) of 3,4-dihydro-8-methyl-7-[2-[4-(7-methyl-1,2-benzisoxazol-3-yl)-1-piperazinyl]ethyl]-2H,6H-pyrimido[2,1-b][1,3]-thiazin-6-one; mp. 170.0° C. (compound 2).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:39]3[CH:40]=[CH:41][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:37][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 12 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-(methanesulphonyl)benzeneboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (12%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C1C=CC2N(O)N=[N:18]C=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.[NH4+].[Cl-]>CN(C=O)C>[NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: On1nnc2ccccc21
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of 2-amino-5-bromonicotinic acid (2.0 g, 9.20 mmol), HOBT (1.40 g, 11.2 mmol), EDCI (3.52 g, 18.4 mmol), Et3N (4.68 g, 46.0 mmol) and NH4Cl (2.48 g, 46.0 mmol) in DMF (100 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, suspended in water and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give the product of 2-amino-5-bromonicotinamide (1.80 g, yield: 80%), which was used for the next step without further purification. 1H NMR (DMSO-d6, 400 MHz) δ 8.14 (dd, J=4.4 Hz, 2.4 Hz, 2H), 8.04 (s, 1H), 7.46 (s, 1H), 7.37 (s, 2H). MS (M+H)+: 216/218.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:20]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:19][CH:18]=2)=[O:22])[CH2:25][CH2:24]1
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Reactant: NC1CC1
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)NC2CC2)s1
Yield: 80 %

Procedure:
As described for example 22b, 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (73 mg, 0.23 mmol) was converted, using cyclopropylamine instead of isopropylamine, to the title compound (66 mg, 80%) which was obtained as an off white solid MS: m/e=355.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O.S(=O)(=O)(O)O>>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: ClCc1csc(-c2ccc(Cl)cc2)n1

Procedure:
In analogy to the procedure described in example 4 a], 4-chlorothiobenzamide was reacted with 1,3-dichloroacetone followed by treatment with concentrated sulfuric acid to obtain 4-chloromethyl-2-(4-chloro-phenyl)-thiazole as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].Cl[CH:17]([C:19]1[C:20]([CH3:35])=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)[CH3:18]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:17]([C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH3:18])=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl
Product: CCOC(=O)CCc1ccc(OC(C)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c(C)c1

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (example 73A]) was reacted with [rac]-3-(1-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 17C]) to give [rac]-3-(3-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][C:14]([OH:16])=O)[C:8]=2[Cl:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.[O:22]([CH2:26][CH2:27][NH2:28])[N+:23]([O-:25])=[O:24].C(OC(C)C)(C)C>>[O:22]([CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][O:12][C:9]1[C:8]([Cl:17])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)[N+:23]([O-:25])=[O:24]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)COc1noc(-c2ccccc2)c1Cl
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=C(COc1noc(-c2ccccc2)c1Cl)NCCO[N+](=O)[O-]
Yield: 45.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.70 g of 5-phenyl-4-chloro-3-isoxazolyloxyacetic acid and 0.46 g of nitroxyethylamine nitrate, 0.42 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([O:16]CC)=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(O)C>[Cl:1][C:2]1[C:3]([C:14]([NH:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:16])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1Cl
Reactant: NC1CCOCC1
Solvent: CCO
Product: O=C(NC1CCOCC1)c1noc(-c2ccc(Cl)cc2)c1Cl

Procedure:
A mixture of ethyl 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylate (20 mg, 0.07 mmol) and 4-aminotetrahydropyran (83 μL, 0.7 mmol) in absolute ethanol (1 mL) was heated to reflux for 36 hours. The volatiles were removed in vacuo and the resulting residue was purified by silica gel chromatography, eluting with dichloromethane, to afford the title compound: (16.8 mg, 0.05 mmol).
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](Cl)(=[O:19])=[O:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:30]>>[CH2:1]([C:8]1[C:16]([S:17](=[O:19])(=[O:18])[NH2:30])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(Cc2ccccc2)c(S(=O)(=O)Cl)c1
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)O)cc(OCc2ccccc2)c1Cc1ccccc1
Reaction time: 4.5 h

Procedure:
4-Benzyl-3-benzyloxy-5-chlorosulfonylbenzoic acid (1.0 g) is in portions added to conc. ammonium hydroxide (10 ml) while stirring at 10°-12° C. After additional stirring at room temperature for about 20 hours, the mixture is left in a refrigerator for 4-5 hours. The separated ammonium salt is then collected by filtration and washed with a small amount of ice-cold water. After drying, the salt is dissolved in hot water (20 ml), and the solution is clarified by filtration hot in the presence of decolorizing carbon. The solution is then acidified with 4 N HCl (2.0 ml) and, after cooling, the resulting precipitate is collected by filtration, washed with water and dried. After recrystallization twice from ethanol, 4-benzyl-3-benzyloxy-5-sulfamylbenzoic acid is obtained with a melting point of 249.5°-251° C.
Reaction SMILES: [CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[CH:1]1([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:20]3=[O:28])[CH2:15][CH2:14]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2Cc3cccc4cccc2c34)CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)n(C2CCN(C3Cc4cccc5cccc3c45)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
(RS)-1-[1-(Acenaphthen-1-yl)piperidin-4-yl]-1,3-dihydro-2H-benzoimidazol-2-one (1.5 g, 4 mmol) was dissolved in dimethylformamide (DMF, 15 ml). Sodium hydride (200 mg, 60%) was added and the suspension was stirred at 50° C. for 30 min. The mixture was cooled to room temperature, ethyl bromoacetate (0.75 g, 4.5 mmol) was added and the mixture was stirred for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated aqueous ammonium chloride solution, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.6 g) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([OH:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33])[C:8](=[O:11])[O:9][CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)C>[C:29]([C:27]1[CH:26]=[CH:25][C:24]([O:32][CH3:33])=[C:23]([C:14]2[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:13]=2[CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=[C:35]([C:37]([F:38])([F:40])[F:39])[CH:34]=2)[C:8](=[O:11])[O:9][CH3:10])[CH:28]=1)(=[O:31])[CH3:30]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)O)ccc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)=O)ccc1OC

Procedure:
Methyl [3,5-bis(trifluoromethyl)benzyl]{[5′-(1-hydroxyethyl)-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (Example 140, 29 mg, 0.048 mmol) was dissolved in methylene chloride, and Dess-Martin periodinane (31 mg, 0.072 mmol) was added. Once the reaction was complete, the solution was diluted in diethyl ether and washed sequentially with saturated sodium thiosulfate, saturated sodium bicarbonate and water. The aqueous extracts were combined and back extracted with diethyl ether then recombined with the previous organic layers. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 2:3 EtOAc:hexane. 1H NMR (CDCl3, 600 MHz) δ 8.02 (d, J=7.8 Hz, 1H), 7.76 (d, J=2.4 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.32-7.55 (m, 4H), 6.99 (m, 1H),4.18-4.58 (m, 4H), 3.79 (s, 3H), 3.69-3.76 (m, 3H), 2.57 (s, 3H). LC-MS (M+1) 608.3 (4.19 min).