Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=1[OH:16])C=CC(O)=O)([CH3:4])([CH3:3])[CH3:2].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=1.[OH:32][C:33]1C2N=NNC=2C=[CH:35][CH:34]=1.C1COCC1>CN(C=O)C>[CH3:20][C:17]([C:14]1[CH:13]=[C:7]([C:34](=[CH2:35])[C:33]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([N+:29]([O-:31])=[O:30])[CH:23]=2)=[O:32])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:15]=1[OH:16])([CH3:18])[CH3:19]
Reactant: Oc1cccc2[nH]nnc12
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(C(=O)Nc1ccc(O)c([N+](=O)[O-])c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
1.78 g (6.4 mmoles) of 3,5-di-tert-butyl-4-hydroxycinnamic acid, 0.99 g (6.4 mmoles) of 4-amino-2-nitrophenol, previously diluted in 10 ml of DMF, 0.86 g (6.4 mmoles) of hydroxybenzotriazol and 1.32 g (6.4 mmoles) of dicyclobexylcarbodiimide are introduced into a 50 ml flask containing 10 ml of THF. The reaction medium is agitated for 15 hours at ambient temperature, the precipitate which appears is filtered and rinsed with ethyl acetate. After concentration of the solution under reduced pressure, the residue is diluted in 20 ml of ethyl acetate and the insoluble part is filtered again. The filtrate is washed with 20 ml of a saturated solution of sodium carbonate followed by 20 ml of water and 20 ml of a saturated solution of sodium chloride. After drying over sodium sulphate, the organic solution is filtered and concentrated to dryness under reduced pressure. The residue is purified on a silica column (eluant: heptane/ethyl acetate: 8/2). The pure fractions are collected and concentrated under vacuum to produce 1.95 g (47%) of the expected compound in the form of a yellow-orange powder. Melting point: 231-232° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C=O.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:11])[CH3:10].[OH-].[Na+].Cl[CH2:21]Cl>O>[N:1]1[CH:2]=[CH:3][CH:4]=[C:5]([C:10](=[CH2:21])[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:6]=1
Reactant: ClCCl
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C(=O)c1ccccc1)c1cccnc1
Yield: 85 %

Procedure:
To a suspension of 3 pyridinecarboxaldehyde (18.9 mL, 0.20 mol) and acetophenone (23.4 mL, 0.20 mol) in 200 mL water at room temperature with vigorous stirring was added dropwise 5% aqueous sodium hydroxide (200 mL) over a 45-minute period. The reaction mixture was stirred for 12 hours. White solid was formed during the reaction. Dichloromethane (500 mL) was added to dissolve the solid. The organic layer was separated, washed with water (300 mL×3), and dried over anhydrous sodium sulfate. After the drying agent and solvent were removed, the crude product was recrystallized to give the title compound as yellow solid (35.62 g, 85%), mp 113°-114° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][C:10]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CCCCCC.BrC1C=CC=C([OH:34])C=1C>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([CH2:11][C:12]([OH:34])=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2(CCCCC2)CC1=O
Reactant: Cc1c(O)cccc1Br
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
3-oxo-2-aza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (253 mg, 1 mmol) was dissolved in THF (5 ml) and an aqueous solution of 1N LiOH (72 mg/3 ml, 3 molequivalents) was added thereto. The mixture was stirred at 25° C. for 6 hours while monitoring the progress of the reaction by TLC, using a 6:4 hexane:ethyl acetate mixture as eluent and bromocresol for developing the TLC plate. Reaction completion was indicated by the appearance of a more polar spot while the starting material gradually disappeared from the middle of the TLC plate. Thereafter, the THF was evaporated under reduced pressure and the basic aqueous residue was acidified by the addition of 15 drops of concentrated HCl (pH 3) and extracted with ethyl acetate. The aqueous layer was washed with ethyl acetate and the combined organic layer was washed with water, dried over NaSO4 and evaporated under reduced pressure to give [1-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-acetic acid (228 mg, 84% yield) as a colorless solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:32]=[CH:31][C:22]([C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:41][CH2:42][CH2:43][OH:44]>C(O)C>[OH:44][CH2:43][CH2:42][CH2:41][N:28]1[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:6]4[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=4)[CH2:12][CH2:13]3)=[O:18])=[CH:32][CH:31]=2)[CH2:30][CH2:29]1
Reactant: OCCCBr
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCNCC3)cc2)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(CCCO)CC3)cc2)CC1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
1-[4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoyl]piperazine (0.5 g) was dissolved in anhydrous ethanol (25 ml) and then, triethylamine (0.3 ml) and 3-bromo-1-propanol (0.5 g) were added. The solution was heated to reflux for 12 hours. The solvent was concentrated under reduced pressure and then, the residue was dissolved in chloroform (50 ml), and the solution was washed with water twice. Water (40 ml), methanol (5 ml) and aqueous 10% sodium hydroxide (10 ml) were added to chloroform solution and the mixture was stirred for 1 hour. The separated organic layers were washed with water and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether, and further recrystallized using ethyl acetate and ether, filtered and dried to give 0.44 g (yield: 78%) of the desired compound as white crystal.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[C:20]([NH2:25])[CH:21]=[CH:22][CH:23]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[C:20]([NH:25][S:28]([CH3:27])(=[O:30])=[O:29])[CH:21]=[CH:22][CH:23]=5)[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(c2ccc3nc(-c4n[nH]c5c(N)cccc45)[nH]c3c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5c(NS(C)(=O)=O)cccc45)[nH]c3c2)CC1

Procedure:
3-[6-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-7-ylamine (1 equivalent), methanesulfonyl chloride (1.1 equivalent), and diisopropylethylamine (2 equivalents) in CH2Cl2 are stirred for 18 hours. The solvent is evaporated, and the resulting residue is purified by preparatory HPLC to provide the title compound.
Reaction SMILES: CN(C(N[C@H](C(O)=O)C(C)C)=O)[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[NH2:22][C@H:23]([C:27]([NH:29][CH:30]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:31][CH:32]([OH:51])[CH:33]([NH:41][C:42]([O:44][CH2:45][C:46]1[S:50][CH:49]=[N:48][CH:47]=1)=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].N[C@@H](CC1C=CC=CC=1)C[C@H](O)[C@@H](NC([O:74][CH2:75][C:76]1SC=NC=1)=O)CC1C=CC=CC=1>>[CH:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:3][CH2:76][C:75]([NH:22][C@H:23]([C:27]([NH:29][C@@H:30]([CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:31][C@H:32]([OH:51])[C@@H:33]([NH:41][C:42]([O:44][CH2:45][C:46]2[S:50][CH:49]=[N:48][CH:47]=2)=[O:43])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:74])[N:5]=1)([CH3:10])[CH3:11]
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)[C@H](N)C(=O)NC(Cc1ccccc1)CC(O)C(Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Product: CC(C)c1nc(CCC(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with the resultant compound of Example 31 D and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with the resultant compound of Example 31F provided, after purification by silica gel chromatography, the desired compound.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12](SC)[N:11]=2)[CH2:4]1.[CH:21]1C=C(Cl)C=C(C(OO)=O)C=1.[S:32]([O-:36])([O-])(=[O:34])=S.[Na+].[Na+]>C(Cl)Cl.CC(C)=O>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12]([S:32]([CH3:21])(=[O:36])=[O:34])[N:11]=2)[CH2:4]1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CO[C@H]1CCC[C@@H](Nc2nc(SC)ncc2C(N)=O)C1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CO[C@H]1CCC[C@@H](Nc2nc(S(C)(=O)=O)ncc2C(N)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a solution of 4-((1R,3S)-3-methoxycyclohexylamino)-2-(methylthio)pyrimidine-5-carboxamide (1.1081 g, 3.74 mmol) in DCM (18.69 mL) and acetone (18.69 mL) at room temperature was added mCPBA (1.676 g, 7.48 mmol) in five batches over 2 min and stirred at room temperature for 16 h. To the crude reaction mixture was added 10% aqueous sodium thiosulfate solution (35 mL) and the mixture was stirred for 5 min before evaporation of the volatile solvents. The material was partitioned between ethyl acetate and water, and the organic layer was then washed with saturated aqueous sodium bicarbonate solution and then brine. The combined aqueous layers were then washed with ethyl acetate (3×), organic layers were combined, dried over sodium sulfate, filtered, and condensed. After drying under high vacuum, 4-((1R,3S)-3-methoxy-cyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (0.9887 g, 3.01 mmol, 81% yield) was obtained as a white solid. MS (ESI) m/z 329.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:49]([F:50])=[CH:48][CH:47]=[C:46]([F:51])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:27]=[C:28]([C:34]2[CH:39]=[CH:38][C:37]([N:40]([S:42]([CH3:45])(=[O:44])=[O:43])[CH3:41])=[CH:36][CH:35]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16](C)[C:17](=O)OC(C)(C)C)[CH2:12][CH2:11]1)=[O:8].CCCCCC>C(Cl)Cl>[ClH:1].[CH3:45][S:42]([N:40]([CH3:41])[C:37]1[CH:38]=[CH:39][C:34]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([CH2:25][N:9]([CH:10]3[CH2:11][CH2:12][CH:13]([NH:16][CH3:17])[CH2:14][CH2:15]3)[C:7]([C:6]3[S:5][C:4]4[C:46]([F:51])=[CH:47][CH:48]=[C:49]([F:50])[C:3]=4[C:2]=3[Cl:1])=[O:8])[CH:27]=2)=[CH:35][CH:36]=1)(=[O:43])=[O:44]
Reactant: COc1ccc(-c2ccc(N(C)S(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Solvent: CCCCCC
Solvent: ClCCl
Product: CNC1CCC(N(Cc2cc(-c3ccc(N(C)S(C)(=O)=O)cc3)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1
Product: Cl

Procedure:
tert-Butyl carbamate 205 (23 mg, 31 mmol) is deprotected using Method F. The isolated salt is then dissolved in the minimum amount of DCM and added dropwise to cold (0° C.) hexane (10 mL). The resultant cream precipitate is isolated by filtration and dried to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([OH:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([O:8][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: Oc1ncc(Br)cc1F
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1cc(Br)cnc1OCC1CC1
Temperature: 70 °C

Procedure:
To a solution of 5-bromo-3-fluoropyridin-2-ol (1.00 g) in DMF (10 mL) were added potassium carbonate (1.44 g) and (bromomethyl)cyclopropane (0.758 mL), and the mixture was stirred with heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (491 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Se](=O)=[O:39]>ClCCl>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([OH:39])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=4)[O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:20][CH2:21][CH:22]([OH:39])[CH:23]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[Se]=O
Reactant: CCOC(=O)COc1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(CC2(O)CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Product: CCOC(=O)COc1cccc(C[C@@H]2CCC(O)C=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1

Procedure:
A solution of ethyl (S)-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenoxy}acetate (380 mg) (prepared by a method described in WO 95/17393) and selenium dioxide (SeO2) (170 mg) in dichloromethane (230 ml) was refluxed for 2 hours under stirring. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography on silica gel to give ethyl {3-{[2-(4,5-diphenyloxazole-2-yl)-1-hydroxy-2-cyclohexen-1-yl]-methyl}phenoxy}acetate (60 mg) as a first fraction and ethyl {3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-4-hydroxy-2-cyclohexen-1-yl]methyl}phenoxy}acetate (80 mg) as a second fraction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2(O)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19](S(O)(=O)=O)=[CH:18][CH:17]=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:26]([N:11]1[CH2:12][CH:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:9][CH2:10]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OC1(c2cccc(Br)c2)CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1cccc(C2=CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
A solution of 28.2 g (81.4 mmol) of 4-(3-bromophenyl)-piperidin-4-ol in 600 ml of toluene was treated with 30 g (157 mmol) of p-toluenesulphonic acid monohydrate and heated to reflux on a water separator for 4 hours. Subsequently, the reaction mixture was cooled to room temperature and adjusted to pH 10 with 3 N sodium hydroxide solution. Thereafter, it was firstly extracted three times with 500 ml of methylene chloride. The combined organic phases were washed three times with 200 ml of water each time, dried over magnesium sulphate and then evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with a 1:1 mixture of methylene chloride and hexane as the eluent. There were obtained 9.5 g (36% of theory) of 1-benzyl-4-(3-bromophenyl)-1,2,3,6-tetrahydro-pyridine as a light yellow oil; MS: 327, 329 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([C:6]1[CH:7]=[C:8]([CH3:15])[CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)=[C:3]([Cl:5])[Cl:4].[NH4+]=S>C(O)C.O>[CH3:15][C:8]1[CH:9]=[C:10]([CH:11]=[C:6]([C:2]([Cl:1])=[C:3]([Cl:4])[Cl:5])[CH:7]=1)[NH2:12]
Reactant: Cc1cc(C(Cl)=C(Cl)Cl)cc([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cc(C(Cl)=C(Cl)Cl)c1
Temperature: 100 °C
Yield: 96.3 %

Procedure:
To a warm solution of 3-(trichlorovinyl)-5-nitrotoluene (10.95 g) in 150 ml of ethanol, an aqueous solution of ammonium sulfide (30 ml of a commercial 4-52% aqueous solution diluted to 90 ml with water) was added in one portion. The resulting heterogeneous solution was heated in a 100° C. oil bath for 30 minutes. The hot reaction mixture was filtered and the precipitate thoroughly washed with ethanol. The filtrate was diluted with 1.2 L of brine and then extracted with methylene chloride (2×400 ml). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Concentration afforded 9.36 g of an oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][C:17](=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH:9]=1)[C:4](O)=[O:5])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.CC(C)([O-])C.[K+].[CH2:50]([C@H:57]1[CH2:61][O:60][C:59](=[O:62])[NH:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>O1CCCC1>[CH2:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][C:17](=[O:29])[NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)[CH:9]=1)[C:4]([N:58]1[C@@H:57]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:61][O:60][C:59]1=[O:62])=[O:5])[CH3:2]
Reactant: CCC(Cc1ccc(OC)c(CC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(Cc1ccc(OC)c(CC(=O)Nc2ccc(C(F)(F)F)cc2)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 13.4 %

Procedure:
(±)-2-Ethyl-3-[4-methoxy-3-[[N-[4-(trifluoromethyl)phenyl]carbamoyl]methyl]phenyl]propanoic acid (compound in Example 88: 14.2 g, 34.7 mmol) and dehydrated tetrahydrofuran (100 mL) were mixed under an argon atmosphere, and triethylamine (4.86 ml, 35.0 mmol) and pivaloyl chloride (4.27 mL, 34.7 mmol) were added dropwise under stirring and cooling with ice. Thereafter, the mixture was stirred for 1 hour at room temperature to synthesize mixed acid anhydride. On the other hand, potassium tert-butoxide (4.67 g, 41.6 mmol) and dehydrated tetrahydrofuran (45 mL) were mixed under cooling with ice and argon atmosphere in another vassel, and (S)-4-benzyl-oxazolidine-2-one (7.38 g, 41.6 mmol) dissolved into dehydrated tetrahydrofuran (60 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 30 minutes. Next, a suspension of the mixed acid anhydride synthesized previously was added dropwise while filtering under an atmosphere of argon. After completion of the drop-wise addition, the reaction mixture was concentrated and then poured in water, which was extracted with ethyl acetate. The extracte was washed with 5% hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate and brine, then dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by means of silica gel column chromatography (eluent: isopropyl ether) to afford 2.65 g (13%) of (4S)-3-[2-ethyl-3-[4-methoxy-3-[[N-[4-(trifluoromethyl)phenyl]carbamoyl]methyl]phenyl]-propanoyl]-4-benzyloxazolidine-2-one with high polarity as a oily product. Also, 3.84 g (20%) of (4S)-3-[2-ethyl-3-[4-methoxy-3-[[N-[4-(trifluoromethyl)phenyl]carbamoyl]-methyl]phenyl]propanoyl]-4-benzyloxazolidine-2-one with low polarity were obtained by purifying by silica gel column chromatography, followed by further recrystallization from a mixed solvent of n-hexane with isopropyl ether, as colorless powder.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.Br[CH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#N.C(N(CC)CC)C.CN(C=[O:37])C>O>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([N:14]3[CH2:20][C:19]4[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]3=[O:37])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: N#Cc1ccccc1CBr
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1Cn1cc(N2Cc3ccccc3C2=O)cn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine-hydrochloride (100 mg, 0.44 mmol), 2-(bromomethyl)benzonitrile (115 mg, 0.6 mmol), and triethylamine (0.5 mL, 3.5 mmol) in DMF (3 mL) were irradiated and stirred in the microwave reactor at 80° C. for 10 minutes. The reaction was cooled, diluted with H2O (50 mL) and extracted with ethyl acetate (3×, 30 mL). The combined organic extracts were dried over sodium sulfate and concentrated on the rotovap. The residue was dissolved in ethanol (70 mL), H2O (3 mL) and acetic acid (1 mL) and the mixture was refluxed for 2 hours. The solution was concentrated on the rotovap, taken up in methanol (3 mL) and purified by reversed phase HPLC in 3-1 mL aliquots (5 to 95% acetonitrile in H2O:16 minute gradient). The pure fractions were combined and concentrated on the rotovap. The residue was triturated with ethyl acetate/hexanes (1/9) to afford 2-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindolin-1-one (85 mg, 61%) as a pure white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.18 (s, 3H), 2.43 (s, 3H), 4.97 (s, 2H), 5.18 (s, 2H), 7.58-7.68 (m, 3H), 7.77 (s, 1H), 8.10 (d, J=8 Hz, 1H), 8.27 (s, 1H), 9.19 (bs, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 value greater than 30 μM.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:28]=[CH:27][C:11]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]([Br:26])=[CH:15][N:14]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C.O>CN(C=O)C>[NH:19]([C:17]1[C:16]([Br:26])=[CH:15][N:14]=[C:13]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:4](=[O:5])[CH2:3][CH2:2][Cl:1])=[CH:28][CH:27]=2)[N:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reactant: O=C(Cl)CCCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCl)Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
Chloropropionyl chloride (0.143 g, 1.13 mmol) was added to a stirred solution of 2-(4-aminoanilino)-4-anilino-5-bromopyrimidine (Method 38; 0.40 g, 1.13 mmol) and triethylamine (0.173 ml, 1.24 mmol) in DMF (1 ml). The mixture was stirred at room temperature and then water (4 ml) was added. The precipitated solid was collected by filtration and washed with ether (1 ml) to give the product (0.21 g, 42%) as a brown solid. MS (MH+): 448, 450.
Reaction SMILES: C([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([CH2:17][NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])([C:12]2S[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7]1)=O)C.[CH3:29][NH:30][CH3:31].O1CC[CH2:34][CH2:33]1>>[CH3:29][N:30]([CH3:31])[C:4]([N:6]1[CH2:7][CH2:8][C:9]([CH2:17][NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])([C:12]2[CH:34]=[CH:33][CH:14]=[CH:15][CH:16]=2)[CH2:10][CH2:11]1)=[O:3]
Reactant: CNC
Reactant: CCOC(=O)N1CCC(CNC(=O)c2ccccc2OC)(c2cccs2)CC1
Reactant: C1CCOC1
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(C(=O)N(C)C)CC1
Temperature: 65 °C

Procedure:
Compound 2 (0.050 g; 0.10 mmol) was treated with 2 M dimethylamine in tetrahydrofuran (2 mL) and heated to 65° C. in a sealed tube for 12 h. The solvent was removed by rotary evaporation and the crude residue was purified by preparative reverse phase HPLC to give 0.018 g of the title compound as a white solid. LRMS m/z 396 (M+H)+.