Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH3:13])[C:5]=1[CH3:14])([O-:3])=[O:2].[N+:15](C1C=C(C)C(C)=C([N+]([O-])=O)C=1[N+]([O-])=O)([O-:17])=[O:16]>>[N+:15]([C:5]1([CH3:14])[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]1[CH3:13])([O-:17])=[O:16]
Reactant: Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C
Reactant: Cc1cc([N+](=O)[O-])c([N+](=O)[O-])c([N+](=O)[O-])c1C
Product: CC1C=C([N+](=O)[O-])C=C([N+](=O)[O-])C1(C)[N+](=O)[O-]
Yield: 91.7 %

Procedure:
The first filtrate from the separation of 1,2,6-trinitro-o-xylene was extracted three times with 80 ml portions of methylene chloride. The extracts were combined and the volatiles were evaporated to yield an oily mixture of 3,5-dinitro-o-xylene with both of the trinitro-o-xylene isomers. This oil was crystallized from 12 parts of isopropyl alcohol to afford 27.4 g (91.7% yield) of pure 1,4,6-trinitro-o-xylene having a melting point of 72° C. as given by Crossly et al.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([OH:9])[N:3]=1.[CH3:10][C:11]([O-])=O.[Na+].ClCC=O>O>[NH2:1][C:2]1[NH:3][C:4](=[O:9])[C:5]2[CH:11]=[CH:10][NH:8][C:6]=2[N:7]=1
Reactant: CC(=O)[O-]
Reactant: Nc1cc(O)nc(N)n1
Agent: O=CCCl
Agent: [Na+]
Solvent: O
Product: Nc1nc2[nH]ccc2c(=O)[nH]1
Temperature: 65 °C
Reaction time: 2 h
Yield: 55.7 %

Procedure:
To a mixture of 2,4-diamino-6-hydroxypyrimidine (20.0 g, 159 mmol) and NaOAc (26.0 g, 317 mmol) in H2O (300 mL) at 65° C. was added a solution of chloroacetaldehyde (22.0 mL, 50% in H2O, 173 mmol) in H2O (22 mL) dropwise for 90 min. The mixture was stirred at 65° C. for an additional 2 h and cooled to room temperature. The reaction mixture was concentrated in vacuo to one third of its original volume and stored at 4° C. for 16 h. The light pink precipitates were filtered, washed with an ice cold H2O (5 mL), and dried under high vacuum for 16 h. The precipitates were placed in Soxhlet extractor and refluxed with methanol (200 mL) for 24 h. The methanol was concentrated to give 13.3 g (56%) of 2-amino-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a light pink solid.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=O)=O.C([Li])CCC.[Si](Cl)(C(C)(C)C)(C)C.[C:25]1(=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>O1CCCC1.CCCCCC>[C:27]1([C:10]2[N:6]=[CH:7][NH:8][CH:9]=2)[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][CH:26]=1
Reactant: O=C1CCc2ccccc21
Reactant: CN(C)S(=O)(=O)n1ccnc1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C1=C(c2c[nH]cn2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(N,N-dimethylsulfamoyl)-1H-imidazole (1.9 g, prepared according to Chadwick, D. J. and Ngochindo, R. I., J. Chem. Soc., Perkin Trans. I 1984, 481) in dry tetrahydrofuran (90 ml) at −70° C. under nitrogen, is added dropwise 2.5 M butyllithium in hexane (5.1 ml). After 30 minutes tert-butyldimethylsilyl chloride (2.0 g) in dry tetrahydrofuran (5 ml) is added and the mixture is allowed to warm to 25° C. After 1.5 hours the mixture is again cooled to −70° C. and treated with 2.5 M butyllithium in hexane (5.3 ml). After 30 minutes, 1-indanone (2.1 g) in dry tetrahydrofuran (5 ml) is added and the mixture is allowed to warm to room temperature. The reaction mixture is then quenched with saturated Na2CO3 solution (2 ml), and the solvent is removed under reduced pressure. The residue is dissolved in methylene chloride and washed with water, dried with sodium sufate and evaporated to dryness under reduced pressure. The bis-protected intermediate is refluxed with 2 N hydrochloric acid (200 ml) for 2 hours. The cooled solution is made basic by ammonium hydroxide solution, and extracted with methylene chloride. The organic layer is washed with water, dried with sodium sulfate and the solvent removed under reduced pressure. The crude product is purified by flash chromatography using methylene chloride-methanol as eluent. The product is converted to the hydrochloride salt in ethyl acetate-ethanol solution, m.p. 232-240° C.
Reaction SMILES: C([CH:6]([O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])[CH2:7][CH2:8][CH3:9])(=O)C(C)C.ClC1[CH:27]=[C:28]([CH:33]=CC=1)[C:29]([O:31]O)=[O:30].C([O-])(O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:29]([O:31][CH:6]([O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:12])[CH2:7][CH2:8][CH3:9])(=[O:30])[CH:28]([CH3:33])[CH3:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCC(OC(=O)NCC1(CC(=O)O)CCCCC1)C(=O)C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCC(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.6 %

Procedure:
To a solution of (104) (780 mg, 2.3 mmol) in dichloromethane (20 mL) was added m-chloroperoxybenzoic acid (1.03 g, 4.6 mmol) and NaHCO3 (386 mg, 4.6 mmol). After stirring for 16 h at room temperature, another batch of m-chloroperoxybenzoic acid (791 mg, 4.6 mmol) and NaHCO3 (386 mg, 4.6 mmol) was added. The resulting mixture was stirred for another 8 h and then treated with 10% citric acid. After filtration, the organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by reverse phase preparative HPLC to afford 79 mg (11%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 0.94 (t, J=7.2 Hz, 3H), 1.153 (d, J=7.2 Hz, 3H), 1.150 (d, J=7.2 Hz, 3H), 1.32-1.58 (m, 12H), 1.74 (m, 2H), 2.28 (s, 2H), 2.56 (m, 1H), 3.23 (m, 2H), 5.27 (t, J=6.8 Hz, 1H, NH), 6.71 (t, J=5.6 Hz, 1H). MS (ESI) m/z 358.30 (M+H+).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]([CH2:19][CH3:20])[C@@H:12]([OH:18])[C:13]1[S:14][CH:15]=[CH:16][N:17]=1)C1C=CC=CC=1.N1CCCCC1.I[Si](C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.CCOC(C)=O.O>[NH2:10][C@@H:11]([CH2:19][CH3:20])[C@H:12]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[OH:18]
Reactant: CC[C@H](NC(=O)OCc1ccccc1)[C@@H](O)c1nccs1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CC[C@H](N)[C@@H](O)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 134.8 %

Procedure:
To a solution of benzyl((1R,2S)-1-hydroxy-1-(thiazol-2-yl)butan-2-yl)carbamate (330 mg, 1.077 mmol) in acetonitrile (25 mL) at 0° C. under argon was added piperidine (0.213 mL, 2.154 mmol) and dropwise iodotrimethylsilane (293 μL, 2.15 mmol) over a period of 5 minutes. Then, the reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 2 hours. To the reaction mixture was added at 0° C. sodium thiosulfate (500 mg), followed by water (0.5 mL), and the reaction mixture was stirred vigorously at 0° C. for 15 minutes. Further 500 mg of sodium thiosulfate was added, and the mixture was diluted with EtOAc (50 mL), dried over Na2SO4, filtered and concentrated. The residue was triturated with EtOAc, filtered, and the filtrate was concentrated to give the title compound (250 mg, 67%) as a yellow oil.
Reaction SMILES: [H-].[H-].COCCO[Al+]OCCOC.[Na+].[Si:15]([O:22][CH:23]1[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]2[N:28]=[C:27]([CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C:26]([C:40]([C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=3)=[O:41])=[C:25]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[C:54]([F:59])[CH:53]=3)[C:24]1=2)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[Si:15]([O:22][CH:23]1[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]2[N:28]=[C:27]([CH:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[C:26]([CH:40]([C:42]3[CH:43]=[CH:44][C:45]([C:48]([F:51])([F:49])[F:50])=[CH:46][CH:47]=3)[OH:41])=[C:25]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[C:54]([F:59])[CH:53]=3)[C:24]1=2)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O[Si](C)(C)C(C)(C)C)C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 3.5 h
Yield: 93.2 %

Procedure:
At 0° C., 1.15 ml (4 mmol) of sodium bis-(2-methoxyethoxy)-aluminium dihydride (65% strength in toluene) were added dropwise to 600 mg (0.93 mmol) of [5-(tert-butyldimethylsilanyloxy)-2-cyclopentyl-4-(3,4-difluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanone dissolved in 6 ml of toluene. After 3.5 hours, the reaction was quenched with methanol, the mixture was extracted with ethyl acetate and the organic phase was washed with potassium-sodium tartrate solution and saturated aqueous sodium bicarbonate solution and dried. The solvent is distilled off under reduced pressure and the residue is then purified over a silica gel column using toluene/ethyl acetate. This gives a total of 0.56 g of a colourless foam.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:12](=O)(=[O:15])([OH:14])[OH:13]>>[N:7]1([C:1]2[CH:2]=[CH:3][C:4]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:5][CH:6]=2)[CH:11]=[CH:10][CH:9]=[N:8]1
Reactant: c1ccc(-n2cccn2)cc1
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1ccc(-n2cccn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution was prepared by adding 1-phenylpyrazole (1.3 ml, 9.8 mmol) to concentrated sulfuric acid (2 ml). To this solution, fuming sulfuric acid (5 ml, 30% SO3) was added gradually over at least 5 minutes at 0° C. The resultant mixture was heated to 35° C., and this temperature was kept for 1 hour. This mixture then was cooled to 0° C. by pouring it over crushed ice, thereby causing sulfate to precipitate. This sulfate was collected by filtration and then vacuum-dried. Thus, a desired compound, 4-(1H-pyrazole-1-yl)benzenesulfonic acid, was obtained in the form of a white solid (the yield calculated based on 1-phenylpyrazole: 37%). The instrumental analysis values of 4-(1H-pyrazole-1-yl)benzenesulfonic acid are shown below.
Reaction SMILES: CO[CH:3]=[C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][CH2:14][CH3:15])[CH2:9][CH2:8]1)[CH:5]=O.Cl.[CH2:17]([C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28]([NH2:30])=[NH:29])[CH2:24][CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21].C[O-].[Na+].[Na]>CO>[CH2:13]([C@H:10]1[CH2:11][CH2:12][C@H:7]([C:4]2[CH:5]=[N:29][C:28]([C@H:25]3[CH2:26][CH2:27][C@H:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24]3)=[N:30][CH:3]=2)[CH2:8][CH2:9]1)[CH2:14][CH3:15]
Reactant: CCC[C@H]1CC[C@H](C(C=O)=COC)CC1
Reactant: CCCCC[C@H]1CC[C@H](C(=N)N)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCC[C@H]1CC[C@H](c2ncc([C@H]3CC[C@H](CCC)CC3)cn2)CC1

Procedure:
In an analogous manner to that described in Example 3, a mixture of 3.2 g of 3-methoxy-2-(trans-4-propylcyclohexyl)acrolein, 4.1 g of trans-4-pentylcyclohexanecarboxamidine hydrochloride and 50 ml of absolute methanol is treated with a sodium methylate solution prepared from 0.53 g of sodium in 20 ml of absolute methanol. The reaction duration, working-up and chromatography are as described in Example 3. The pure fractions (in accordance with thin-layer chromatography) resulting in the chromatography are combined and recrystallized twice from hexane. There is obtained pure 5-(trans-4-propylcyclohexyl)-2-(trans-4-pentylcyclohexyl)pyrimidine; m.p. 98° C., cl.p. 178° C. (smectic).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]2[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=2[CH:7]=1)=[O:4].[O:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[O:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([NH:5][C:6]2[CH:16]=[CH:15][C:9]3[NH:10][C:11](=[O:14])[CH2:12][O:13][C:8]=3[CH:7]=2)=[O:4])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCC(=O)N2
Solvent: CCOCC
Product: O=C(CN1CCC(Oc2ccccc2)CC1)Nc1ccc2c(c1)OCC(=O)N2

Procedure:
The title compound is prepared from 2-chloro-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-acetamide (Example 153a) and 4-phenoxy-piperidine according to the method described in Example 142b. Melting Point: 206-208° C. (diethylether)
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[C:15]([CH2:23][C:24](=O)[CH3:25])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:23]=[C:24]([CH3:25])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2)nc2nc(SCc3ccccc3)nn12
Yield: 14 %

Procedure:
A solution of 20.6 g (100 mmol) of 3-amino-5-benzylthio-1,2,4-triazole and 16.2 g (100 mmol) of benzoyl acetone in 100 ml of glacial acetic acid was heated at reflux for 14 hours. The solvent was removed by evaporation at reduced pressure and the residue was chromatographed on silica gel (HPLC) eluting with EtOAc-hexane (3:7, v/v) to afford 4.81 g (14% of 2-benzylthio-7-methyl-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine as a pale yellow wolid, m.p. 154°-155° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: N1CCC[C@@H]1CNC(C1SC=CC=1NC1C=CN=C2NC=CC=12)=O.C(OC([N:32]1[CH2:36][CH2:35][CH:34]([NH:37][C:38]([C:40]2[CH:44]=[CH:43][S:42][C:41]=2[NH:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[NH:52][CH:53]=[CH:54][C:47]=23)=[O:39])[CH2:33]1)=O)(C)(C)C>>[NH:32]1[CH2:36][CH2:35][CH:34]([NH:37][C:38]([C:40]2[CH:44]=[CH:43][S:42][C:41]=2[NH:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[NH:52][CH:53]=[CH:54][C:47]=23)=[O:39])[CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccsc2Nc2ccnc3[nH]ccc23)C1
Agent: O=C(NC[C@H]1CCCN1)c1sccc1Nc1ccnc2[nH]ccc12
Product: O=C(NC1CCNC1)c1ccsc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid ((R)-1-pyrrolidin-2-ylmethyl)-amide using 3-{[2-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-3-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester instead of (R)-2-({[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}methyl)pyrrolidine-1-carboxylic acid tert-butyl ester LCMS (ESI) 328 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.58 (1H, br. s.) 11.49 (1H, s) 8.89 (1H, d, J=6.93 Hz) 8.18 (1H, d, J=6.74 Hz) 7.67 (1H, d, J=5.86 Hz) 7.46 (1H, dd, J=3.32, 2.34 Hz) 7.42 (1H, d, J=5.86 Hz) 6.80 (1H, d, J=6.83 Hz) 6.76 (1H, dd, J=3.42, 1.56 Hz) 4.49 (1H, dt, J=6.66, 4.53 Hz) 3.33 (2H, dt, J=12.40, 6.30 Hz) 3.18 (2H, td, J=10.93, 6.44 Hz) 2.12 (1H, dd, J=13.42, 7.47 Hz) 1.84-2.00 (0H, m) 1.16-1.42 (1H, m)
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[CH:7][N:6]=1>CCO>[Cl:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]([NH:3][CH2:1][CH3:2])[CH:10]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCN
Solvent: CCO
Product: CCNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 174.5 %

Procedure:
Ethylamine (70% in water, 16 ml, 45.08 mmol, 2.5 eq.) is added dropwise (15 min) to a suspension of 4,6-dichloropyrimidine (12 g, 80.5 mmol) in EtOH (36 ml) at RT. The resulting yellowish solution is allowed to stir for 1 h at RT and then cooled to 0° C. The resulting white precipitate is collected by vacuum filtration, washed with water and dried in vacuo to afford 12.4 g of the title compound: ESI-MS: 157.9 [MH]+; single peak at tR=2.02 min (purity: 100%, gradient J).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@H:7]([OH:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:11]([O:13][C:14](=[O:27])[C@@H:15]([O:24][CH2:25][CH3:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:11]([O:13][C:14](=[O:27])[C@@H:15]([O:24][CH2:25][CH3:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:9][C@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])[CH3:8])=[CH:19][CH:18]=1)[CH3:12]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(O[C@@H](C)C(=O)OC(C)(C)C)cc1)OCC
Temperature: 0 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a solution of 2-(R)-hydroxypropionic acid tert-butyl ester (1.23 g, 8.44 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (2.01 g, 8.44 mmol) in THF (100 ml) was added the triphenyl phosphine (2.21 g, 8.44 mmol). The mixture was cooled to 0° C. and added the DIAD (diisopropyl azodicarboxylate) (1.70 g, 8.44 mmol) dropwise over 5 minutes. The reaction mixture was stirred for 18 hours while warmed to room temperature. The reaction was quenched with water (2 ml) and concentrated to a residue, purified by silica gel chromatography with 20% EtOAc/Hexanes to afford product (0.99 g, 32%) and recovered starting material ((S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester, 0.85 g).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C(=O)=O.C([O:15][C:16]([C:18]1[C:19]([C:34]([F:37])([F:36])[F:35])=[N:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[N:22][CH:23]=1)=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[F:37][C:34]([F:35])([F:36])[C:19]1[C:18]([CH2:16][OH:15])=[CH:23][N:22]=[C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[N:20]=1
Reactant: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: O=C=O
Solvent: C1CCOC1
Product: OCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C(F)(F)F
Temperature: -30 °C
Reaction time: 2.5 h
Yield: 16.6 %

Procedure:
Within 10 min was dropped 5.5 ml (6.6 mmol) of DIBALH (1.2 M solution in toluene) to a dry ice cooled (−30° C.) solution of 1.09 g (3.0 mmol) 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester in 15 ml of THF. The reaction was stirred for 2.5 h at −30° C., warmed up (0° C. for 2 h) and stirred 1 h at 0° C. The reaction was neutralized with saturated NaHCO3 solution. The mixture was extracted with ether (3×), the organic phase was washed with a NaCl solution (10%), dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography over silica gel with heptane/isopropanol 9:1, to give 0.16 g of pure [4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[CH:29]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:30]=1.C(O)C>O1CCCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:29][CH3:30])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc(CN(Cc2ccc(F)cc2F)c2cccc([N+](=O)[O-])c2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 33A(39 mg, 0.1 mmole) and di-t-butylazo dicarboxylate (35 mg, 0.15 mmole) in tetrahydrofuran (1.5 ml) were added to PPh3 on resin (70 mg, 0.3 mmole: loading 3 mmole/g) followed by ethanol (5.7 mg, 0.125 mmole) in 50 microliter tetrahydrofuran. Reaction mixture was shaken at room temperature overnight. Filtered off and solvent removed. Solaris 530 organic synthesis system from PE Biosystems was used to do this reaction. The residue purified by HPLC (CH3CN:0.1 TFA in H2O) on a YMC ODS guardpak column.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26]>C(#N)C>[C:27]1([CH:25]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:12]=[C:11]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[O:10][N:9]=3)=[CH:6][CH:7]=2)[CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(Br)c1ccccc1
Reactant: NC(=O)OCc1cc(-c2ccc(O)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(-c2cc(COC(N)=O)on2)cc1)c1ccccc1

Procedure:
Carbamic acid 3-(4-hydroxy-phenyl)-isoxazol-5-ylmethyl ester (150 mg, 0.64 mmol) and potassium carbonate (180 mg, 1.28 mmol) were dissolved in 10 ml of acetonitrile, to which was added dropwise (1-bromoethyl)benzene (131 μl, 0.96 mmol), and reacted at room temperature overnight. The completion of the reaction was confirmed by liquid chromatography, and then acetonitrile was distilled under reduced pressure. A crude solid compound was extracted with ethyl acetate and the solvent was distilled under reduced pressure to obtain a white solid compound. This was recrystallized from methylene chloride:MeOH (9:1) to obtain carbamic acid 3-[4-(1-phenyl-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester as a white solid compound.
Reaction SMILES: FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:15]2[C:19](=[O:20])[CH:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][S:38]([CH3:41])(=[O:40])=[O:39])=[CH:33][CH:32]=4)=[CH:24][CH:23]=3)[O:17][C:16]2=[O:42])C=CC=CC=1>ClCCl>[CH3:41][S:38]([O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([CH2:21][CH:18]3[O:17][C:16](=[O:42])[NH:15][C:19]3=[O:20])=[CH:23][CH:24]=2)=[CH:36][CH:35]=1)(=[O:39])=[O:40]
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC3OC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC3OC(=O)NC3=O)cc2)cc1
Yield: 88.2 %

Procedure:
1 ml trifluoroacetic acid was added to a solution of 0.214 g (0.33 mmole) 3-triphenylmethyl-5-([4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl]methyl)oxazolidine-2,4-dione in 10 ml dichloromethane. After stirring for 45 minutes at room temperature 20 ml more of dichloromethane was added, the reaction mixure was washed twice with water, dried (sodium sulfate) and the solvent was evaporated in vacuo. The crude product was purified by chromatography on silica gel using heptane:ethyl acetate:acetic acid (10:10:1) as eluent to give 0.118 g (yield 88%) of 5-([4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl]methyl)oxazolidine-2,4-dione.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:32])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=O)[CH3:20])=[C:14]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CO.C(=O)(O)[O-].[K+]>O>[C:1]1([S:7]([NH:10][C:11]([C:12]2[CH:17]=[CH:16][C:15]3[N:18]=[C:19]([CH3:20])[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[F:31])[C:14]=3[CH:13]=2)=[O:32])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
N-benzenesulfonyl-4-acetylamino-3-(2,4-difluorobenzylamino)benzamide (0.370 g) is added to a mixture solvent of 10% hydrochloric acid (3.3 g), methanol (6 ml), and water (4 ml). Furthermore, 35% hydrochloric acid (0.5 g) is added and the solution is stirred for three hours at 60° C. After 20% potassium bicarbonate aqueous solution is added to turn the reaction solution into a basic, its acidity is adjusted to pH 5˜6 with 10% hydrochloric acid. Precipitated crystals are separated through filtration, dried and thus, 0.182 g of 6-benzenesulfonylcarbamoyl-1-(2,4-difluorobenzyl)-2-methyl-benzimidazole is obtained. 1H-NMR (DMSO-d6, δ): 2.53 (3H, s), 5.56 (2H, s), 6.95-7.01 (1H, m), 7.04 (1H, dt, J=8.7 and 1.4 Hz), 7.32 (1H, dt, J=10.7 and 2.1 Hz), 7.59-7.66 (3H, m), 7.68-7.74 (2H, m), 8.00 (2H, d, J=8.1 Hz), 8.13 (1H, s), 12.43 (1H, s).