Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: OCc1ccc(Br)nc1
Yield: 74.5 %

Procedure:
After dissolving 6-bromonicotinic acid (65.7 g, 0.325 mol) in tetrahydrofuran (1600 ml), triethylamine (54 ml, 0.39 mol) and ethyl chloroformate (32.6 ml, 0.341 mol) were added while stirring on ice. The mixture was stirred for 20 minutes while cooling on ice, and the white crystals which precipitated upon filtration were removed and washed with tetrahydrofuran. The filtrate was stirred while cooling on ice, and an aqueous solution (211 ml) of sodium borohydride (18.4 g, 0.488 mol) was gradually added dropwise over a period of 30 minutes. After continued stirring for 1 hour and 20 minutes while cooling on ice, 800 ml of water was added and extraction was performed with ethyl acetate (600 ml×2), and then after washing the combined organic layers with brine (300 ml) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield the title compound (45.5 g, 74.5%). This was used without further purification for the following reaction.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][C:5](=[O:7])[O:4][C:3]1=O.[CH2:9]([N:11](CC)CC)C.Cl.CN.C1N=CN(C(N2C=NC=C2)=O)C=1>ClCCl>[CH3:9][N:11]1[C:5](=[O:7])[CH2:6][C@H:2]([CH3:1])[C:3]1=[O:4]
Reactant: C[C@H]1CC(=O)OC1=O
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C[C@H]1CC(=O)N(C)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
600 mg (5.26 mmol) of (3S)-3-methyldihydro-2,5-furandione (preparation: S. G. Davies, D. J. Dixon, J. Chem. Soc., Perkin Trans. 1, 1998, 17, 2635-2643) are introduced to a vessel together with 559 mg (0.77 ml, 5.52 mmol) of triethylamine in 5 ml of dichloromethane at 0° C., and 373 mg (5.52 mmol) of methylamine hydrochloride are added. The reaction mixture is stirred at room temperature overnight and then 938 mg (5.78 mmol) of N,N-carbonyldiimidazole are added in portions. The mixture is stirred at room temperature for 1.5 h and at reflux temperature for 30 minutes. After it has cooled to room temperature the reaction mixture is washed with 5% strength hydrochloric acid and water, the organic phase is dried over magnesium sulfate, filtered and concentrated and the product is dried under a high vacuum. This gives 605 mg of the product (88% of theory).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](=O)[NH2:15])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1N=C(Cl)N=C(Cl)N=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]#[N:15])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](C(N)=O)C1
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](C#N)C1
Temperature: 0 °C
Yield: 75 %

Procedure:
To a solution of tert-butyl[trans-3-carbamoylcyclohexyl]-carbamate (180 mg) in N,N-dimethylformamide (2 ml) was added 2,4,6-trichloro-1,3,5-triazine (76 mg) under stirring at 0° C. After stirring at ambient temperature for 2 hours, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane:EtOAc=80:20-50:50 to give tert-butyl[trans-3-cyanocyclohexyl]carbamate (125 mg) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].N12CCCN=C1CCCC[CH2:17]2.IC.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:17])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15]
Reactant: O=C1CCc2c(Br)cc([N+](=O)[O-])c(O)c21
Reactant: C1CCC2=NCCCN2CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c([N+](=O)[O-])cc(Br)c2c1C(=O)CC2
Temperature: 25 °C
Reaction time: 40 h
Yield: 78.9 %

Procedure:
4-Bromo-7-hydroxy-6-nitroindan-1-one (8.07 g, 29.7 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.33 mL, 35.6 mmol) were dissolved in N,N-dimethylformamide (150 mL), iodomethane (18.5 mL, 297 mmol) was added, and the mixture was stirred at room temperature for 40 hr. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with diethyl ether, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→60/40) to give the title compound (6.70 g, yield 79%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][N:15]([CH:48]2[CH2:50][CH2:49]2)[C:16](=[O:47])[CH:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][C:38]3[C:43]([Cl:44])=[CH:42][C:41]([CH3:45])=[CH:40][C:39]=3[Cl:46])=[CH:30][CH:29]=2)[CH2:18][NH:19]C(=O)OC(C)(C)C)=[CH:4][C:5]([CH2:9][CH2:10][CH2:11][O:12][CH3:13])=[N+:6]([O-:8])[CH:7]=1.Cl>C(Cl)Cl>[NH2:19][CH2:18][CH:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][C:38]2[C:43]([Cl:44])=[CH:42][C:41]([CH3:45])=[CH:40][C:39]=2[Cl:46])=[CH:30][CH:29]=1)[C:16]([N:15]([CH2:14][C:3]1[C:2]([Cl:1])=[CH:7][N+:6]([O-:8])=[C:5]([CH2:9][CH2:10][CH2:11][O:12][CH3:13])[CH:4]=1)[CH:48]1[CH2:50][CH2:49]1)=[O:47]
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c(Cl)c[n+]1[O-]
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c(Cl)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a CH2Cl2 solution (0.07 M) of tert-butyl (3-[{[5-chloro-2-(methoxypropyl)-1-oxidopyridin-4-yl]methyl}(cyclopropyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 16 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography (SiO2, 95:5 (v/v) CH2Cl2: 2.0 M NH3 in MeOH) to afford the title compound as an oil. MS (ESI+): 651.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]2)[CH:6]=[CH:5][C:4]=1[C:15]([N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][N:20]2[CH:28]=[CH:29][CH:30]=[C:19]2[CH2:18]1)=[O:16].B(Br)(Br)Br.[OH-].[NH4+]>ClCCl>[OH:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][C:11]([CH3:14])=[N:10]2)[CH:6]=[CH:5][C:4]=1[C:15]([N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][N:20]2[CH:28]=[CH:29][CH:30]=[C:19]2[CH2:18]1)=[O:16]
Reactant: COc1cc(-n2ccc(C)n2)ccc1C(=O)N1Cc2cccn2Cc2ccccc21
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(O)c2)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 24 %

Procedure:
[2-Methoxy-4-(3-methyl-pyrazol-1-yl)-phenyl](5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepin-10-yl) methanone (0.82 g) from Example 107 was dissolved in dichloromethane (20 ml) and cooled to −78° C. Boron tribromide (6.2 ml) was added and the reaction stirred at 0° C. for five minutes. Ammonium hydroxide (15 ml) was added and extracted with dichloromethane. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. The solid was removed by filtration and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica pressure eluting with hexane/ethyl acetate (3/1 then 2/1) to afford 0.19 g of the title compound as a colorless solid, m.p. 134-136° C.
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([C:66]3[CH:71]=[CH:70][C:69]([S:72]([CH3:75])(=[O:74])=[O:73])=[CH:68][CH:67]=3)=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:44][CH2:43][C@H:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:47][CH2:46]3)[C:50]=2[C:66]2[CH:71]=[CH:70][C:69]([S:72]([CH3:75])(=[O:73])=[O:74])=[CH:68][CH:67]=2)[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2ccc(S(C)(=O)=O)cc2)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(S(C)(=O)=O)cc2)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(methylsulfonyl)phenyl)naphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 36% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(methylsulfonyl)phenyl)naphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z 493.26 [M−16]+. 1H NMR (MeOD) δ: 8.03-8.12 (m, 2H), 7.91-7.99 (m, 2H), 7.55-7.63 (m, 2H), 7.42-7.53 (m, 2H), 7.32-7.40 (m, 1H), 4.21 (br. s., 1H), 3.58-3.76 (m, 2H), 3.25 (br. s., 3H), 2.05 (br. s., 2H), 1.80 (br. s., 2H), 1.52 (br. s., 3H), 1.05-1.25 (m, 4H), 0.90-1.04 (m, 1H), 0.87 (br. s., 9H)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([OH:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([N:34]1[CH2:33][CH2:32][CH:31]([C:27]2[O:26][CH:30]=[CH:29][N:28]=2)[CH2:36][CH2:35]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1coc(C2CCNCC2)n1
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ncco4)CC3)cnc12
Yield: 72.7 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.20 g, 0.58 mmol) obtained in Example 21, step 4 and 4-(oxazol-2-yl)piperidine (WO2001/036980, 0.11 g, 0.70 mmol), the title compound (0.20 g, 72%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[N+:13]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.O1CCOCC1>C1COCC1>[NH2:13][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:5]=1[O:4][C:3]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:2]=1[CH3:1])[C:9]#[N:10]
Reactant: Cc1ccc(C)c(Oc2ccc(C#N)cc2[N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1ccc(C)c(Oc2ccc(C#N)cc2N)c1
Yield: 89.1 %

Procedure:
The coupled product 30 (12.00 g, 44.73 mmol) was reduced with sodium hydrosulfite (30.47 g, 175.00 mmol) in a mixture of THF (75 mL), water (100 mL), and dioxane (45 mL). After the reaction is complete, volatile organic solvents were removed in vacuo and the precipitate in the remaining water was collected via vacuum filtration to afford compound 31 as a white solid (9.50 g, 89.0% yield, 99.5% pure). 1H NMR (500 MHz, DMSO-d6): δ 7.19 (d, J=8 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 6.86 (dd, J1=8 Hz, J2=2 Hz, 1H), 6.74 (s, 1H), 6.45 (d, J=8 Hz, 1H), 5.52 (s, 2H), 2.23 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:19]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: Oc1ccccc1
Reactant: C=CCCCCCCCCCC
Product: CCCCCCCCCCCCc1ccccc1O
Reaction time: 4 h
Yield: 59.9 %

Procedure:
First, dodecyl phenol was prepared. Specifically, to a 2-liter four-necked flask, 325 g of phenol and 30 g of dried activated clay (manufactured by MIZUSAWA INDUSTRIAL CHEMICALS, LTD.: product name, Galeonite #136) were added. 575 g of 1-dodecene was dropped in this mixture with agitation at 135 degrees C. for 4 hours. The activated clay was filtered, and then 537 g of dodecyl phenol was obtained by vacuum distillation.
Reaction SMILES: [Na].[C:2]([O:12]CC)(=[O:11])[CH2:3][C:4]([C:6]([O:8]CC)=O)=O.[OH-].[Na+].Cl.[CH:18]1([C:21](=[NH:23])[NH2:22])[CH2:20][CH2:19]1.Cl>CO.O>[CH:18]1([C:21]2[NH:23][C:6](=[O:8])[CH:4]=[C:3]([C:2]([OH:12])=[O:11])[N:22]=2)[CH2:20][CH2:19]1
Reactant: N=C(N)C1CC1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(=O)[nH]c(C2CC2)n1
Temperature: 30 °C
Reaction time: 5 h
Yield: 58.4 %

Procedure:
To a mixture of diethyl oxalacetate sodium salt (210 g, 950 mmol) in methanol (500 mL) and water (400 mL) was added 50% aqueous sodium hydroxide (80 g, 1.0 mol) in water (60 mL) over 30 minutes, over which time the temperature remained at 25-30° C. and the pH at 11-12. Then the stirred mixture was heated for an additional 30 min at 30° C. To this mixture was added cyclopropanecarboximidamide monohydrochloride (110 g, 910 mol). The orange solution was heated to 50° C. over 30 minutes and held at that temperature for 5 h. The reaction mixture was cooled to 30° C. and concentrated to half volume at reduced pressure at 35-40° C. and concentrated hydrochloric acid (140 g, 1.4 mol) was added gradually (resulting in foaming) over 30 minutes at 25-30° C. until the pH was about 1-2. The mixture was stirred at 5° C. for 1 h to complete crystallization of the product. After the mixture was cooled to 0° C. the solid was collected by filtration. The solid was washed with water (3×60 mL), suction-dried, and then dried in a vacuum-oven at 70° C. to afford the title compound as a beige solid (100 g); m.p. 235-236° C. (dec.).
Reaction SMILES: C([O:8][C:9](=[O:25])[C@H:10]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[NH:11][C:12]([O:14][CH3:15])=[O:13])C1C=CC=CC=1.O1CCCC1>[Pd].O>[CH3:15][O:14][C:12]([NH:11][C@H:10]([C:9]([OH:25])=[O:8])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:13]
Reactant: COC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](Cc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A mixture of N-methoxycarbonyl-O-methyl-L-tyrosine benzyl ester (14.5 g), 10% palladium on carbon (0.73 g), and tetrahydrofuran (145 ml)-water (14.5 ml) was shaken under hydrogen at ambient temperature for 2 hours. An additional 10% palladium on carbon (0.73 g) was added to the mixture and shaking was continued for an additional 2 hours. The catalyst was filtered off and washed with tetrahydrofuran. The filtrate and washings were combined and concentrated in vacuo to afford N-methoxycarbonyl-O-methyl-L-tyrosine (10.5 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]([C:13]2[N:17]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=2)[OH:12])[CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2].O=[Mn]=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([C:13]2[N:17]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:16]=[N:15][CH:14]=2)=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: OC(c1cccc2cccnc12)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Mn]=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1cccc2cccnc12)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of quinolin-8-yl(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 12) 3.7 g, 7.9 mmol) in CH2Cl2 (50 mL) was treated with manganese(IV) oxide, activated (commercially available from Aldrich): MnO2 (4.1 g, 47.4 mmol) at room temperature. The mixture was heated to 60° C. for 2 h. The mixture was then cooled to room temperature and filtered through celite and the solvent was removed under vacuum to get quinolin-8-yl(1-trityl-1H-imidazol-5-yl)methanone, (Intermediate 13) (3.6 g, 97%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13].Cl>C(Cl)Cl>[C:5]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([C@H:17]3[CH2:18][CH2:19][C@H:14]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16]3)=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccccc3)cc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(C)=O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
First, 23.6 g of anhydrous aluminum chloride and 120 ml of methylene chloride were put in a 300 ml flask. After 14.0 g of acetyl chloride was dropped into the mixture at 5° C. or less, the resultant mixture was stirred keeping the same temperature for 30 minutes. Then, 45.2 g of 4-(trans-4-pentylcyclohexyl)biphenyl was added to resultant mixture at 5° C. or less and stirred for 30 minutes at room temperature. After the reaction, the reaction solution was poured into dilute hydrochloric acid, and an organic layer was separated. The organic layer was then washed with water and dried with sodium sulfate. The solvent was then distilled off. The residue was recrystallized from acetone to obtain 24.0 g (Y: 46.0%) of 4-acetyl-4′-(trans-4-pentylcyclohexyl)biphenyl. The purity of the resultant compound was 99.7% as measured by GC.
Reaction SMILES: FC1C=C(CCC(O)=O)C=CC=1OC.[CH3:15][O:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:19][C:18]=1[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1.[OH-].[Na+]>>[CH3:15][O:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:19][C:18]=1[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1
Reactant: COC(=O)CCc1cc(-c2ccc3ccccc3c2)c(OC)c([N+](=O)[O-])c1
Agent: COc1ccc(CCC(=O)O)cc1F
Agent: [Na+]
Agent: [OH-]
Product: COc1c(-c2ccc3ccccc3c2)cc(CCC(=O)O)cc1[N+](=O)[O-]
Reaction time: 0.67 h
Yield: 83.2 %

Procedure:
According to the procedure described in the synthesis method of Intermediate 9 provided that the reaction was carried out for 40 minutes, Intermediate 49 (2.45 g) and 2 N aqueous sodium hydroxide (6.7 ml) were reacted and treated to obtain the title compound (Intermediate 60, 1.96 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>COCCOC>[F:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1-c1cccc(F)c1
Yield: 16.7 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.123 mmol) in DME (4 ml)/2M Na2CO3 (0.645 ml, 1.29 mmol) was treated with 3-fluorophenylboronic acid (34.4 mg, 0.246 mmol) and Pd[PPh3]4 (70.2 mg, 0.061 mmol) for 65 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient. Further purification by RP HPLC afforded the product (8.7 mg, 16.7%). MS m/e 423.21 (M+H+)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:17])[C:8]3[C:13]([S:14][C:15]=2[CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:18]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:17])[C:8]4[C:13]([S:14][C:15]=3[CH:16]=2)=[CH:12][CH:11]=[CH:10][CH:9]=4)=[N:2][N:20]=[N:19]1
Reactant: N#Cc1ccc2c(=O)c3ccccc3sc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2sc2cc(-c3nnn[nH]3)ccc12

Procedure:
A mixture of 3-cyanothioxanthone (2.56 g), sodium azide (0.84 g) and ammonium chloride (0.70 g) in dimethylformamide (20 ml) was heated on a steam bath for 5 hrs. The nitrile dissolved after 2 hrs., at the same time a precipitate of the product forming. Much solid crystallised out on cooling. The reaction mixture was poured into excess dilute hydrochloric acid, and the yellow precipitate was filtered off and washed with water. It was dissolved in dilute aqueous sodium hydroxide, filtered and reprecipitated with dilute hydrochloric acid. The product was filtered off and dried at 110° C., and then recrystallised from dimethylformamide and dried at 154° C./15 mm Hg, decomposes 290° C.
Reaction SMILES: [CH3:1][C:2]1([C:21]([F:24])([F:23])[F:22])[O:6][C:5](=[O:7])[N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:3]1=[O:20].C(O)C.[OH2:28]>>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:4]([C:3](=[O:20])[C:2]([OH:6])([CH3:1])[C:21]([F:22])([F:23])[F:24])[C:5](=[O:7])[OH:28])=[CH:9][C:10]=1[C:16]([F:17])([F:19])[F:18])#[N:13]
Reactant: O
Reactant: CC1(C(F)(F)F)OC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Solvent: CCO
Product: CC(O)(C(=O)N(C(=O)O)c1ccc(C#N)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 17 %

Procedure:
100 mg of 4-(5-methyl-2,4-dioxo-5-(trifluoromethyl)oxazolidin-3-yl)-2-(trifluoromethyl)-benzonitrile, as prepared in Example 1, were dissolved in 20 ml of a 7/3 ethanol/water mixture and stirred for 5 days at room temperature. The reaction mixture was evaporated to dryness and then purified by chromatography on an RP18 silica column (eluent: 6/4 water/acetonitrile). 18 mg of (4-cyano-3-(trifluoromethyl)phenyl)(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)carbamic acid were obtained, for a yield of 17%.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(N(CC)CC)C>[C:18]1([S:24]([NH:2][CH:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC(N)c1cccc(OC)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(OC)c1

Procedure:
Corresponding to Example 1c, 10 g of (8b) were treated with phenylsulphonyl chloride and triethylamine. A yellowish solid was obtained (yield: 13.2 g).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>[Br-].C([N+](CC)(CC)CC)C.O>[C:1]([O:8][CH2:9][CH:11]1[O:13][CH2:12]1)(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6]
Reactant: ClCC1CO1
Reactant: C/C=C/C=C/C(=O)O
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: O
Product: C/C=C/C=C/C(=O)OCC1CO1
Temperature: 110 °C

Procedure:
To 1.8 g of sorbic acid (manufactured by Wako Pure Chemical) were added 1 g of tetraethylammonium bromide (manufactured by Wako Pure Chemical) and 60 ml of epichlorohydrin (manufactured by Wako Pure Chemical), the mixture was heated to reflux at 110° C. for 3 hours, 30 ml of distilled water was added thereto and an organic layer was separated and concentrated in vacuoat 80° C. to give 3.5 g of glycidyl sorbate. An epoxy equivalent of this glycidyl sorbate was 367.4.