Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[F:42][C:43]1[CH:48]=[CH:47][C:46]([C@H:49]([NH2:51])[CH3:50])=[CH:45][CH:44]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:51][C@@H:49]([C:46]2[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=2)[CH3:50])=[O:40])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: C[C@@H](N)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@H](C)c4ccc(F)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1R)-1-(4-fluorophenyl)ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (28 mg, yield 60%).
Reaction SMILES: [OH:1][CH:2]1[C@@H:7]2[C:8]([CH2:11][OH:12])=[CH:9][CH2:10][C@@H:6]2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][O:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCCCCC.C(OC(=O)C)C>C(Cl)Cl>[CH:11]([C:8]1[C@H:7]2[CH:2]([OH:1])[O:3][CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C@H:6]2[CH2:10][CH:9]=1)=[O:12]
Reactant: COC(=O)C1=COC(O)[C@@H]2C(CO)=CC[C@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)C1=COC(O)[C@@H]2C(C=O)=CC[C@H]12
Reaction time: 3 h
Yield: 75.9 %

Procedure:
0.5 g (2.21 mmol) of methyl (4aS,7aS)-1-hydroxy-7-hydroxymethyl-1,4a, 5,7a-tetrahydrocyclopenta[c]pyran4carboxylate was dissolved in 10 ml of dried methylene chloride, then 0.954 g (4.42 mmol) of pyridiniumchlorochromate was added thereto. The reaction solution was stirred for 3 hours, filtered through cellite and then the filtrate was concentrated. The residue was subjected to silica gel column chromatography (eluent: n-hexane/ethylacetate=2/1, v/v) to obtain 0.376 g (Yield 76%) of methyl (4aS,7aS)-7-formyl-1-hydroxy-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-4-carboxylate.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:38][C:39]1([F:45])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:42]3[CH2:43][CH2:44][C:39]([F:45])([F:38])[CH2:40][CH2:41]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: FC1(F)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CCC(F)(F)CC1
Temperature: 0 °C
Reaction time: 1.75 h
Yield: 13.9 %

Procedure:
A cold (0° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (0.500 g, 1.0 eq.) in CH2Cl2 (20 mL) was treated sequentially with EDC HCl (0.409 g, 1.5 eq.), 4,4-difluoropiperidine hydrochloride (0.269 g, 1.2), DIPEA (0.220 g, 1.2 eq) and HOBT (0.261 g, 1.2 eq.). The clear reaction mixture was stirred at 0° C. for 1.5-2 h then quenched with 50 mL ice-water slurry. The aqueous layer was extracted with CH2Cl2 (2×25 mL) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 0.60 g of crude compound. Purification by preparative TLC (eluting with MeOH/CH2Cl2) afforded 0.090 g compound which was further triturated using ether: petroleum ether to remove aliphatic impurity affording 0.06 g pure compound. Yield: 9.28%.
Reaction SMILES: C([S:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])C1C=CC=CC=1.S(Cl)(Cl)(=O)=O>ClCCl.CCCCCCC>[Cl:18][C:15]1[CH:16]=[CH:17][C:9]2[S:8][N:13]=[C:11]([OH:12])[C:10]=2[CH:14]=1
Reactant: NC(=O)c1cc(Cl)ccc1SCc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCCCCCC
Product: Oc1nsc2ccc(Cl)cc12
Reaction time: 1 h
Yield: 117.7 %

Procedure:
2-Benzylsulphanyl-5-chlorobenzamide (523 mg, 1.89 mmol) was dissolved in dichloromethane (20 mL) and sulphuryl chloride (0.183 mL, 3.29 mmol) added dropwise. The resultant white suspension was stirred for a further 1 h, diluted with heptane (15 mL), filtered, washed with heptane and dried under suction to afford the title compound as a white solid (413 mg, >100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15]COC)=[CH:11][CH:10]=2)=[O:8])[CH:2]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])[CH:2]=1
Reactant: COCOc1ccc(C(=O)c2cccnc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 2.01 g of the thus obtained 4-methoxymethyloxyphenyl 3-pyridyl ketone which has been dissolved in 35 ml of methylene chloride and cooled down to 0° C. was added dropwise 2.01 g of titanium tetrachloride dissolved in 35 ml of methylene chloride. After 2 hours of stirring at room temperature, the resulting reaction mixture was neutralized with saturated sodium hydrogencarbonate solution and mixed with 200 ml of ethyl acetate to separate the organic layer and to extract the water layer with ethyl acetate. Thereafter, the organic phases were combined, washed with saturated sodium chloride aqueous solution and dried using anhydrous magnesium sulfate, followed by the removal of solvents by distillation under a reduced pressure to obtain 1.32 g of 4-hydroxyphenyl 3-pyridyl ketone.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].O.O1CCCC1.[C:15](Cl)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>[OH-].[Na+]>[C:15]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 10 °C

Procedure:
29 g of L-valine is dissolved in 250 ml of 1N aqueous NaOH, and to the solution is added water so that 400 ml of the solution is obtained. To the solution is added 150 ml of tetrahydrofuran. Then, while vigorously stirring at 10° C., to the solution are added 100 ml of Boc-Cl by 1/5 amounts at intervals of ten minutes, while 2N aqueous NaOH is added after every addition of Boc-Cl in such amount as will provide a pH value of about 8 to 9. Two hours later, the mixture is extracted with diethyl ether. The aqueous layer is acidified with an aqueous solution of 0.5 M aqueous citric acid, whereby an oily substance is precipitated. The precipitate is extracted with ethyl acetate. The extract is washed with a small amount of water, dried over Na2SP4, and concentrated under reduced pressure. To the concentrated extract is added petroleum ether, and the mixture is allowed to stand in a refrigerator, whereby a crystal is formed. The crystal is filtered off and dried. Thus, there is obtained 30 g of Boc-valine having a melting point of 78° C. The yield of the product is 55%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][CH:7]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:33])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:17][CH2:18][C:19]2[C:27]3[C:22](=[CH:23][C:24]([NH:28][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:25][CH:26]=3)[NH:21][C:20]=2[C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)/C=C/c1ccc(C2CCCN2CCc2c(C(C)(C)C)[nH]c3cc(N)ccc23)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc(C2CCCN2CCc2c(C(C)(C)C)[nH]c3cc(NS(C)(=O)=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
To a solution of (E)-3-(4-{1-[2-(6-amino-2-tert-butyl-1H-indol-3-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester (0.70 g, 1.6 mmol) in dichloromethane (7 mL) was added methanesulfonyl chloride (0.198 g, 1.73 mmol), triethylamine (241 μL, 1.73 mmol). The resulting solution was stirred at room temperature for 1 h, diluted with ethyl acetate, and washed with 1 N hydrochloric acid, a saturated sodium bicarbonate solution, and a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel column chromatography to give the title compound (0.21 g, 26% yield). LCMS (m/z): 523.9 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])C)C=O)(=[O:3])[CH3:2].O[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].B(F)(F)F.CCOCC>C(Cl)Cl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[O:12][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(=[O:27])[CH3:26]
Reactant: CCOC(=O)CCCCCO
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCCCCO[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.8 %

Procedure:
To mannose pentaacetate (10.00 g, 25.64 mmol) dissolved in 60 mL of CH2Cl2, ethyl 6-hydroxyhexanoate (8.3 mL, 51.28 mmol) was added at room temperature and then BF3.Et2O at 0° C. After 4 days under stirring at room temperature, the reaction mixture was washed twice with NaHCO3 (2×20 mL) and then with brine (20 mL). The organic layer was dried (MgSO4) and concentrated under vacuum. Compound 1 (7.14 g, 57%) was obtained after column chromatography on silica gel (hexane/AcOEt; 6:4).
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]1[CH2:13][CH:12]1[CH:14]=[CH2:15])=[O:9])([CH3:6])([CH3:5])[CH3:4].C1COCC1.[Mn]([O-])(=O)(=O)=O.[K+].[OH2:27]>>[C:3]([O:7][C:8]([NH:10][CH:11]1[CH2:13][CH:12]1[CH:14]([OH:27])[CH2:15][OH:1])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: O
Reactant: C=CC1CC1NC(=O)OC(C)(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC1C(O)CO
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydroxide solution (114 mg in 10 mL of water) was added to N-tert-butoxycarbonyl-2-ethenylcyclopropylamine (59 mg, 0.3 mmol), from Step C of Example 1, until the N-tert-butoxycarbonyl-2-ethenylcyclopropylamine oiled out to form a separate organic layer. THF (10 mL) was added until a cloudy solution was formed. An additional 2.5 mL of water was added and the solution became clear. The clear colorless solution was cooled to 0° C. in an ice-water bath. A solution of potassium permanganate (80 mg, 0.5 mmol) in 10 mL of water was added and the cold reaction mixture was stirred vigorously for 5 minutes at 5° C. TLC analysis (on silica gel plates eluted with 25% ethyl acetate in hexane) showed that all of the starting material had been consumed in the reaction. The reaction mixture was concentrated in vacuo and the residue dissolved in water. The resultant aqueous solution was extracted 3 times with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated in vacuo. N-tert-Butoxycarbonyl-2-(1',2'-dihydroxyethyl)cyclopropyl amine was obtained in 86% crude yield (56 mg) as a clear colorless oil. The crude product was carried on to Step B without further purification. DCI NH3MS, M/Z: 218 (M+H)+, 235 (M+NH4)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=1)=[O:4].C1COCC1.O.[OH-].[Li+].Cl>O>[CH:11]1([C:9]2[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7][C:8]=2[O:17][CH2:18][C:19]([F:21])([F:22])[F:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
5-Cyclohexyl-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid methyl ester (95 mg, 299 μmol) was combined with THF (4 mL) and water (2 mL) to give a light yellow solution. Lithium hydroxide hydrate (25.1 mg, 599 μmol) was added under argon. The reaction mixture stirred at ambient temperature overnight, subsequently poured into 6 mL 2 M HCl and extracted with isopropyl acetate (2×60 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo to give the title compound (92 mg, quant.) as white solid; MS (ESI) 302.0 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[O:13]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:18][CH:15]1[CH2:16][CH2:17][O:13][CH2:14]1
Reactant: CS(=O)(=O)c1ccc(F)c(Br)c1
Reactant: NC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(NC2CCOC2)c(Br)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 69.2 %

Procedure:
A mixture of 2-bromo-1-fluoro-4-methylsulfonylbenzene (0.8 g, 3.16 mmol), oxolan-3-amine (1.38 g, 15.8 mmol) and K2CO3 (0.87 g, 6.32 mmol) in DMSO (15 mL) was stirred at 100° C. for 5 hrs. It was cooled to r.t. and water (50 mL) was added. The mixture was extracted with EtOAc (50 mL×3) and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (PE:EA=50:13:1) to give the title compound (0.7 g, yield: 69.16%). 1H NMR (CDCl3, 400 MHz) δ 8.00 (d, J=1.2 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 5.03 (d, J=6.4 Hz, 1H), 4.23-4.13 (m, 1H), 4.07-3.98 (m, 2H), 3.96-3.87 (m, 1H), 3.83-3.76 (m, 1H), 3.03 (s, 3H), 2.43-2.32 (m, 1H), 1.98-1.88 (m, 1H). LCMS (M+H)+=320.0 (M+H)+, 322.0
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([C@@H:14]1[C:20]2=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=[C:19]2[NH:18][CH2:17][CH2:16][CH2:15]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:37][O:38][C:39](=[O:47])[CH2:40][C:41]([CH3:46])([CH3:45])[CH2:42][CH:43]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH3:37][O:38][C:39](=[O:47])[CH2:40][C:41]([CH3:46])([CH3:45])[CH2:42][CH2:43][N:18]1[C:19]2[C:20](=[CH:21][C:22]3[CH2:23][O:24][CH2:25][C:26]=3[CH:27]=2)[C@@H:14]([N:7]([CH2:6][C:5]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:3]([C:2]([F:1])([F:35])[F:36])[CH:4]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc4c(cc32)COC4)n1
Reactant: COC(=O)CC(C)(C)CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COC(=O)CC(C)(C)CCN1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc3c(cc21)COC3
Reaction time: 12 h

Procedure:
To a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(3,5,6,7,8,9-hexahydro-1H-2-oxa-5-aza-cyclohepta[f]inden-9-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (0.195 mmol) in dichloroethane (5 mL), add 3,3-dimethyl-5-oxo-pentanoic acid methyl ester (0.585 mmol) along with a catalytic amount of acetic acid. To this stirred solution add sodium triacetoxyborohydride (0.975 mmol). After stirring for 12 h, quench the reaction with aqueous sodium carbonate (5 mL) and dilute with dichloromethane (5 mL). Dry the organic portion, filter, and remove the solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (2-35%) to afford the title compound as a colorless oil. MS (ES+): 655.2 (M+H).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[S:19]1[C:23]([CH:24]=[O:25])=[CH:22][N:21]=[CH:20]1.Cl>O1CCCC1.C1(C)C=CC=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:24]([C:23]2[S:19][CH:20]=[N:21][CH:22]=2)[OH:25])[CH:14]=1
Reactant: O=Cc1cncs1
Reactant: Brc1cccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OC(c1cccnc1)c1cncs1
Yield: 44.6 %

Procedure:
According to Reference Example 8-68, a 1.55 mol/L solution of n-butyllithium in hexane (2.24 mL, 3.48 mmol) was added to toluene (6 mL), and the mixture was stirred with a toluene solution (2 mL) of 3-bromopyridine (500 mg, 3.16 mmol), tetrahydrofuran (2 mL), thiazole-5-carbaldehyde (0.329 mL, 3.79 mmol) and 4 mol/L hydrochloric acid (2.37 mL, 9.48 mmol). Then, purification by preparative thin-layer chromatography (chloroform/methanol=12/1) was performed to give pyridin-3-yl(thiazol-5-yl)methanol (Compound EQ) (271 mg, yield: 45%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:4]1[CH:3]=[C:2]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][C:15]=2[F:17])[CH:7]=[CH:6][C:5]=1[NH2:8]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Nc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ccc(-c2ccc(F)cc2F)cc1F
Yield: 89.6 %

Procedure:
To a solution of 4-bromo-2-fluoro-phenylamine (190 mg, 1 mmol) and 2,4-difluorophenylboronic acid (240 mg, 1 mmol) in 2.5 ml of 1,2-dimethoxy-ethane was added tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.1 mmol) and 0.5 ml of 2M sodium carbonate aqueous solution. The mixture was microwaved at 150° C. for 15 min. The solvents were evaporated and the residue was diluted with CH2Cl2 and filtered. The filtration was concentrated and purified on a flash chromatography column with 0-80% EtOAc/hexanes to give 3,2′,4′-trifluoro-biphenyl-4-ylamine as an off-white solid (200 mg, 90%). LRMS calcd for C12H8F3N (m/e) 223, obsd 224 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]([CH2:17][O:18][C:19](=[O:21])[CH3:20])=O)[CH3:11].[CH2:23]([O:25][C:26](=[O:31])/[CH:27]=[C:28](\[NH2:30])/[CH3:29])[CH3:24]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[C:27]([C:26]([O:25][CH2:23][CH3:24])=[O:31])=[C:28]([CH3:29])[NH:30][C:15]=1[CH2:17][O:18][C:19](=[O:21])[CH3:20])=[O:22])[CH3:11]
Reactant: CCOC(=O)CC(=O)COC(C)=O
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1ccccc1Cl
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1ccccc1Cl
Yield: 40 %

Procedure:
7 g of 2-chlorobenzaldehyde, 9.4 g of γ-acetoxy-acetoacetic acid ethyl ester and 6.5 g of β-aminocrotonic acid ethyl ester in 40 ccs of ethanol are heated under reflux overnight and cooled and light yellow crystals of melting point 102° C. are obtained, yield: 40%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1.[CH3:9][C:10]([Si:13](Cl)([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.CCOCC.O>[Si:13]([O:1][CH2:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][CH:4]=1)([C:10]([CH3:12])([CH3:11])[CH3:9])([CH3:15])[CH3:14]
Reactant: Nc1ncc(CO)s1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cnc(N)s1
Yield: 44.4 %

Procedure:
A solution of 5-(hydroxymethyl)-thiazol-2-ylamine (0.787 g, 6.05 mmol), TBDMSCl (1.003 g, 6.65 mmol) and imidazole (0.49 g, 7.26 mmol) in DMF (15 mL) is stirred at room temperature for 24 h. The reaction mixture is diluted with ether and water. The organic layer is washed with water (3×). The aqueous washings are backwashed with ether (2×). The organic layers are combined, dried over MgSO4 and condensed. The crude material is purified using a plug of silica and eluting with 1:1 petrol:ethyl acetate to give the product (0.656 g, 44%). 1H-NMR (400 MHz, d6-DMSO) =0.01 (s, 6H, 2×CH3), 0.82 (s, 9H, tBu), 4.61 (s, 2H, CH2), 4.74 (brs, 2H, NH2), 6.8 (s, 1H, CH). LCMS: Rt 2.62 min (92.7%). MS (MH+, m/z) 245.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([OH:14])[C:7]([CH3:13])=[CH:8][CH:9]=[C:10]([CH3:12])[CH:11]=1.C1(O)C=CC=CC=1.[N:22]([O-])=[O:23].[Na+]>O.C(O)(=O)C>[N:22]([C:9]1[CH:8]=[C:7]([CH3:13])[C:6]([OH:14])=[CH:11][C:10]=1[CH3:12])=[O:23]
Reactant: O=N[O-]
Reactant: Cc1ccc(C)c(O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: Cc1cc(N=O)c(C)cc1O
Reaction time: 0.21 h

Procedure:
A solution of 20 mL of 36N sulfuric acid solution in 40 mL of water (60 mL of 12N sulfuric acid) is added to a mixture of 6I g (500 mmol) of 2,5-xylenol and 200 mL of glacial acetic acid. A homogeneous solution is produced initially, but on continued stirring some of the phenol crystallizes. A solution of 35 g (500 mmol) of sodium nitrite in 60 mL of water is added dropwise to the previous mixture over 60 minutes at 5° to 10° C. Stirring is continued for 10 to 15 minutes and the heterogeneous mixture is poured into 1 L of water. The reaction flask is rinsed with water and the solid nitroso derivative collected, washed with water, and dried to a moist cake.
Reaction SMILES: [C:1]1([OH:14])[C:2]([C:7]2[C:8]([OH:13])=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH-].[Na+].Cl[CH2:18][CH2:19][OH:20].[CH2:21]([OH:23])[CH3:22]>>[C:8]1([OH:13])[C:7]([C:2]2[C:1]([OH:14])=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:12]([CH2:22][CH2:21][OH:23])[C:11]([CH2:18][CH2:19][OH:20])=[CH:10][CH:9]=1
Reactant: Oc1ccccc1-c1ccccc1O
Reactant: OCCCl
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: OCCc1ccc(O)c(-c2ccccc2O)c1CCO

Procedure:
To biphenol (0.5 mole) and 200 milliliters of absolute ethanol and sodium hydroxide (1.1 millimole) at 80° C. was added dropwise a solution of 2-chloroethanol (1 mole) in 50 milliliters of absolute ethanol. The mixture was refluxed for 48 hours, and then filtered hot and washed twice with boiling ethanol (100 milliliters). Recrystallization from boiling water provided the precursor product biphenol-diethanol, 80 to 85 percent yield of colorless crystals. The melting point for this product was 210° to 211° C.