Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[S:15](=[O:18])(=[O:17])[NH2:16].[C:19](Cl)(=O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH3:19])=[O:12])=[CH:4][C:3]=1[S:15](=[O:17])(=[O:18])[NH2:16]
Reactant: CC(=O)Cl
Reactant: NS(=O)(=O)c1cc(C(=O)CCC(=O)O)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CCC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
27 g of 4-(4-chloro-3-sulfamoylphenyl)-4-oxobutanoic acid are dissolved in 200 ml of methanol, 1 g of acetyl chloride is added and the mixture is stirred at room temperature. After 24 hours, only small amounts of starting material can still be detected in the thin layer chromatogram. The solvent is driven off, the residue is treated with 200 ml of acetic acid/200 ml of water and, after the pH has been adjusted to 8 with saturated sodium bicarbonate solution, the mixture is stirred vigorously for 30 minutes. After separating off the organic phase and drying it over sodium sulfate, the solvent is distilled off and methyl 4-(4-chloro-3-sulfamoylphenyl)-4-oxobutanoate is obtained.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:10]2[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:10]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH:11]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Nc1cccc(-c2ncccc2[N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2[N+](=O)[O-])c1)NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a suspension of 3-(3-nitropyridin-2-yl)aniline (400 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (616 mg) and diisopropylethylamine (0.745 ml) in dichloromethane (18.6 ml) was added 1-methyl-2-chloropyridinium iodide (618 mg), and the mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 30 g, n-hexane:ethyl acetate=4:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-nitropyridin-2-yl)phenyl)guanidine (730 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:27])=O>CN(C=O)C>[Cl:27][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCN(C)CC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1

Procedure:
After repetition of the previous reaction, a mixture of 6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-3,4-dihydroquinazolin-4-one (2.15 g), thionyl chloride (25 ml) and DMF (0.18 ml) was stirred and heated to reflux for 2 hours. The thionyl chloride was evaporated under vacuum and the residue azeotroped twice with toluene. The residue was taken up in water, basified by the addition of a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride (4 times). The combined extracts were washed in turn with water and brine and filtered through phase separating paper. The filtrate was evaporated under vacuum and the residue was purified by column chromatography on silica using a 100:8:1 mixture of methylene chloride, methanol and a concentrated aqueous ammonium hydroxide solution (0.88 g/ml) as eluent. The solid so obtained was triturated under acetone, filtered and dried to give 4-chloro-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinazoline (1.2 g); Mass Spectrum: M+H+ 351.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([CH2:17][O:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:15][CH2:16]1)=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(CC[C@H]1CC[C@H](CO)CC1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC[C@H]1CC[C@H](COS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of 10 g (36.8 mmol) of trans-[2-(4-hydroxymethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester in 100 mL of CH2Cl2 were added 3.15 mL (40.5 mmol, 1.3 eq) of methanesulfonyl chloride followed by 6.68 mL (47.9 mmol, 1.3 eq) of triethylamine. Then the reaction mixture was stirred at RT for 1 h. 1M HCl was added, the phases were separated and the inorganic phase was washed with ether. The combined organic phases were washed with water and dried over magnesium sulfate. Concentration of the solution yielded 12.64 g (98%) of trans-methanesulfonic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester as colorless oil, MS: 367 (M+NH4+).
Reaction SMILES: [Mg:1].CO.[CH3:4][O:5][C:6]1[CH:27]=[CH:26][C:9]2[NH:10][C:11]([S:13]([CH2:15][C:16]3[C:21]([CH3:22])=[C:20]([O:23][CH3:24])[C:19]([CH3:25])=[CH:18][N:17]=3)=[O:14])=[N:12][C:8]=2[CH:7]=1.C[O-].[Mg+2].C[O-]>O.C(Cl)Cl>[CH3:25][C:19]1[C:20]([O:23][CH3:24])=[C:21]([CH3:22])[C:16]([CH2:15][S@@:13]([C:11]2[N-:10][C:9]3[CH:26]=[CH:27][C:6]([O:5][CH3:4])=[CH:7][C:8]=3[N:12]=2)=[O:14])=[N:17][CH:18]=1.[CH3:25][C:19]1[C:20]([O:23][CH3:24])=[C:21]([CH3:22])[C:16]([CH2:15][S@@:13]([C:11]2[N-:10][C:9]3[CH:26]=[CH:27][C:6]([O:5][CH3:4])=[CH:7][C:8]=3[N:12]=2)=[O:14])=[N:17][CH:18]=1.[Mg+2:1]
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2c1
Reactant: [Mg]
Agent: C[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2[n-]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1
Reaction time: 5 h
Yield: 44.5 %

Procedure:
Magnesium (0.11 g, 4.5 mmol) was dissolved and reacted with methanol (50 ml) at 40° C. with a catalytic amount of methylene chloride. The reaction was run under nitrogen and was finished after five hours. At room temperature a mixture of the two enantiomers [90%(-)-isomer and 10%(+)-isomer] of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (2.84 g, 8.2 mmol) was added to the magnesium methoxide solution. The mixture was stirred for 12 hours whereupon a small amount of water (0.1 ml) was added in order to precipitate inorganic magnesium salts. After 30 minutes stirring, these inorganic salts were filtered off and the solution was concentrated on a rotavapor. The residue was now a concentrated methanolic solution of the enantiomeric mixture (i.e. the title compound contaminated with the (+)-isomer), with an optical purity (enantiomeric excess, e.e.) of 80%. This mixture was diluted with acetone (100 ml) and after stirring at room temperature for 15 minutes, a white precipitate was obtained. Additional stirring for 15 minutes and thereafter filtration afforded 1.3 g (50%) of the title compound as white crystals. Chiral analyses of the crystals and mother liquor were performed by chromatography on an analytical chiral column. The optical purity of the crystals and mother liquor was found to be 98.4 e.e. and 64.4% e.e., respectively. Thus, the optical purity (e.e.) has been enhanced from 80% to 98.4% simply by crystallising the Mg-salt from a mixture of acetone and methanol. The product was crystalline as shown by powder X-ray diffraction and the magnesium content was 3.44% as shown by atomic absorption spectroscopy. [α]D20 =-131.5°(c=0.5%, methanol).
Reaction SMILES: O[N:2]=[C:3]([C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])(=O)C.[NH4+:21].[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH:25]=O>C(O)(=O)C.CO>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[C:25]1[NH:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:21]=1
Reactant: [NH4+]
Reactant: O=Cc1c(F)cccc1F
Reactant: CCOC(=O)C(=NO)C(=O)c1ccccn1
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(-c2c(F)cccc2F)nc1-c1ccccn1
Temperature: 160 °C
Yield: 6.9 %

Procedure:
A mixture of ethyl 2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propanoate (0.300 g, 1.4 mmol), ammonium acetate (0.104 g, 1.4 mmol) and 2,6-difluorobenzaldehyde (0.145 mL, 1.3 mmol) in acetic acid (6 mL) was heated in the microwave at 160° C. for 2 minutes. The reaction mixture was diluted with MeOH and purified by SPE using a MP-TsOH resin cartridge (2500 mg). The crude mixture obtained was purified by preparative HPLC to afford ethyl 2-(2,6-difluorophenyl)-4-(pyridin-2-yl)-1H-imidazole-5-carboxylate (0.029 g, 0.09 mmol, 7%) as a pale solid. LCMS (2) Rt: 2.46 min; m/z (ES+) 330.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Sn:5]([CH2:12][CH2:13][CH3:14])([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8].[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20].C(=O)(O)[O-].[Na+]>C(OCC)C>[Sn:5]([CH2:4][CH2:3][CH2:2][NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH3:21])[CH3:15])([CH2:12][CH2:13][CH3:14])([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8]
Reactant: CCC[Sn](CCC)(CCC)CCCBr
Reactant: CN(C)CCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCC[Sn](CCC)(CCC)CCCNCCCN(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Over a period of 0.5 hour 9.25 g (0.025 mol) of (3-bromopropyl) tripropyltin was added to 25 ml of 3-dimethylaminopropyl amine at room temperature. The mixture was stirred for 1 hour at 60° C. Under cooling 75 ml of diethylether and 60 ml of a 15% aqueous solution of sodium bicarbonate were added. After stirring for 0.5 hour the organic phase was separated, dried and evaporated in vacuo. Distillation gave 7.5 g (77%) of Pr3Sn(CH2)3NH(CH2)3NMe2 ; b.p. 113°-114° C./0.1 mm Hg, nD20 =1.4855.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([Br:13])=[CH:8][C:7]=1[Cl:14].[F:18][C:19]1([F:27])[CH2:24][CH2:23][C:22]([CH3:26])([OH:25])[CH2:21][CH2:20]1>C(Cl)Cl.C1CCCCC1.FC(F)(F)S(O)(=O)=O>[Br:13][C:9]1[CH:8]=[C:7]([Cl:14])[C:6]([CH2:5][O:25][C:22]2([CH3:26])[CH2:23][CH2:24][C:19]([F:27])([F:18])[CH2:20][CH2:21]2)=[CH:11][C:10]=1[F:12]
Reactant: N=C(OCc1cc(F)c(Br)cc1Cl)C(Cl)(Cl)Cl
Reactant: CC1(O)CCC(F)(F)CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC1(OCc2cc(F)c(Br)cc2Cl)CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 56 h
Yield: 18.1 %

Procedure:
To a solution of 4-bromo-2-chloro-5-fluorobenzyl 2,2,2-trichloroacetimidate (4.00 g, 10.40 mmol) and 4,4-difluoro-1-methylcyclohexanol (1.21 g, 8.05 mmol) in methylene chloride (50 mL) and cyclohexane (25 mL) was added trifluoromethanesulfonic acid (0.1 mL, 0.14 mmol) at 0 ?C. The reaction mixture was stirred for 56 hours at ambient temperature and quenched by addition of saturated sodium bicarbonate solution (10 mL), and then diluted with methylene chloride (100 mL). The organic layer was separated and washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) and recrystallization from methanol afforded the title compound (0.54 g, 17%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J=6.0 Hz, 1H), 7.30 (d, J=9.3 Hz, 1H), 4.37 (s, 2H), 2.11-1.86 (m, 6H), 1.72-1.59 (m, 2H), 1.26 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:16]C)=[C:4]([C@@H:9]2[C@H:14]3[C@@H:10]2[CH2:11]O[C:13]3=[O:15])[C:5]([F:8])=[CH:6][CH:7]=1.[BrH:18].CC(O)=O>O>[Br:18][CH2:11][C@H:10]1[C@@H:9]2[C@H:14]1[C:13](=[O:15])[O:16][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[C:5]([F:8])[C:4]=12
Reactant: Br
Reactant: COc1c(F)ccc(F)c1[C@H]1[C@H]2COC(=O)[C@H]21
Solvent: O
Solvent: CC(=O)O
Product: O=C1Oc2c(F)ccc(F)c2[C@@H]2[C@H](CBr)[C@H]12
Temperature: 90 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
(1S,5R,6S)-6-(3,6-difluoro-2-methoxyphenyl)-3-oxabicyclo[3.1.0]hexan-2-one (130 mg, 0.55 mmol) was mixed with 1.2 ml of 30% HBr/AcOH (6 mmol) and heated in a sealed vessel at stirring for about 4 h at 90° C. The reaction mixture was then cooled down, mixed with water and extracted into diethyl ether (3×20 ml). Ether extract was washed with sat sodium bicarbonate solution and brine. Dried over magnesium sulfate. Concentration gave 160 mg of white solid material. 98% yield.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:18][C:19](Cl)=[O:20].[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C@H:32]2[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]2)=[CH:27][C:26]=1[C:39]([F:42])([F:41])[F:40])([O-:24])=[O:23]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:19](=[O:20])[CH2:18][O:38][C@H:35]3[CH2:36][CH2:37][C@H:32]([NH:31][C:28]4[CH:29]=[CH:30][C:25]([N+:22]([O-:24])=[O:23])=[C:26]([C:39]([F:40])([F:41])[F:42])[CH:27]=4)[CH2:33][CH2:34]3)[CH2:13][CH2:12]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1ccc(N2CCNCC2)cc1
Product: CC(C)(C)c1ccc(N2CCN(C(=O)CO[C@H]3CC[C@H](Nc4ccc([N+](=O)[O-])c(C(F)(F)F)c4)CC3)CC2)cc1

Procedure:
1-[4-(4-Tert-butyl-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-Tert-butyl-phenyl)-piperazine was prepared with a 92% yield from 1-(4-Tert-butyl-phenyl)-piperazine and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 1-[4-(4-tert-butyl-phenyl)-piperazin-1-yl]-2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone was prepared from the trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (32% yield). The structure was confirmed using Protocol II-A. Calculated mass=563; observed mass=563; HPLC retention time=4.79 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>ClCCl.N1C=CC=CC=1>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:6][C@@H:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[O:14])=[O:23])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
2.0 g (9.3 mmol) L-phenylalanine methylester hydrochloride and 1.73 g (9.3 mmol) 4-nitrobenzoyl chloride were dissolved in a mixture of 10 ml dichloromethane and 5 ml pyridine and stirred over night at room temperature. The mixture was evaporated in vacuo, while a colorless solid precipitated, which was filtered by suction, recrystallized from ethanol, washed with diisopropylether, and dried in vacuo to give the title compound in colorless needles, m.p. 115°-116° C.
Reaction SMILES: [NH3:1].[O:2]1[C:6]2([CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([NH2:1])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: N
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC1CCC2(CC1)OCCO2
Temperature: 5 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Ammonia gas was bubbled into a solution of 1,4-dioxaspiro[4.5]decan-8-one (31.2 g, 199.77 mmol, 1.00 equiv) in methanol (300 mL). The resulting solution was stirred for 8 hrs at 0-10° C. This was followed by the addition of sodium borohydride (11.4 g, 301.35 mmol, 1.51 equiv) in several batches at 0-10° C. The resulting solution was stirred for 1 h at room temperature. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 4×300 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 2×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 20 g (64%) of 1,4-dioxaspiro[4.5]decan-8-amine as colorless oil.
Reaction SMILES: [Zn](C)[CH3:2].[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH:20]=[O:21])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CCOCC.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH2:4]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([C@@H:20]([OH:21])[CH3:2])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C[Zn]C
Reactant: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Product: C[C@H](O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Using Schlenck glassware and air-free conditions, anhydrous ethyl ether freshly distilled from sodium/benzophenone (2.43 mL) was added to catalyst 13 prepared according to Example 11, protocol 1. Freshly distilled titanium tetraisopropoxide (0.430 mL, 1.46 mmol) was added, and the reaction was cooled to −78° C. Commercial Me2Zn (1.21 mL, 2 M in toluene) was added, and the reaction was stirred at −78° C. for 1 hour. Aldehyde 9 (0.300 g, 1.21 mmol) in Et2O (0.3 mL) was added, and the reaction was warmed to −30° C. and stirred overnight. The reaction was then quenched at −30° C. with saturated aqueous NH4Cl. Et2O was added, and the reaction was filtered through Celite wet with Et2O. The reaction was dried with sodium sulfate, filtered, concentrated, and purified using an ISCO CombiFlash column (silica, 2:1 Hexane:EtOAc) to obtain 15 (0.162 g, 51%). HLPC analysis of the product presented in the Figures. 1H NMR (CDCl3, 300 MHz) 7.43–7.31 (5H, broad s), 5.16 (2H, s), 4.30–3.60 (2H, broad m), 3.63 (1H, dq, J=6.4, 6.4 Hz), 3.30–2.70 (2H, broad s), 2.15–1.90 (1H, broad s), 1.84–1.72 (1H, m), 1.76–1.56 (1H, m), 1.58–1.36 (2H, m), 1.23 (3H, d, J=6.4 Hz) ppm. 13C NMR (CDCl3, 75 MHz) 155.81, 137.04, 128.61, 128.08, 127.93, 68.35, 67.19, 46.61, 45.02, 43.25, 27.08, 24.37, 20.95 ppm. LRMS m/z 263.68 (M+, C15H21NO3, requires 263.15. Protocol 2
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]([F:16])([F:15])[F:14])[CH2:3][CH2:2]1.C(Cl)Cl.[F:20][C:21]([F:27])([F:26])[S:22]([OH:25])(=[O:24])=[O:23].CCOCC>C(#N)C>[O-:25][S:22]([C:21]([F:27])([F:26])[F:20])(=[O:24])=[O:23].[CH:1]1([C:4]2[S+:12]([C:13]([F:16])([F:14])[F:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: FC(F)(F)Sc1ccccc1C#CC1CC1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC#N
Product: FC(F)(F)[s+]1c(C2CC2)cc2ccccc21
Product: O=S(=O)([O-])C(F)(F)F
Temperature: -50 °C
Yield: 80.1 %

Procedure:
1-cyclopropylethynyl-2-trifluoromethylsulfanylbenzene (0.67 g, 2.77 mmol) prepared in Example 1 and anhydrous methylene chloride (5 ml) were charged into a 25-ml round-bottomed flask equipped with a stirrer, and cooled to −50° C. with stirring. To this mixture, trifluoromethanesulfonic acid (0.5 ml, 5.54 mmol) was added dropwise, and the solution was heated, and stirred at room temperature overnight. After completion of the reaction, a solvent was removed, ether (10 ml) was added to form a deposit, and the deposit was collected by filtration. The obtained crude product was dissolved in acetonitrile. After then, ether was added to form a precipitation, which was collected by filtration. This operation was repeated three times to purify the product. After the purification, target 2-cyclopropyl-1-trifluoromethylbenzo[b]thiophenyl triflate was obtained as a white solid (0.87 g, yield: 80%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:16])[CH3:15])[CH:9]=2)=[CH:4][CH:3]=1.[I-:17].[K+].II>N.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:16])[CH3:15])[CH:9]=2)=[CH:6][C:7]=1[I:17]
Reactant: [I-]
Reactant: CC(=O)c1cccc(-c2ccc(O)cc2)c1
Agent: II
Agent: N
Agent: [K+]
Solvent: O
Product: CC(=O)c1cccc(-c2ccc(O)c(I)c2)c1
Yield: 21 %

Procedure:
The product from Example 136A (5.76 g, 27 mmol) was suspended in concentrated aqueous ammonia (400 mL) and treated with a solution of potassium iodide (23.3 g, 140 mmol) and iodine (7.24 g, 28.5 mmol) in water (100 mL). As the reaction did not go to completion, the mixture was treated with a second solution of potassium iodide (15.8 g, 95 mmol) and iodine (4.83 g, 19 mmol) in water (50 mL). After an hour the ammonia was removed under reduced pressure on a rotary evaporator. The mixture was extracted with EtOAc, and the combined organic phases were washed consecutively with pH 6 potassium phosphate buffer and brine, then dried (Na2SO4), concentrated, and chromatographed through silica with 1% acetic acid in a gradient of 0 to 5% EtOAc/CH2Cl2 to provide the title compound as a beige powder (21% yield). MS (ESI APCI negative ion detection) m/z 337 (M−H)−; 1HNMR (300 MHz, CDCl3) δ 2.65 (s, 3 H), 5.37 (bs, 1 H), 7.08 (d, 1 H), 7.48-7.55 (m, 2 H), 7.71 (ddd, 1 H), 7.88-7.93 (m, 2 H), 8.09 (dd, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][C:14]([CH3:16])=[CH2:15])[CH:12]=2)[CH:7]=1.C[N+]1([O-])CC[O:32]CC1.C1COCC1.[OH2:41]>[Os](=O)(=O)(=O)=O>[CH3:15][C:14]([OH:32])([CH2:13][N:11]1[CH:12]=[C:8]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[N:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][N:19]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=2)[CH:9]=[N:10]1)[CH2:16][OH:41]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C(C)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC(C)(O)CO)c2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Osmium tetroxide (290 μl, 0.04 mmol) was added to a flask containing N-(3-methyl-5-(1-(2-methylallyl)-1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (56 mg, 0.15 mmol), N-methylmorpholine N-oxide (26.4 mg, 0.225 mmol), THF (1000 μL) and water (500 μL). The reaction mixture was stirred at room temperature for 3.5 hours. Silica was added and the mixture concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-10% MeOH/DCM) and concentrated under reduced pressure. The racemic mixture was purified by chiral SFC (IA column, 40% MeOH with 0.25% DMEA/CO2) to afford 2-methyl-3-(4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)propane-1,2-diol (Example 21.1, Isomer 1, early eluting): MS ESI calcd. for C19H21F3N5O2 [M+H]+ 408. found 408, 1H NMR δ ppm (DMSO-d6): 10.11 (1H, s), 8.80 (1H, d, J=4.88 Hz), 7.95 (1H, s), 7.81 (1H, s), 7.73 (1H, s), 7.33 (1H, s), 7.24 (1H, d, J=4.88 Hz), 7.05 (1H, s), 4.80 (1H, t, J=5.61 Hz), 4.67 (1H, s), 4.11 (1H, d, J=13.94 Hz), 4.05 (1H, d, J=13.90 Hz), 3.18-3.20 (2H, m), 2.29 (3H, s), 0.95 (3H, s), and 2-methyl-3-(4-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)propane-1,2-diol (Example 21.2, Isomer 2, late eluting): MS ESI calcd. for C19H21F3N5O2 [M+H]+ 408. found 408, 1H NMR δ ppm (DMSO-d6): 10.11 (1H, s), 8.80 (1H, d, J=4.88 Hz), 7.95 (1H, s), 7.81 (1H, s), 7.73 (1H, s), 7.33 (1H, s), 7.24 (1H, d, J=4.88 Hz), 7.05 (1H, s), 4.80 (1H, t, J=5.61 Hz), 4.67 (1H, s), 4.11 (1H, d, J=13.94 Hz), 4.05 (1H, d, J=13.90 Hz), 3.18-3.20 (2H, m), 2.29 (3H, s), 0.95 (3H, s).