Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11]([N:15]=[C:16]=S)([CH3:14])([CH3:13])[CH3:12].C1(N=C=NCCN2CCOCC2)CCCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>N1C=CC=CC=1>[C:11]([NH:15][C:16]1[NH:9][C:5]2[CH:6]=[C:7]([Cl:8])[C:2]([Cl:1])=[CH:3][C:4]=2[N:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N=C=S
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: CC(C)(C)Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 80 °C
Yield: 26.8 %

Procedure:
4,5-Dichlorophenylene diamine (8.0 g, 45.2 mmol) (Aldrich, Milwaukee, Wis.) was combined with tert-butyl isothiocyanate (6.3 mL, 49.7 mmol) (Aldrich, Milwaukee, Wis.) in anhydrous pyridine (100 mL). The solution was heated at 80° C. for 1 h under nitrogen. 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-ρ-toluene-sulphonate (24.9 g, 58.8 mmol) (Fluka Chemika) was added along with anhydrous pyridine (90 mL). This solution was heated at 90° C. for 2.5 h. The pyridine. was removed by rotoevaporation, and the residue was dissolved in ethyl acetate (300 μM) and extracted with water (4×100 mL). The ethyl acetate layer was treated with decolorizing carbon and washed through a silica gel filter pad (4×8 cm, 230-400 mesh) using ethyl acetate. The crude product was purifed on a silica gel column (5×16 cm, 230-400 mesh) using (1:4) ethyl acetate:hexane. Crude fractions were repurified on a second identical column using (1:3) ethyl acetate: hexane. Pure fractions from the two columns were combined to give a tan solid (3.13 g, 12.1 mmol, 27%); m.p. 219-221° C.; MS (API+): m/z (rel. intensity) 258 (100, M+1); 1H NMR (DMSO-d6) d 10.31 (s, 1H, NH), 7.31 (s, 2H, Ar-H), 6.61 (s, 1H, NH), 1.38 (s, 9H, t-butyl).
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][N:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:13]2=[O:14])=[O:10])C(=O)C1.CCN(CC)CC.[CH3:26][CH2:27][O:28][C:29]([CH3:31])=O>CC#N>[O:28]1[CH2:29][CH2:31][C@H:26]([O:8][C:9](=[O:10])[O:11][N:12]2[C:13](=[O:14])[CH2:15][CH2:16][C:17]2=[O:18])[CH2:27]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Yield: 92 %

Procedure:
Compound 21 (250 mg, 2.84 mmol), N,N′-disuccinimidyl carbonate (799 mg, 3.12 mmol), and Et3N (431 mg, 4.27 mmol) in CH3CN (5 mL) were stirred for 12 hours at room temperature. Then the reaction mixture was diluted with EtOAc (20 mL), washed with brine, then concentrated under reduced pressure to obtain compound 22 (595 mg, 92%) as a solid. M.P.: 97-99° C.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[Cl-].[Al+3].[Cl-].[Cl-].[C:8](OC(=O)C)(=[O:10])[CH3:9].[S:15]([N:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>ClCCl>[C:8]([C:27]1[CH:28]=[CH:29][N:25]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=2)(=[O:16])=[O:17])[CH:26]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)n2cccc2)cc1
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccn(S(=O)(=O)c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
In a 1-liter three-neck flask fitted with a thermometer, a 50 cm3 funnel and a condenser with calcium chloride guard, 500 cm3 of dichloromethane and 80 g anhydrous aluminum chloride (600 mmoles) were added. 30 cm3 of acetic anhydride (320 mmoles) was dropwise added. The solution was stirred during 10 minutes. Then a 60 cm3 of dichloromethane solution containing 27 g of 1-tosyl pyrrole 1 (122 mmoles) was dropwise added. The stirring was maintained during 2 hours at room temperature, then the resulting solution was poured on 500 cm3 of water-ice mixture. After decantation, the aqueous layer was extracted with dichloromethane. The combine organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 31 g of purple crystals 2 (M=263, yield: 96.7%). F (° C)=87 (purified by chromatography). NMR: (CDCl3) ppm 7.7 d J(Hz) 8 2H; 7.2 4H; 6.62 2H; 2.35 s 6H.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[NH:45][C:46]([NH:48][C:49]1[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=1)=[O:47].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[CH:32][C:31]([NH:45][C:46]([NH:48][C:49]3[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=3)=[O:47])=[C:30]([F:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3ccncc3)c(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(NC(=O)Nc4ccncc4)c(F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (40 mg, 0.09 mmol) in dioxane (2 ml) were added 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(pyridin-4-yl)urea (62 mg, 0.14 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (7.5 mg, 0.01 mmol) and 136 μl of a 2M aqueous solution of cesium carbonate. The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 25 mg (45% yield) as a white solid. Purity 97%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[C:19]([N:24]3[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]3)=[N:20][CH:21]=[CH:22][N:23]=2)[CH2:13][CH2:12]1.[C:31]([O-])([O-])=O.[Cs+].[Cs+].IC>C(#N)C>[CH3:31][O:30][CH:27]1[CH2:28][CH2:29][N:24]([C:19]2[C:18]([O:17][CH:14]3[CH2:13][CH2:12][N:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:1]=4)[CH2:16][CH2:15]3)=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:25][CH2:26]1
Reactant: OC1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-(3-((1-(quinolin-2-yl)piperidin-4-yl)oxy)pyrazin-2-yl)piperidin-4-ol (see EXAMPLE 1.1; 100 mg, 0.25 mmol) in dry acetonitrile (CH3CN) (10 mL) was added Cs2CO3 (162 mg, 0.5 mmol). The reaction mixture was cooled to 0° C. with an ice bath, and iodomethane (70 mg, 0.50 mmol) was added dropwise to the reaction mixture. 1 hour later, the reaction mixture was warmed to RT, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified via flash chromatography on silica gel (20% to 45% EtOAc in petroleum ether) to give 2-(4-((3-(4-methoxypiperidin-1-yl)pyrazin-2-yl)oxy)piperidin-1-yl)quinoline (81 mg, 0.19 mmol, 78% yield) as a white solid. ESI-MS (M+1): 420 calc. for C24H29N5O2 419.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:17][C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7]=1[CH3:18])=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:3][CH2:4][C:6]1[S:17][C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7]=1[CH3:18]
Reactant: CCOC(=O)c1sc2nc3ccccc3n2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(CO)sc2nc3ccccc3n12
Reaction time: 1 h

Procedure:
Under ice-cooling, 3-methylthiazolo[3,2-a]benzoimidazole-2-carboxylic acid ethyl ester (Can. J. Chem., 45 (23), 2903-2912 (1967) (10 g) was added to THF (250 ml) suspension of LiAlH4 (1.46 g) and stirred at the same temperature for 1 hour. While cooling, the reaction solution was mixed with Na2SO4.10H2O and stirred, and then the insoluble matter was removed by filtration and the solvent was evaporated under a reduced pressure to obtain the title compound (6.36 g).
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([CH2:8][O:9][CH:10]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[N:14]([C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:25][CH:24]=2)[CH2:13][CH2:12][CH2:11]1)=O)C.Cl>O1CCCC1>[OH:5][CH2:6][CH2:8][O:9][CH:10]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[N:14]([C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:38])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])=[CH:25][CH:24]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)COC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccc(Cl)cc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCO)c3cc(Cl)ccc32)cc1
Yield: 79.1 %

Procedure:
0.28 g of lithium borohydride was added to a solution of 2.2 g of 5-ethoxycarbonylmethoxy-7-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine dissolved in 50 ml of tetrahydrofuran, at room temperature with stirring. The mixture was refluxed for 30 minutes. The reaction mixture was poured into a diluted hydrochloric acid. The mixture was subjected to extraction with dichloromethane. The extract was dried over magnesium sulfate and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=100/1→50/1) and then recrystallized from dichloromethane-diethyl ether to obtain 1.6 g of 5-(2-hydroxyethoxy)-7-chloro-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine.
Reaction SMILES: [CH3:1][CH:2]([CH:9]1[C:17]2([CH3:18])[CH:12]([CH:13]([OH:19])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].I([O-])(=O)(=O)=O.[Na+].C(Cl)(Cl)(Cl)Cl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O.O.[Ru](Cl)(Cl)Cl.C(#N)C>[CH3:1][CH:2]([CH:9]1[C:17]2([CH3:18])[CH:12]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16]2)[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CCCC(C)C1CCC2C(O)CCCC12C
Agent: Cl[Ru](Cl)Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)CCCC(C)C1CCC2C(=O)CCCC21C
Temperature: 45 °C
Reaction time: 68 h

Procedure:
[1R-(1β(R*),3aα,7aβ)] octahydro-1-(1,5-dimethylhexyl)-7a-methyl-4H-inden-4-ol (2.66 g, 0.01 mol) (prepared as described in Inhoffen et al., F. Chem. Ber. 1957, 90.664), sodium metaperiodate (7.48 g), ruthenium (III) chloride hydrate (0.207 g, 10 mol %), carbon tetrachloride (40 ml), acetonitrile (40 ml) and pH 7.0 buffer (monobasic potassium phosphate-sodium hydroxide, 0.05M in water) (52 ml) were stirred vigorously by mechanical stirring for 68 hours at 45° C. After this period, 30 ml water was added and this was extracted with methylene chloride (2×40 ml). The extracts were combined, dried over magnesium sulfate and evaporated. Flash chromatography (hexanes -EtOAc=20:1, later 4:1) afforded 0.73 g (26%) of [1R-(1β(R*), 3aα, 7aβ)]octahydro-1-(1,5-dimethylhexyl)-7a-methyl-4H-inden-4-one, the compound of formula III, and 1.15 g (41%) of [1R-(1β(R*), 3aα, 4β, 7aβ)]octahydro-1-(5-hydroxy-1,5-dimethylhexyl)-7a-methyl-4H-inden-4-one, the compound of formula I, as a pale yellow oil which solidifies upon standing in the freezer.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][C@@H:7]([C:11]([NH:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])[CH2:6]1)(=[O:4])=[O:3].[CH:21](/[S:29](Cl)(=[O:31])=[O:30])=[CH:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([S:29](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[C@@H:7]([C:11]([NH:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[O:12])[CH2:6]1)(=[O:3])=[O:4]
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: CS(=O)(=O)N1CCN[C@@H](C(=O)NOC2CCCCO2)C1
Product: CS(=O)(=O)N1CCN(S(=O)(=O)/C=C/c2ccccc2)[C@@H](C(=O)NOC2CCCCO2)C1
Yield: 66.1 %

Procedure:
(2R)-4-Methanesulfonyl-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (266 mg) and trans-β-styrenesulfonyl chloride (210 mg) were used to give 271 mg of (2R)-4-methanesulfonyl-1-(2-phenyl-2-trans-ethenylsulfonyl)-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as amorphous powder in substantially the same manner as in Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:24]([O:23][C:21]([C:20]1[C:19]([CH3:26])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:7]=[CH:8][CH:9]=2)=[O:22])[CH3:25]
Reactant: N#Cc1c(N)cccc1OCC1CCCCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclohexylmethoxy)benzonitrile (Example 115b) and ethyl 3-oxobutanoate as a pale yellow solid (47%). 1H NMR (400 MHz, MeOD) δ 1.12-1.37 (m, 6H), 1.42 (t, J=4.0 Hz, 3H), 1.73-2.01 (m, 5H), 2.68 (s, 3H), 4.06 (d, J=4.0 Hz, 2H), 4.42 (q, J=8.0 Hz, 2H), 6.96 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.0
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1([CH2:35][OH:36])[CH2:34][O:33][CH2:32]1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][C:31]2([CH2:35][OH:36])[CH2:34][O:33][CH2:32]2)[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: OCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)COC2)c1OC
Temperature: 80 °C
Yield: 18.7 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.268 mmol) in acetonitrile (7 mL) was added potassium carbonate (111 mg, 0.80 mmol) and (3-(bromomethyl)oxetan-3-yl)methanol (97 mg, 0.536 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (20 mg, 19%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:14][O:15][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCC1(c2ccc(F)cc2)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COCC1(c2ccc(F)cc2)CCCCC1
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
A solution of (1-(4-fluorophenyl)cyclohexyl)methanol (Intermediate I-10A, 108.5 mg, 0.52 mmol) in toluene 91 mL) was cooled to 0° C. A 5N aq. sodium hydroxide solution (500 μL) was added followed by tetra-n-butyl ammonium hydrogen sulfate (44 mg, 0.13 mmol) and stirring was continued for 30 min at 0° C. Tert-butyl bromoacetate (152 mg, 0.78 mmol) was added, the ice bath was removed, and stirring was continued for 2 hrs. The reaction mixture was diluted with ethyl acetate and water. The organic extract was separated, washed with water and brine, dried over sodium sulfate and concentrated in vacuo to obtain a colorless oil, which was purified by flash chromatography on silica gel (Teledyne-Isco REDISEP® 12 g silica gel column). Elution with hexanes (50 mL), followed by 1% and 3% EtOAc in hexanes (100 mL each) afforded tert-butyl 2-((1-(4-fluorophenyl)cyclohexyl)methoxy)acetate (100 mg, 60% yield) as a viscous oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.46 (2H, m), 6.92-7.09 (2H, m), 3.78 (2H, s), 3.39 (2H, s), 2.09 (2H, d, J=15.31 Hz), 1.67-1.86 (2H, m), 1.47-1.59 (4H, m), 1.44 (9H, s), 1.31-1.38 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].B(F)(F)F.CCOCC.[CH3:19][C:20]1([CH:26]=[CH2:27])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>O1CCOCC1.CCOCC>[CH3:19][C:20]1([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:26][CH2:27][C:4]2[C:3](=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][CH:5]=2)[O:9]1
Reactant: Cc1cccc(O)c1C
Reactant: C=CC1(C)CCC(=O)O1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc2c(c1C)OC(C)(CCC(=O)O)CC2
Temperature: 25 °C

Procedure:
To a solution of 2,3-dimethylphenol (0.01 mol) and boron trifluoride diethyl etherate (0.016 mol) in dioxane (10 mL, dried on sodium) in a flask was added γ-methyl-γ-vinylbutyrolactone (0.016 mol) in dioxane (5.0 mL) via syringe pump over 50 min at 110° C. (oil bath, reflux) under nitrogen. The reaction mixture was cooled to room temperature and diluted with ether (200 mL), then washed with water (100 mL, 2×50 mL) and dried over sodium sulfate. Ether was then removed in vacuum. The residue was dissolved in methanol (30 mL), and solvent was removed in vacuum. The reaction mixture was purified by flash column chromatography on silica gel (eluant ethyl acetate/hexane, 1:1). Fractions containing the desired chroman were pooled, solvent was removed, and the compound was crystallized from ethyl acetate/hexane. M.P.: 93-94° C.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:16]3[CH:24]4[CH:19]([N:20]([C:25]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:26])[CH2:21][CH2:22][CH2:23]4)[CH2:18][CH2:17]3)[C:10]=2[CH:9]=[CH:8]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([N:16]2[CH:24]3[CH:19]([N:20]([C:25]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:26])[CH2:21][CH2:22][CH2:23]3)[CH2:18][CH2:17]2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(N3CCC4C3CCCN4C(=O)OCc3ccccc3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCCC2C1CCN2c1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the product of Step 2 (2.77 g, 5.46 mmol) in DCM (28 mL) was added TFA (28 mL). The resulting solution was stirred for 1 hour at room temperature. Heptanes were then added, and the mixture was concentrated in vacuo, azeotroping with DCM and heptanes until a constant weight was achieved. The resulting oil was taken up into acetonitrile (28 mL), and ammonium hydroxide (28 mL) was added. The solution was stirred at ambient temperature for approximately 5 minutes, then the reaction mixture was scratched with a glass pipette in order to promote crystallization. The reaction mixture was stirred for approximately 19 hours before being heated at 50° C. for 1 hour. The reaction mixture was cooled, and diluted with water (28 mL). The solids were filtered and the filter cake was rinsed with water and dried under high vacuum until constant weight was achieved to afford the desired product as an off-white solid. LRMS calc'd for C21H24N5O2 [M+H]+, 378; found 378. 1H NMR (500 MHz, DMSO-D6) δ 11.6 (s, 1H), 8.06 (s, 1H), 7.40-7.28 (br m, 5H), 7.10 (s, 1H), 6.52 (s, 1H), 5.13-5.07 (m, 2H), 4.61 (br s, 1H), 4.32 (br s, 1H), 3.98-3.64 (br m, 3H), 2.98-2.80 (m, 1H), 2.36-2.12 (br m, 2H), 2.04 (br m, 1H), 1.64 (br m, 1H), 1.50-1.22 (br m, 2H). Jak1 activity: ++.
Reaction SMILES: [CH2:1]([N:12]([CH2:17][C:18]([O-:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[CH2:2][N:3]([CH2:8][C:9]([O-:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6].[Na+].[Na+].[NH2:23][CH2:24][C:25]([OH:27])=[O:26].[O:28]=[CH:29][C@@H:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])[OH:31]>O>[CH2:2]([N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6])[CH2:1][N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15].[NH2:23][CH2:24][C:25]([OH:27])=[O:26].[O:28]=[CH:29][C@@H:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])[OH:31]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: NCC(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: O
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Yield: 1 %

Procedure:
A 10% (volume/volume) Tween 80 solution prepared by adding 10 ml Tween 80 to 90 ml H2O. A 1% (weight/volume) EDTA solution was prepared by adding 1 g Na2EDTA to 100 ml H2O. A 0.1 M glycine solution was prepared by adding 1.5 g glycine (M.W. 75) to 200 ml H2O. A 0.5% (w/v) hydroxypropyl-methyl-cellulose (HPMC, 100 centipoise) solution was prepared by adding 1 g HPMC to 200 ml H2O and gently mixing until fully dissolved. A 250 unit/ml GOX (Type VII from Aspergillus niger, Sigma Chemicals) was prepared in H2O. A 0.1 M glucose solution was prepared by adding 1.8 g D-glucose (M.W. 180) to 100 ml H2O.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)=O.B.CSC.CO.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:15][CH2:16]1
Reactant: COc1ccccc1N1CCN(C(=O)Cc2ccccc2Br)CC1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccccc1N1CCN(CCc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
A stirred solution of the product of Example 1 (25.7 g, 66.1 mmol) in dry tetrahydrofuran (THF, 100 ml) was heated under reflux under an atomosphere of argon, treated dropwise over 25 min with borane-dimethylsulphide (12.5 ml, 131.7 mmol) in THF (100 ml), after 90 min cooled to room temperature, and the suspension treated dropwise with methanol (100 ml), followed by concentrated hydrochloric acid (50 ml). The solution was stirred for 1 h and the precipitate filtered and washed with acetonitrile (20 ml) and ether (3×20 ml) to give the product (15.7 g) m.p. 190°-195°.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH:13]([CH3:28])[C:14]([NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=O)=[CH:4][CH:3]=1.B#B>O1CCCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH:13]([CH3:28])[CH2:14][NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)Oc2ccc(Cl)c3ccccc23)cc1
Agent: B#B
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NCC(C)Oc2ccc(Cl)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cold, stirred solution of ethyl p-[2-(4-chloro-1-naphthyloxy)propionamido]benzoate (9.5 g.) in 100 ml. dry tetrahydrofuran is added slowly 35 ml. of 1 M diborane in tetrahydrofuran. The reaction mixture is stirred at room temperature for 20 minutes, then refluxed for 31/2 hours. The mixture is poured onto 500 ml. of ice, giving a cloudy solution. After saturating this solution with sodium chloride, it is extracted twice with ether and twice with chloroform. The combined organic phases are dried and flash-evaporated to a yellow oil. The oil is dissolved in a small amount of ethyl acetate and hexane and purified on a column of silica gel, giving a white powder, m.p. 122° C.