Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>ClCCl.O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:7][CH2:6][CH2:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CC(C)OCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OCCOS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 148 %

Procedure:
To a solution of 2-isopropoxy-1-ethanol (1.5 g, 14.4 mmol) and triethylamine (2.2 g, 21.6 mmol) in dichloromethane (20 mL) at 0° C. was added 4-bromobenzenesulfonyl chloride (2.12 g, 8.36 mmol) in dichloromethane (10 mL) dropwise over 30 minutes. The reaction was then warmed to room temperature and stirred for 16 hours. The mixture was then poured into water (50 mL) and acidified with 2N aqueous hydrochloric acid (15 mL). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude residue. This was purified by column chromatography on silica gel (50 g), eluting with hexane:ethyl acetate (9:3), to give the title compound (4.0 g, 86%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H](C3C=CC=CC=3)C)[CH2:9]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+].CO.O>O1CCCC1.[Pd]>[NH:10]1[CH2:11][CH2:12][O:13][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH2:9]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccc([C@H]2CNCCO2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of (2S)-2-(4-aminophenyl)-4-((1R)-1-phenylethyl)morpholine (17.45 g, 61.8 mmol) and ammonium formate (11.7 g, 185.4 mmol) in a mixture of tetrahydrofuran (180 ml), methanol (180 ml) and water (45 ml) was added 10% palladium on carbon (wet, 1.8 g) and the solution was stirred at 95° C. for 3 hours. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give 4-((2S)-morpholin-2-yl)phenylamine (10.45 g, 95%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12](O)=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)Cl.[C:25]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>O1CCCC1>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:12]2[C:11]3[CH:18]=[CH:19][C:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)=[CH:9][C:10]=3[S:14](=[O:16])(=[O:15])[N:13]=2)=[CH:34][CH:35]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC2=NS(=O)(=O)c3cc(-c4ncccc4Cl)ccc32)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A suspension of the product of Example 1B (0.1507 g, 0.51 mmol) in POCl3 (4.0 mL, 42.9 mmol) was stirred at 90° C. for 90 minutes, cooled to room temperature and excess POCl3 was removed under vacuum. The resulting residue was treated with 4-tert-butylaniline (0.1027 g, 0.69 mmol) in tetrahydrofuran (3 mL), followed by the addition of a solution of triethylamine (0.25 mL, 1.79 mmol) in tetrahydrofuran (2 mL), and stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO3 (5 mL) and diluted with dichloromethane (5 mL). The isolated aqueous phase was extracted with dichloromethane (2×10 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated. The residue was purified by silica gel column chromatography, eluted with ethyl acetate/dichloromethane to afford the title compound. MS (ESI+) m/z 426 (M+H)+; (ESI−) m/z 424 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 1.32 (s, 9H), 7.55 (m, 3H), 7.79 (m, 2H), 8.16 (dd, J=8.3, 1.5 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.30 (s, 1H), 8.60 (d, J=8.1 Hz, 1H), 8.71 (dd, J=4.7, 1.4 Hz, 1H), 10.94 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[NH2:19][CH2:20][CH:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:22]([NH:24][CH3:25])=[O:23].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:19][CH2:20][CH:21]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[C:22]([NH:24][CH3:25])=[O:23])=[CH:3][C:4]=1[NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=1)#[N:9]
Reactant: CNC(=O)C(CN)NC(=O)OC(C)(C)C
Reactant: Cc1cc(C)nc(Nc2cc(Br)cnc2C#N)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)C(CNc1cnc(C#N)c(Nc2cc(C)cc(C)n2)c1)NC(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
Dioxane (1.65 ml) was added to a nitrogen purged flask containing 5-bromo-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile (PrepEx 1.4) (100 mg, 0.330 mmol), tert-butyl 3-amino-1-(methylamino)-1-oxopropan-2-ylcarbamate (72 mg, 0.33 mmol), Xantphos (19 mg, 0.033 mmol), Pd2(dba)3 (24 mg, 0.026 mmol) and cesium carbonate (215 mg, 0.660 mmol). Nitrogen was bubbled through the reaction mixture for 5 minutes. The reaction vessel was then sealed and heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered through CELITE, and the filter cake was washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% methanol/ethyl acetate, linear gradient) to afford tert-butyl [3-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)-1-(methylamino)-1-oxopropan-2-yl]carbamate. MS ESI calc'd. for C22H30N7O3 [M+H]+ 440. found 440.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:32][C:33]1[O:37][C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:35][CH:34]=1>O>[C:8]1([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][C:22]3[N:23]([CH2:32][C:33]4[O:37][C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:35][CH:34]=4)[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:19][CH2:20]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ccccc32)o1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To 470 parts of N,N-dimethylformamide were added portionwise 17.3 parts of a dispersion of sodium hydride in mineral oil (50%) and 91.6 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole (as prepared in Example 16 of U.S. Pat. No. 4,695,575) while stirring under a nitrogen atmosphere. After stirring for 1 hour, 67.9 parts of ethyl 5-chloromethyl-2-furancarboxylate were added dropwise while cooling. Stirring was continued for 1 hour and then water was added to the reaction mixture. The product was extracted with methylbenzene and the extract was washed with water, dried, filtered and evaporated. The residue was dried azeotropically with methylbenzene (2x), yielding 119 parts (86.7%) of ethyl 5-[[2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazol-1-yl]methyl]-2-furancarboxylate (interm. 4). Following the same procedure and starting from the appropriate starting materials, there were also prepared:
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:17])=[CH:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([OH:13])[C:9]([CH3:14])=[C:8]([CH3:15])[C:7]=1[OH:16].FC(F)(F)S(O)(=O)=O.O>C(Cl)(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1([CH3:17])[CH2:4][CH2:5][C:6]2[C:7](=[C:8]([CH3:15])[C:9]([CH3:14])=[C:10]([OH:13])[C:11]=2[CH3:12])[O:16]1
Reactant: CC(=CCc1c(C)c(O)c(C)c(C)c1O)CCl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCl)O2
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
2-(1-Chloro-2-methylbut-2-en-4-yl)-1,4-dihydroxy-3,5,6-trimethylbenzene (4.2 g, 16 mol) was suspended in carbon tetrachloride (200 ml). Trifluoromethanesulfonic acid (1.44 ml, 2.44 g, 16 mmol) was then added and the reaction mixture was stirred. After 30 min., water (100 ml) was added and the mixture was extracted with methylene chloride (100 ml). The organic phase was dried (MgSO4) and concentrated. This gave crude 2-chloromethyl-6-hydroxy-2,5,7,8-tetramethylchroman (5.3 g). Recrystallization from hexane (40 ml) gave 2.7 g (64 percent) of pure 2-chloromethyl-6-hydroxy-2,5,7,8-tetramethylchroman. The melting point of the product was 77 to 82° C. Other data regarding the product was:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH:11]=2)[C:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:5]1[CH2:33][C:34]([CH3:39])([CH3:38])[C:35]([OH:37])=[O:36])[CH:2]=[CH2:3]>CCOC(C)=O.[Pd]>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH:11]=2)[C:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[C:5]1[CH2:33][C:34]([CH3:38])([CH3:39])[C:35]([OH:37])=[O:36])[CH2:2][CH3:3]
Reactant: C=CCn1c(CC(C)(C)C(=O)O)c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCn1c(CC(C)(C)C(=O)O)c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
A solution of methyl 3-[N-allyl-3-(4-chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (Example 42, methyl ester) (190 mg) was hydrogenated in EtOAc (4 mL) in the presence of 5% Pd on charcoal at atmospheric pressure for 1 hour. Filtration on Celite pad and evaporation of liquors afforded the methyl ester of the title product. Hydrolysis of this ester under the conditions described in Step B of Example 1 provided the title compound. Anal. C, H, N for sodium salt·11/2H2O Calc. C 67.17; H 5.98; N 4.75 Found C 67.38; H 5.44; N 4.85.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:31]=[C:32]([C:36](=[O:38])[CH3:37])[CH:33]=[CH:34][CH:35]=1>>[C:36]([C:32]1[CH:31]=[C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)c1cccc(Br)c1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cccc(C(C)=O)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (140 mg, 0.36 mmol) is coupled to 3′-bromoacetophenone (85 mg, 0.43 mmol) using Method B to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[O-]CC.[Na+].[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:17][CH:16]([O:19][CH2:20][CH3:21])[O:15][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: CCOC(CBr)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(CSc1ccc(Br)cc1)OCC
Temperature: 55 °C
Yield: 96.5 %

Procedure:
1-Bromo-4-[(2,2-diethoxyethyl)thio]benzene (Chemical Abstracts number 96804-05-6) was prepared as described in Banfield et al.; J. Chem. Soc.; 1956; 2603-2607, and in Amin, et al.; J. Chem. Soc. Perkin Trans. 2; 1982; 1489-1492. 4-Bromothiophenol (20 g, 95%) in ethanol (80 mL) was treated with 21 wt % of sodium ethoxide in ethanol (36 g, 1.05 eq). The solution was heated at 55° C. for 30 minutes and bromoacetaldehyde diethylacetal (22.56 g, 1.05 eq) was added. The mixture was heated at reflux for 10 hours, ethanol was removed and the residue was diluted with 80 mL of water. The product was extracted with 2×120 mL of ethyl acetate. The combined ethyl acetate layer was washed with 2×40 mL of 15% NaCl and concentrated under vacuum to a brown oil (32.0 g, 92.5% potency, 96.5% yield). The product can be further purified by column chromatography (silica gel, 5:95 EtOAc:hexane).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:42]([O:46][C:47](=[O:58])[C@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=1)[NH2:49])([CH3:45])([CH3:44])[CH3:43]>C(#N)C>[CH2:4]([O:3][C:1]([NH:11][C@@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:17]([NH:49][C@@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][CH:52]=1)[C:47]([O:46][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:58])=[O:19])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of N-carbobenzyloxy-L-leucine (8.6 g) in acetonitrile (150 ml), under a nitrogen atmosphere, was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.83 g) and 1-hydroxybenzotriazole (4.81 g). After stirring for 30 mins at 20° C. L-tyrosine tert-butyl ester (7.7 g) was added and stirring was continued for 18 h. The mixture was concentrated in vacuo to ca. 10 ml and the residue was partitioned between 1M hydrochloric acid (300 ml) and ethyl acetate (150 ml). The layers were separated and the aqueous phase was further extracted with ethyl acetate (150 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (150 ml), water (2×150 ml) and brine (100 ml), dried over sodium sulphate and evaporated in vacuo. The residue was co-evaporated with chloroform to give the title compound as a white foam (15 g, 96%). LCMS: Rt 3.56 min; m/z 485 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O>N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CO)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
Chromium trioxide (2.4 g) is added in portions to pyridine (29 mL) to maintain the temperature between 0°–10° C. A yellow suspension is formed. A solution of (4-hydroxymethylphenyl)carbamic acid tert-butyl ester (1.8 g) in pyridine (29 mL) is added dropwise to the yellow suspension. The reaction mixture is warmed to room temperature and stirred for 30 minutes. The reaction mixture is poured into water and extracted twice with ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on silica gel (4:1 ethyl acetate/hexane used as eluant) to give 1.09 g product as a white solid. MS: m/z 222 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]([O:20]CC)=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.CO.[OH-].[Na+].Cl>O.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]([OH:20])=[O:19])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Temperature: 70 °C
Yield: 79.8 %

Procedure:
Ethyl 6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxylate (394 mg, 1.09 mmol) was dissolved into MeOH (10 mL) and THF (10 mL) and then 1M aqueous NaOH (7.5 mL, 7.50 mmol) was added and the reaction was heated at 70° C. for 1 h. The reaction was treated with aqueous 1M HCl (8 mL) (white prec. formed), cooled to rt, diluted with water (30 ml) and filtered to collect the precipitate (rinsed with water). The solid was dried overnight under vacuum to yield 6-bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxylic acid (290 mg, 0.87 mmol, 80% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 13.40 (br s, 1H), 9.53 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.78 (d, J=9.5 Hz, 1H), 7.73 (dd, J=9.5, 1.5 Hz, 1H), 7.30 (d, J=8.9 Hz, 1H), 7.28 (d, J=8.9 Hz, 1H). LC-MS retention time 0.94 min; m/z 334, 336 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% acetonitrile/90% H2O/0.1% TFA and solvent B was 10% H2O/90% acetonitrile/0.1% TFA. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C:20](=[CH:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4][OH:5].[C:26](OCC(F)(F)F)(=[O:30])[CH2:27][CH2:28][CH3:29]>CC(C)=O>[OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C:20](=[CH:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4][O:5][C:26](=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(=O)OCC(F)(F)F
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Solvent: CC(C)=O
Product: CCCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C

Procedure:
A mixture of 1 g (2.879 mM) of 17α,21-dihydroxy-pregna-4,9(11)-diene-3,20-dione and 10 ml of trifluoroethyl butanoate in 100 ml of acetone was reacted at 45° C. in the presence of 5 g of Candida cylindracea lipase for 8-10 hours, adding 1 g of lipase at regular time intervals. After completion of the reaction, the lipase was filtered off and the filtrate was concentrated under vacuum, taking up the residue three times with acetone. The semi-solid residue was purified by chromatography on a silica gel column with a dichloromethane/methanol 99:1 mixture. The less polar components were removed, to obtain the richer fraction which was evaporated to yield 0.95 g (2.29 mM) of 17α-hydroxy-21-butanoyloxy-pregna-4,9(11)-diene-3,20-dione.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[C:13]([CH2:15][C@:16]4([CH3:22])[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]4[C@@H:11]3[CH2:10][CH2:9][C:8]1=[CH:7][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:14]>O1CCOCC1.Cl>[CH3:22][C@:16]12[CH2:15][C:13](=[O:14])[C@H:12]3[C@@H:11]([CH:10]=[CH:9][C:8]4[C@:2]3([CH3:1])[CH2:3][CH2:4][C:5](=[O:6])[CH:7]=4)[C@@H:17]1[CH2:18][CH2:19][C:20]2=[O:21]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Solvent: C1COCCO1
Product: C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 1.5 h

Procedure:
Adrenosterone (androst-4-ene-3,11,17-trione, A-1, 50 g, 166.7 mmol) was dissolved in dioxane (1200 mL, dry), which had been saturated with HCl gas at 10° C. under argon, and a chilled solution of 2,3-dichloro-5,6-dicyanoquionone (DDQ, 50 g, 220 mmol) in hydrogen chloride saturated dioxane (450 mL) was added slowly to the stirred solution. Solid dihydro-DDQ rapidly separated from the solution. After 1.5 h, the mixture was filtered through a sintered glass funnel, most of the dioxane was evaporated under reduced pressure and the residue was chromatographed over silica gel (1000 g) using chloroform as the eluting solvent. The light-yellowish material from evaporation of the eluate was 48.7 g of the dienone compound A-2: mp 237° C.; UV (MeOH) λmax 278 nm (ε 24,600); IR (CHCl3) 1745 (17-C=0), 1705 (11-C=0) and 1650 (3-conjugated C=0)cm-1 ; 1H NMR (CDCl3) δ 0.9(s,3, 18-CH3), 1.32 (s, 3, 19-CH3), 5.63 (s, 1, 4-H) and 6.13 (s, 2, 6- and 7-H); m/z 298 (M+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([C:8]1[C:32]([F:33])=[CH:31][C:11]([N:12](CC2C=CC(OC)=CC=2)CC2C=CC(OC)=CC=2)=[CH:10][C:9]=1[F:34])([CH3:7])[CH3:6])[CH3:2].Cl>CO.[C].[Pd]>[CH2:1]([O:3][CH2:4][C:5]([C:8]1[C:9]([F:34])=[CH:10][C:11]([NH2:12])=[CH:31][C:32]=1[F:33])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOCC(C)(C)c1c(F)cc(N(Cc2ccc(OC)cc2)Cc2ccc(OC)cc2)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOCC(C)(C)c1c(F)cc(N)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
A mixture of 4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoro-N,N-bis(4-methoxybenzyl)aniline (8.51 g, 18.12 mmol), 1N hydrochloric acid (36.2 mL) and 10% palladium-carbon (1.929 g, 0.91 mmol, 50%, wet) in MeOH (164 mL) under hydrogen atmosphere (4 atm), and the mixture was stirred at room temperature for 1.5 hr. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, and the solution was washed with 1N aqueous sodium hydroxide solution and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→20% ethyl acetate/hexane) to give 4-(1-ethoxy-2-methylpropan-2-yl)-3,5-difluoroaniline (3.87 g, 16.88 mmol, 93%) as a white solid.
Reaction SMILES: CO.[CH3:3][NH2:4].[C:5]([C:7]1[CH:8]=[C:9]([S:13](Cl)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1)#[N:6]>>[NH2:6][CH2:5][C:7]1[CH:8]=[C:9]([S:13]([NH:4][CH3:3])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1
Reactant: CN
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CO
Product: CNS(=O)(=O)c1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(Step 1) To a 40% methylamine methanol solution (5 ml) was added 3-cyanobenzenesulfonyl chloride (0.88 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure, saturated brine was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure. 10% Palladium carbon powder (0.46 g) was added to a solution (10 ml) of the residue in ethanol, and the mixture was stirred overnight under a hydrogen atmosphere (1 atm). The solution was filtered through celite. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) to give 3-(aminomethyl)-N-methylbenzenesulfonamide (0.38 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:13]([N:15]2[CH2:20][C:19](=O)[CH2:18][CH2:17][CH:16]2[CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:36][NH2:37]>>[CH3:1][C:2]1[S:3][C:4]([C:13]([N:15]2[CH2:20][CH:19]([NH:37][CH3:36])[CH2:18][CH2:17][CH:16]2[CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])=[O:14])=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: Cc1nc(-c2ccccc2)c(C(=O)N2CC(=O)CCC2CNC(=O)c2cccc3cccnc23)s1
Reactant: CN
Product: CNC1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2sc(C)nc2-c2ccccc2)C1

Procedure:
N-((1-(2-Methyl-4-phenylthiazole-5-carbonyl)-5-(methylamino)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((1-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and methyl amine. (ESI) 500 (M+H).