Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](C=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[CH2:30]1[CH2:43][O:42][C:37]23[O:38][CH2:39][CH2:40][O:41][C:32]2([C@:33]2([CH2:56][CH2:55][C@H:54]4[C@@H:44]([CH2:45][C:46](=[CH2:57])[CH:47]5[C@:52]4([CH3:53])[CH2:51][CH2:50][CH2:49][CH2:48]5)[C@@H:35]2[CH2:36]3)[CH3:34])[O:31]1>>[CH2:40]1[CH2:39][O:38][C:37]23[O:42][CH2:43][CH2:30][O:31][C:32]2([C@:33]2([CH2:56][CH2:55][C@H:54]4[C@@H:44]([CH2:45][C@H:46]([CH:57]=[CH2:1])[CH:47]5[C@:52]4([CH3:53])[CH2:51][CH2:50][CH2:49][CH2:48]5)[C@@H:35]2[CH2:36]3)[CH3:34])[O:41]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCCCC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C=C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Yield: 70 %

Procedure:
17,17-Bis(ethylendioxy)-6α-vinylandrostane was prepared in 70% yield from 3,3:17,17-bis(ethylendioxy)-6α-formylandrostane (Prepn. 14) by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane (Prepn. 13). The crude was purified by flash chromatography (SiO2, n-hexane/EtOAc 88/12). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.47 (1H, m), 4.91 (2H, m), 3.94-3.73 (8H, m), 2.00-0.67 (21H, m), 0.88 (3H, s), 0.83 (3H, s).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].Cl>N1C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([S:27]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:28])=[O:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.2 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.43 g of 3,4-dimethoxy-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the organic phase was separated and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated as an oil upon neutralization and was thereupon treated once more with active charcoal. The product separated upon renewed neutralization with concentrated hydrochloric acid. Recrystallization from 25 ml of 60% ethanol yielded 0.12 g of 3,4-dimethoxy-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as colourless crystals.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)(=[O:37])=[O:36])[CH:30]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:38]1([S:35]([C:31]2[CH:30]=[C:29]([CH2:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][CH2:2][C@@H:3]([C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[OH:4])[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: O=S(=O)(c1cccc(CCCCOCCCCCCBr)c1)C1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCCCCCOCCCCc2cccc(S(=O)(=O)C3CCCC3)c2)ccc1O
Temperature: 25 °C
Reaction time: 113 h

Procedure:
N-{5-[(1R)-2-Amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide (33.2 mg) was added to a solution of 1-{4-[(6-bromohexyl)oxy]butyl}-3-(cyclopentylsulfonyl)benzene (Example 1v.) (50 mg) in DMF (5 ml). The reaction mixture was treated with N,N-diisopropylethylamine (29.3 μl) and stirred at room temperature for 113 h. The reaction mixture was partitioned between EtOAc and water and the organic extracts were washed with ammonium chloride, dried (MgSO4) and concentrated in vacuo. The residue was purified by column DCM) to afford the title compound. LCMS RT=2.73 min 610(M+H)+
Reaction SMILES: [CH3:1][N:2]([C:11](SC)=[N:12][C:13](=O)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:3]=CC1C=CC=CC=1.[CH3:22][N:23]([CH3:30])[CH2:24][C:25]1[O:26][CH:27]=[CH:28][CH:29]=1>C(#N)C>[CH3:22][N:23]([CH2:24][C:25]1[O:26][C:27]([CH2:18][S:15][CH2:14][CH2:13][NH:12][C:11]2[N:2]([CH3:1])[N:3]=[C:13]([CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[N:12]=2)=[CH:28][CH:29]=1)[CH3:30]
Reactant: CSC(=NC(=O)CS(C)(=O)=O)N(C)N=Cc1ccccc1
Reactant: CN(C)Cc1ccco1
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCNc2nc(CS(C)(=O)=O)nn2C)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 135.2 %

Procedure:
Methyl 1-methyl-N-[(methylsulphonyl)acetyl]-2-(phenylmethylene)hydrazinecarboximidothioate (1.05 g) and 5-[[2-aminoethyl)thio]methyl]-N,N-dimethylfuranmethanamine (0.85 g)in acetonitrile (3 ml) were heated on a steam bath at atmospheric pressure for 5 minutes then under water vacuum for 10 minutes. The oily residue was dissolved in acetonitrile (3 ml) and the solution re-evaporated under water vacuum. The oily residue was dissolved in 2N hydrochloric acid (3 ml) and 5N hydrochloric acid (4 ml) added to the solution. The solution was heated on a steam bath for 15 minutes and after cooling to room temperature, water (10 ml) was added and the oily suspension extracted with ethyl acetate. The aqueous phase was basified with sodium carbonate and the oily suspension extracted with ethyl acetate to yield an oil (0.84 g). This was chromatographed (using solvent system D) to give the title compound (0.78 g) as an oil. T.l.c. System D, Rf 0.5.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=1)=O.[NH2:27][C:28]([NH2:30])=[S:29]>C(O)C.C(Cl)(Cl)Cl>[NH2:30][C:28]1[S:29][CH:2]=[C:3]([C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:7]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:6]=2)[N:27]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)CBr)sc2-c2ccc(F)cc2)cc1
Reactant: NC(N)=S
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2cc(-c3csc(N)n3)sc2-c2ccc(F)cc2)cc1
Yield: 32.6 %

Procedure:
A mixture of 5-(bromoacetyl)-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (2 g) and thiourea (0.61 g) in ethanol (80 ml) was refluxed for 30 minutes. The mixture was dissolved in chloroform, washed with an aqueous solution of sodium bicarbonate and water, dried, and concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and acetone (10:1) to give pale yellow crystals to 5-(2-amino-4-thiazolyl)-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (0.62 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[C:14]3[CH:13]=[C:12]([F:16])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:17][CH3:18])[C:7]=2[C:6](=[O:19])[N:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:4]=1.[C-:26]#[N:27].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[CH2:17]([N:8]1[C:9]2[CH:10]=[CH:11][C:12]([F:16])=[CH:13][C:14]=2[C:15]2[C:3]([CH2:2][C:26]#[N:27])=[N:4][N:5]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6](=[O:19])[C:7]1=2)[CH3:18]
Reactant: [C-]#N
Reactant: CCn1c2ccc(F)cc2c2c(CBr)nn(-c3ccccc3)c(=O)c21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCn1c2ccc(F)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Yield: 93.3 %

Procedure:
A two-phase mixture of 7.2 g (18 mmol) of 1-(bromomethyl)-5-ethyl-8-fluoro-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one, of 3.53 g (72 mmol) of sodium cyanide and of 0.58 g (1.8 mmol) of tetrabutylammonium bromide in 300 ml of dichloromethane and 150 ml of water is stirred vigorously for 12 h. The organic phase is separated, washed several times with water, dried over magnesium sulphate and concentrated under reduced pressure. 5.8 g (16.8 mmol) of compound are isolated, which compound is used as is in the following stage.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].CC1NC=NC=1CSC[CH2:21][NH:22][C:23]1[C:27](OC)=[N:26][S:25](=[O:30])[N:24]=1.CN>>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:27]1[C:23]([NH:22][CH3:21])=[N:24][S:25](=[O:30])[N:26]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: COC1=NS(=O)N=C1NCCSCc1nc[nH]c1C
Agent: CN
Product: CNC1=NS(=O)N=C1NCCSCc1nc[nH]c1C

Procedure:
A solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide obtained from the above Step A is reacted with an equimolar amount of 2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine and the resulting 3-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole 1-oxide is treated with an excess of methylamine, and the title compound is thereby produced.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.I[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([S:37][CH3:38])[N:32]=1>C1(C)C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([S:37][CH3:38])[N:32]=3)[C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]2)=[CH:14][CH:15]=3)=[CH:6][CH:7]=1
Reactant: CSc1nccc(I)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]c(-c4ccc(F)cc4)nc3n2)CC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
KN(TMS)2 (812 mg, 3.85 mmol) in toluene (3.85 ml) is added at 0° C. to a solution of 2-(4-Fluorophenyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl)imidazo[4,5-b]pyridine (1.4 g, 3.5 mmol) in DMF (7 ml). After stirring at room temperature for 30 min., 4-iodo-2-methylthiopyrimidine (970 mg, 3.85 mmol) in toluene (3.85 ml) is added and the reaction stirred at room temperature for 1 h. Toluene is evaporated, the reaction mixture heated to 120° C. for 18 h, poured on water and extracted with ethyl acetate (containing 5% EtOH) three times. The combined organic phases are washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Purification over SiO2 (acetone/hexanes 20/80) renders the title compound (950 mg, 52%) as colorless foam.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([N:5]1[CH2:6][CH2:7][CH:8]([CH2:11][C:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)N1CCC(CC(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)N1CCC(CC(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a mixture of (1-tert-butyl-piperidin-4-yl)-acetic acid (672 mg, 3.37 mmol), aniline (0.32 ml, 3.5 mmol), and HOBt (568 mg, 4.2 mmol) in DMF (20 ml), EDC (805 mg, 4.2 mmol) was added. It was stirred at r.t. for 2 hours and partitioned between water (200 ml) and ethyl acetate (200 ml). The organic phase was washed with 0.5 N aq. NaOH (2×50 ml) and brine (3×50 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on (SiO2, gradient heptane-ethyl acetate) to give 250 mg of the title compound. 1H NMR (500 MHz, DMSO-d6): 1.07 (s, 9H), 1.32 (br. m, 2H), 1.81 (br. d, 2H), 1.89 (m, 1H), 2.11 (br. t, 2H), 2.25 (d, 2H), 3.03 (br. d, 2H), 7.1 (t, 1H), 7.24 (br., 1H), 7.31 (t, 2H), 7.52 (d, 2H).
Reaction SMILES: [C:1]1([CH:7]2[C:12]3[C:13]([C:16]([O:18]CC)=[O:17])=[N:14][O:15][C:11]=3[CH2:10][CH2:9][N:8]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[Li].O>C(O)C.O>[C:24]([O:23][C:21]([N:8]1[CH2:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]([OH:18])=[O:17])[C:12]=2[CH:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1noc2c1C(c1ccccc1)N(C(=O)OC(C)(C)C)CC2
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2onc(C(=O)O)c2C1c1ccccc1

Procedure:
5-tert-Butyl 3-ethyl 4-phenyl-6,7-dihydroisoxazolo[4,5-c]pyridine-3,5(4H)-dicarboxylate (1.75 mmol) was hydrolyzed to corresponding acid by using LiOH.H2O (1.5 eq.) as a base in ethanol-water (10 ml, 4:1). Yield: quantitative.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3S[CH2:7][C:6]2=1.O[O:22][S:23]([O-:25])=O.[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[S:23](=[O:25])(=[O:22])[CH2:7][C:6]2=1
Reactant: O=S([O-])OO
Reactant: COc1ccc2c(c1)c1c(n2C)-c2ccccc2SC1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)c1c(n2C)-c2ccccc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-methoxy-11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene in MeOH (3 mL) and H2O (5 mL) was added OXONE (1.68 g, 2.74 mmol). The reaction mixture was stirred overnight at 25° C. The solvent was removed in vacuo and the residue was then partitioned between saturated NaHCO3 aqueous solution and CH2Cl2, the aqueous layer was extracted with CH2Cl2 and the organic layers were dried and concentrated to yield crude product. The crude product was then purified by flash chromatography to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([S:17](C)(=O)=O)[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[S:17])[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4]
Reactant: COC(=O)c1nc(S(C)(=O)=O)[nH]c1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1[nH]c(=S)[nH]c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 107.5 %

Procedure:
The sulfone 10 (19.8 g, 66.4 mmol) was treated with a mixture of LiOH (4.8 g, 200 mmol) in THF (240 mL) and water (80 mL) at 85° C. for 3 h. The resulting mixture was cooled to rt and then concentrated under reduced pressure. The aqueous solution was diluted with water (150 mL) and extracted with ethyl acetate (50 mL×2, discarded). The aqueous solution was acidified with 1N HCl aq. to pH 1 and then extracted with ethyl acetate (150 mL×3). The combined extracts were washed with brine (50 mL×2), dried over anhydrous MgSO4, filtered, and evaporated to afford crude product 7 (18.0 g) as a white solid. ESI MS m/z 285.2 (M+H)+. The crude product was suspended in a mixture of MTBE (50 mL) and dichloroethane (200 mL) and stirred at rt for 72 h. The remaining solid was collected by filtration, dried over vacuum to afford pure 5-(4-Fluoro-phenyl)-2-methanesulfonyl-1H-imidazole-4-carboxylic acid (S-17) as a white solid (14 g, 74%) with 96% purity by UV254 nm and 100% purity by ELS.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][C:13]1([F:38])[O:37][C:16]2=[CH:17][C:18]3[NH:22][C:21]([S:23][CH2:24][C:25]4[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([O:34][CH3:35])=[CH:27][N:26]=4)=[N:20][C:19]=3[CH:36]=[C:15]2[O:14]1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[F:38][C:13]1([F:12])[O:37][C:16]2=[CH:17][C:18]3[NH:22][C:21]([S:23]([CH2:24][C:25]4[C:30]([CH3:31])=[C:29]([O:32][CH3:33])[C:28]([O:34][CH3:35])=[CH:27][N:26]=4)=[O:6])=[N:20][C:19]=3[CH:36]=[C:15]2[O:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c(C)c1OC
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cnc(CS(=O)c2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c(C)c1OC
Reaction time: 0.33 h

Procedure:
21 ml of a 0.1N solution of m-chloroperoxybenzoic acid in methylene chloride are added dropwise to a suspension, cooled to -40° C., of 0.80 g of 2,2-difluoro-6[(4,5-dimethoxy-3-methyl-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]-benzimidazole in 10 ml of methylene chloride in the course of 10 minutes. The mixture is stirred for a further 20 minutes, during which the temperature is allowed to rise to -20° C., and 0.5 ml of triethylamine are added and the reaction mixture is poured into 40 ml of 5% strength sodium thiosulfate solution and 5% strength sodium carbonate solution. After phase separation, the aqueous phase is extracted twice more with 20 ml of methylene chloride each time; the combined organic phases are washed with a mixture of 5 ml of sodium thiosulfate solution and 5 ml of sodium carbonate solution, dried and concentrated. The residue is recrystallized from methylene chloride/diisopropyl ether. 0.62 g (75% of theory) of the title compound is obtained; decomp. 189°-190° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6](O)[C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1.FC1C=CC(O)=CC=1>C1COCC1.ClCCl>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1
Reactant: CN1CCC(O)c2ccc(-c3cccnn3)cc2C1
Agent: Oc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCCc2ccc(-c3cccnn3)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a solution of the 2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ol (170 mg, 0.67) from Step H above in THF (5 mL) was added 4-fluorophenol (98 mg, 0.87 mmol), tributylphosophine (176 mg, 0.52 mmol) and 1,1′-(azodicarboyl)dipiperidine (220 mg, 0.87 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane and washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (98:2 to 95:5 ethyl acetate/methanol), followed by preparative HPLC to give 544-fluorophenoxy)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (120 mg, 51%) as a gum-like solid. This compound was resolved using Chiralcel OJ column (eluente:80 Hep:20 EtOH:0.1 DEA) to give (+)-enantiomer (36 mg)) and (−)-enantiomer (37 mg).
Reaction SMILES: [CH2:1]([CH:19]1[CH2:24][C:23](=[O:25])[O:22][C:20]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:26]([CH2:28][NH2:29])[OH:27]>>[OH:27][CH2:26][CH2:28][N:29]1[C:23](=[O:25])[CH2:24][CH:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:20]1=[O:22]
Reactant: NCCO
Reactant: CCCCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Product: CCCCCCCCCCCCCCCCCCC1CC(=O)N(CCO)C1=O
Yield: 53.7 %

Procedure:
A 50 mL reaction flask was charged with 17.6 g of octadecyl succinic anhydride (manufactured by Tokyo Chemical Industry Co., Ltd.) and 3.1 g of ethanolamine (manufactured by Tokyo Chemical Industry Co., Ltd.), and the resulting mixture was reacted at 160° C. for 4 hours under continuous nitrogen purging and with vigorous stirring. The reaction product was purified by silica gel column chromatography (mobile phase: ethyl acetate/hexane), yielding 10.6 g of N-(2-hydroxyethyl)octadecyl succinimide (yield: 54%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([Mg]Br)=[CH:23][CH:22]=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:10]=1[CH:11]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OCc2ccccc2)c(C=O)c1
Reactant: COc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc(OC)ccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
In a nitrogen stream, to a solution of 2-benzyloxy-5-methoxy-benzaldehyde (2.0 g, 8.25 mmol) in THF (50 mL), a solution of 4-methoxyphenylmagnesium bromide in THF (0.5 M, 19.8 mL) was added dropwise under cooling with ice. The mixture solution was stirred at room temperature for one hour, and then a saturated ammonium chloride aqueous solution was added thereto under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:1)] to obtain the title compound (2.9 g, 100%).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[S:37](Cl)(=[O:39])=[O:38].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:37]([C:33]1[O:32][CH:36]=[CH:35][CH:34]=1)(=[O:39])=[O:38]
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccco1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. furan-2-sulfonyl chloride (12 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 24 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)furan-2-sulfonamide (percentage yield: 94%), was obtained.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][CH:14]([C:18]1([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:15]([OH:17])=O.[CH2:36]([O:43][NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl.CN1CCOCC1>C(Cl)Cl>[CH2:36]([O:43][NH:44][C:15](=[O:17])[CH:14]([CH3:13])[C:18]1([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)CC1(C(C)C(=O)O)CCN(CCc2ccccc2)C1=O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC1(C(C)C(=O)NOCc2ccccc2)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
CDI (39.7 mg, 0.245 mmol) is added to a solution of α-methyl-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (74.0 mg, 0.233 mmol) and CH2Cl2 (2.0 mL). The solution is stirred for 1 hour at room temperature. To this is added O-benzylhydroxylamine.HCl (63.2 mg, 0.396 mmol) and N-methylmorpholine (44 μL, 0.40 mmol). The resultant solution is stirred for 16 hours at room temperature. Aqueous workup (CH2Cl2, MgSO4) and purification by flash chromatography (2:1 EtOAc:hexane) gives 88.1 mg (89%) of the title compound as an oil.