Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]1[N:37]=[CH:38][C:39]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:40][CH:41]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(OCCCOCc3ccccc3)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(OCCCOCc5ccccc5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 50 mg, 0.132 mmol) and 2-(3-benzyloxy-propoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 20.1.1, 68 mg, 0.184 mmol) to give the title compound as an off-white solid. (HPLC: tR 3.22 min (Method A); M+H=535 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.31-8.26 (m, 1H), 8.15-8.05 (m, 2H), 7.93-7.86 (m, 1H), 7.79-7.73 (m, 1H), 7.50-7.45 (m, 1H), 7.35-7.22 (m, 5H), 6.93-6.87 (m, 1H), 4.55 (s, 2H), 4.36 (t, 2H), 3.91 (s, 3H), 3.60-3.55 (m, 5H), 2.05-1.97 (m, 2H), 1.95 (s, 3H))
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3]1.C1(C)C=CC=CC=1.C1CCCCC1.CC([O-])C.CC([O-])C.CC([O-])C.[Al+3]>CCOCC>[CH3:18][CH:16]([CH2:15][CH2:14][CH2:13][C@H:12]([C@@H:11]1[C@:20]2([CH3:28])[C@H:8]([C@H:7]3[C@H:23]([CH2:22][CH2:21]2)[C@:24]2([CH3:27])[C:4](=[CH:3][C:2](=[O:1])[CH2:26][CH2:25]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1)[CH3:19])[CH3:17]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
111 g. of 3β-hydroxy-5-cholestene is heated in 2.2 l. of toluene and 111 ml. of cyclohexane to boiling. A solution of 55.5 g. of aluminum isopropylate in 666 ml. of toluene is added dropwise thereto. The mixture is then further heated for 90 minutes with gradual distillation. The cooled reaction solution is diluted with ether, washed with dilute sulfuric acid and water, and concentrated. The residue is distilled with steam and the crude product, obtained after extraction with methylene chloride, is chromatographed on silica gel. After recrystallization from methanol, 70 g. of 4-cholesten-3-one is obtained, m.p. 79° - 80.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]3[C:20]=2[CH3:21])=[CH:4][C:3]=1[OH:22].[CH3:23][N:24]=[C:25]=[O:26].C(OCC)(=O)C>O1CCCC1.CO>[OH:22][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][N:13]3[C:20]=2[CH3:21])[CH:6]=[CH:7][C:2]=1[NH:1][C:25]([NH:24][CH3:23])=[O:26]
Reactant: COc1ccn2c(C)c(CCc3ccc(N)c(O)c3)nc2c1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1ccc(CCc2nc3cc(OC)ccn3c2C)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-[2-(4-amino-3-hydroxyphenyl)ethyl]-7-methoxy-3-methylimidazo[1,2-a]pyridine (2.5 g) and methyl isocyanate (0.6 ml) in tetrahydrofuran (25 ml) and methanol (2.5 ml) was stirred for 1 hour at ambient temperature. To the reaction mixture was added ethyl acetate (30 ml) and the resulting precipitate was collected by filtration. The precipitate was washed with ethyl acetate and dried to give 2-[2-{3-hydroxy-4-(3-methylureido)phenyl}ethyl]-7-methoxy-3-methylimidazo[1,2-a]pyridine (2.11 g).
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[O:5][C:6]2[C:18](CC#N)=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:22]([OH:24])[CH3:23]>>[Br:3][C:4]1([CH2:23][C:22]([OH:1])=[O:24])[CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[C:15]2[CH:16]=[CH:17][CH:18]=[C:6]2[O:5]1
Reactant: CCO
Reactant: [OH-]
Reactant: N#CCc1cccc2c(-c3ccccc3)c(Br)oc12
Agent: [Na+]
Product: O=C(O)CC1(Br)OC2=CC=CC2=CC1c1ccccc1

Procedure:
To a mixture of 50% sodium hydroxide solution (35 ml.) and ethanol (100 ml.) is added 2-bromo-7-cyanomethyl-3-phenylbenzofuran (10 g., 0.032 mole). The mixture is heated to reflux temperature and maintained at reflux for about sixteen hours, then concentrated in vacuo. The residue is diluted with water, then extracted (washed) with diethyl ether. The aqueous layer is acidified with hydrochloric acid, yielding a precipitate which is collected by filtration and recrystallized twice from benzene-hexane mixtures to give 2-bromo-3-phenyl-7-benzofuranacetic acid, m.p. 162°-163.5° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C[CH:26]1[O:28][CH:27]1[CH3:29].[CH3:30]O>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:26][C:27]([CH3:29])([OH:28])[CH3:30])[CH2:21][CH2:20]3)=[CH:13][N:12]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CO
Reactant: CC1OC1C
Reactant: CS(=O)(=O)N1CC=C(c2ccc(OCC3CCNCC3)cn2)CC1
Product: CC(C)(O)CN1CCC(COc2ccc(C3=CCN(S(C)(=O)=O)CC3)nc2)CC1
Reaction time: 88 h

Procedure:
4-(1′-Methanesulfonyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-5-yloxymethyl)-piperidine is suspended in 800 mL of methanol and added to an autoclave with a mechanical stirrer. 1500 mL of methanol are added and then dimethyloxirane (117 g, 1.62 mol) is added. The mixture is stirred at 60˜70° C. for 88 h, cooled to 25˜30° C. and concentrated to 1000 mL. The mixture is heated at 60˜70° C. and 4200 mL of water are added. The resulting mixture is stirred at 60˜70° C. during 30 min and cooled slowly to 0˜5° C. in 1.5˜2 h. It is stirred at this temperature for 30 minutes and filtered. The cake is slurried with H2O: MeOH=3:1 (600 mL) pre-cooled to 0˜5° C. and concentrated (2×). The product is dried under vacuum at 40˜50° C. to provide 320 g of off-white solid with 98.3% HPLC purity.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49].NCCN1CC[O:58][CH2:57]C1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][NH:41][C:57]([NH:46][C:47]([CH3:51])([CH3:50])[CH2:48][OH:49])=[O:58])=[CH:33][C:32]=3[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NCCN1CCOCC1
Reactant: CC(C)(N)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1cc(OCCCNC(=O)NC(C)(C)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 19 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 4-(2-aminoethyl)morpholine, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21]1[S:22][C:23]([CH2:26]O)=[CH:24][N:25]=1)[NH:6]2.O1[CH2:32][CH2:31]CC1.S(Cl)(Cl)=O.[OH2:37]>>[C:7]([N:6]1[CH2:32][CH2:31][N:25]([CH2:26][C:23]2[S:22][C:21]([C:5]3[NH:6][C:7]4[C:3]([CH:4]=3)=[C:2]([Cl:1])[CH:10]=[CH:9][C:8]=4[N:11]([CH3:20])[S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])=[N:25][CH:24]=2)[CH2:21][CH2:5]1)(=[O:37])[CH3:3]
Reactant: CN(c1ccc(Cl)c2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O
Reactant: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(=O)N1CCN(Cc2cnc(-c3cc4c(Cl)ccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a mixture of N-{4-chloro-2-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.26 g) and tetrahydrofuran (10 ml) was added thionyl chloride (0.08 ml) at 0° C., and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. A mixture of the obtained residue, 1-acetylpiperazine (0.15 g), triethylamine (0.17 ml) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.08 g, yield 25%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 224-225° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[H-].[Na+].[Cl:17][CH2:18][CH2:19][CH2:20]I.C(OCC)(=O)C>CN(C)C(=O)N(C)C>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:20][CH2:19][CH2:18][Cl:17])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CCNC(=O)C2
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C(=O)N(C)C
Product: COc1ccc2c(c1)CCN(CCCCl)C(=O)C2
Reaction time: 2 h

Procedure:
First, 7-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (1.15 g, 6 mmol) is dissolved in absolute tetramethylurea (30 ml), mixed with 55% sodium hydride dispersion in oil (300 mg) and stirred for 2 hours at 20°-25° C. under a nitrogen atmosphere. The resulting reaction mixture is added dropwise, with stirring, at 15°-20° C. under a nitrogen atmosphere to 1-chloro-3-iodopropane (1.6 g, 7.8 mmol) dissolved in tetramethylurea (20 ml) and stirred for 3 hours at ambient temperature. Then, ethyl acetate (300 ml) are added and the mixture is extracted six times with water. The organic solution is dried over magnesium sulphate, concentrated by evaporation and the residue is purified oer a silica gel column with methylene chloride and increasing amounts of ethanol (up to 2%). Yield: 410 mg. IR spectrum (methylene chloride): 1650 cm-1 (C=O).
Reaction SMILES: C1(N2CC[O:9]CC2)CCCC=1.[OH:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH:15]=O.Cl.[CH:24]1[CH:29]=[CH:28][CH:27]=[CH:26]C=1>>[OH:12][C:13]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:14]=1[CH:15]=[C:26]1[CH2:27][CH2:28][CH2:29][C:24]1=[O:9]
Reactant: C1=C(N2CCOCC2)CCC1
Reactant: COc1ccc(C=O)c(O)c1
Reactant: c1ccccc1
Agent: Cl
Product: COc1ccc(C=C2CCCC2=O)c(O)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
With reflux device installed, 36.8 g (0.24 mol) of N-cyclopentenyl morpholine, 0.20 mol of 2-hydroxy-4-methoxybenzaldehyde and 200 mL of benzene were added to a round bottom flask and heated under reflux for 20 h. The resulting solution was cooled to 30° C., and slowly stirred while 62 mL of hydrochloric acid (6 mol/L) was added. After stirring for 2 h at room temperature, the benzene layer was separated and washed with water to neutral, and dried over anhydrous sodium sulfate overnight. Then the mixture was filtered to remove anhydrous sodium sulfate and benzene was recovered by evaporation under reduced pressure. The residue was cooled and solidified, then recrystallized in cyclohexane/ethanol to yield a light yellow flaky crystal product with a yield of 70.6%.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22](Cl)[N:17]2[N:16]=1)(=[O:14])=[O:13].Cl.[CH3:27][OH:28]>>[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22]([O:28][CH3:27])[N:17]2[N:16]=1)(=[O:14])=[O:13]
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COc1cc(C)nc2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nn12
Reaction time: 1.5 h

Procedure:
Sodium (0.6 g, 26 mmol) was added to about 40 ml of methanol and allowed to react. N-(2,6-dichloro-3-methylphenyl)-7-chloro-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (2.5 g, 6.9 mmol) was added with stirring. After about 90 minutes, thin layer chromatography indicated the starting material had reacted. The solution was then acidified by adding 6N hydrochloric acid dropwise and then concentrated by evaporation under reduced pressure. The residue was triturated with water and the solid that formed was washed with water and dried to obtain 1.35 g of the title compound as a white solid, m.p. 239°-42° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:4]=[C:5]([NH:11][C:12](=O)[CH3:13])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.O.Cl.[OH-].[Na+]>C1COCC1.C(Cl)Cl>[CH2:12]([NH:11][C:5]1[CH:4]=[C:3]([N:2]([CH3:15])[CH3:1])[CH:8]=[CH:7][C:6]=1[O:9][CH3:10])[CH3:13]
Reactant: COc1ccc(N(C)C)cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1cc(N(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
N-(3-dimethylamino-6-methoxyphenyl)acetamide 26 (0.10 gm, 0.48 mmoles) was dissolved in 2 ml THF and stirred under argon at room temperature. Borane-methylsulfide complex (0.6 ml, 2.0M, 1.2 mmoles) was added by syringe. After 10 minutes at ambient temperature, the mixture was heated to reflux for 3 hours. After cooling to room temperature, 0.6 ml water was cautiously added with stirring 0.1 ml conc. HCl. After heating for 1 hour, 5 ml DCM and 0.3 ml 2N NaOH were added sequentially with vigorous stirring. The aqueous portion was extracted with three 30 ml portions of DCM which were combined, dried over MgSO4, filtered, and concentrated by rotary evaporation under reduced pressure to give 95 mg of crude [3-(ethylamino)-4-methoxyphenyl]dimethylamine 27.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:21](=[O:22])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]ccc1C
Reactant: COc1cccc(CC(=O)Cl)c1
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2cccc(OC)c2)c1C

Procedure:
4-[2-(3-Methoxy-phenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (91) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-methoxyphenyl)-acetyl chloride following the procedure described in Example 32. crude yield: 95%. 1H-NMR (400 MHz, CDCl3): δ 1.36 (t, 3H), 2.61 (s, 3H), 3.77 (s, 3H), 3.99 (s, 2H), 4.32 (q, 2H), 6.81 (m, 3H), 7.24 (m, 1H), 7.45 (d, 1H), 9.41 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ □□ 11.75, 14.40, 47.59, 55.19, 60.66, 112.19, 115.04, 121.71, 127.22, 129.58, 136.75, 159.75, 193.65 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.75, 14.40, 55.19; CH2 carbons: 47.59, 60.66; CH carbons: 112.19, 115.04, 121.71, 127.22, 129.58 ppm. LC/MS: 60.20%, m/z=301
Reaction SMILES: [CH2:1]([N:4]1[C@H:13]2[C@@H:8]([CH2:9][C:10](=O)[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3].[BrH:15].BrBr.[NH2:18][C:19]([NH2:21])=[S:20]>C(O)(=O)C.C(O)C>[BrH:15].[BrH:15].[NH2:21][C:19]1[S:20][C:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][CH2:6][CH2:5][N:4]3[CH2:1][CH2:2][CH3:3])[CH2:9][C:10]=2[N:18]=1
Reactant: NC(N)=S
Reactant: CCCN1CCC[C@@H]2CC(=O)CC[C@H]21
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCO
Product: CCCN1CCC[C@H]2Cc3nc(N)sc3C[C@@H]21
Temperature: 0 °C

Procedure:
Five grams of trans-(±)-1-n-propyl-6-oxodecahydroquinoline were dissolved in 30 ml. of glacial acetic acid. Five and eight tenths milliliters of 37% by weight hydrogen bromide in glacial acetic acid were added followed by the dropwise additions of 1.5 ml. of bromine dissolved in glacial acetic acid. The reaction mixture was illuminated with ultraviolet radiation using a commercially available sunlamp. The illuminated reaction mixture was stirred for one-half hour after all the reactants had been added. Volatile constituents were removed from the reaction mixture in vacuo yielding, as a residue, trans-(±)-1-n-propyl-6-oxo-7-bromodecahydroquinoline hydrobromide. One hundredth mole of this salt was dissolved in 50 ml. of ethanol. Eighty-four hundredths grams of thiourea were added thereto. The resulting mixture was refluxed for about 18 hours under a nitrogen blanket. A colorless solid began to form after about 20 minutes. The reaction mixture was cooled to about 0° C. and the solid, which had continued to form, was separated by filtration. The filter cake was dried in vacuo. One and fifteen hundredths grams of trans-(±)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline dihydrobromide salt were obtained. The salt melted above 255° C., tlc (9:1 chloroform:methanol plus a trace of ammonium hydroxide) Rf =0.13.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:33]2[CH2:32][C@H:31]([OH:38])[C@@:29]2([CH3:30])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[CH:39]([CH3:55])[CH2:40][CH:41]=[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(C2C=CN=CC=2)CCCC1.[CH3:67][C:68]([CH3:74])([CH2:72][CH3:73])[C:69](Cl)=[O:70]>N1C=CC=CC=1.CCOCC.CCCCCC>[Si:1]([O:18][C@@H:19]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:33]2[CH2:32][C@H:31]([O:38][C:69](=[O:70])[C:68]([CH3:74])([CH3:67])[CH2:72][CH3:73])[C@@:29]2([CH3:30])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[CH:39]([CH3:55])[CH2:40][CH:41]=[C:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:20]1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)(C)C(=O)Cl
Reactant: CC(CC=C(c1ccccc1)c1ccccc1)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC(C)(C)C(=O)O[C@H]1C[C@H]2[C@@H](CC[C@@H]3C[C@H](O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CC[C@@]32C)[C@@H]2CC[C@H](C(C)CC=C(c3ccccc3)c3ccccc3)[C@@]12C
Temperature: 110 °C
Reaction time: 1 h

Procedure:
3α-tert-butyldiphenylsilyloxy-17β-[(1,1-diphenyl)-1-penten-4-yl]-12α-hydroxy-5β-androstane (10.6 g), 4-pyrrolidinopyridine (0.207 g) and 2,2-dimethylbutyryl chloride (2.25 g) are dissolved in pyridine (55 ml) and the solution warmed to 110° C., stirred for about 1 hour, additional 2,2-dimethylbutyryl chloride (2.25 g) is added and stirring continued for about 14 hours at 110° C. The mixture is cooled, diluted with 20% ether in hexane and washed with water, then 1M hydrochloric acid. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography in 10% ether in hexane to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][CH:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:11])=[N:7][OH:8])=[CH:4][CH:3]=1
Reactant: ON=Cc1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: ON=C(Cl)c1ccc(F)cc1
Temperature: 50 °C

Procedure:
A solution of 4-fluorobenzaldehyde oxime (222 mg, 1.60 mmol) dissolved in 3 mL of DMF was treated with N-chlorosuccinimide (212 mg, 1.60 mmol) and the reaction mixture was heated at 50° C. for 3 hours. The reaction mixture was diluted with 25 mL of ethyl acetate and then washed with H2O (4×20 mL). The organic portion was washed with brine, dried over Na2SO4, filtered and concentrated to give 4-fluoro-N-hydroxybenzenecarboximidoyl chloride as a white solid. The material was dissolved in 10 mL of CH2Cl2 and the solution was cooled to 0° C. A solution of (11S)-11-ethynyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (190 mg, 0.76 mmol) dissolved in 3 mL of CH2Cl2 was then added followed by triethylamine (318 μL, 2.29 mmol). The reaction was allowed to warm to ambient temperature overnight. The reaction mixture was concentrated and chromatography (0-2% methanol/CHCl3) gave (11R)-11-[3-(4-fluorophenyl)isoxazol-5-yl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a light-brown solid.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[CH2:25](OC(OCC)OCC)C.O.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[N:17]=[C:18]4[NH:23][CH:25]=[N:22][C:19]4=[CH:20][CH:21]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CCOC(OCC)OCC
Reactant: CN(c1ccc(N)c(N)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CN(c1ccc2nc[nH]c2n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
A solution of (R)—N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine-2,5,6-triamine (35 mg, 0.11 mmol), triethoxymethane (0.58 mL, 3.45 mmol) and 4-methylbenzenesulfonic acid monohydrate (62 mg, 0.33 mmol) in methanol (3.0 mL) was stirred at 150° C. for 5 min in an Initator™ Biotage microwave reactor. The volatiles were removed and the residue is purified by chromatography to give the title product. MS (m/z): 335 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:19])[CH:8]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CC(N(C)C)=O>[CH2:17]([N:12]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH:29]([CH3:28])[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:20])[CH2:11]1)[CH3:18]
Reactant: CCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCC(C)Oc1ccc2c(c1)C(N(CC)S(C)(=O)=O)CC(C)(C)O2
Temperature: 120 °C
Reaction time: 2 h

Procedure:
1.5 g (5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-ethylmethane-sulfonamide (Example 1g) were stirred at 80° C. for 30 min with 0.7 g of powdered potassium carbonate in 75 ml of DMA. 0.8 ml (5 mmol) of ethyl 5-bromovalerate was then added and the mixture was stirred at 120° C. for 120 min. After reaction was complete (TLC), the mixture was concentrated in vac., treated with ice water and aqueous hydrochloric acid and a crystalline crude product was obtained, which was chromatographed on silica gel using n-heptane/EA (2:1). Appropriate fractions were crystallized using petroleum ether, 1.5 g, m.p. 65-67° C.