Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][CH3:31])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:40]2[CH:52]=[CH:51][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:40]2[CH:41]=[CH:42][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:51][CH:52]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][CH3:31])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(propyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (0.2 g, 0.412 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (0.148 g, 0.488 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.108 g, 1.01 mmol) was added and reaction mixture purged with argon for 15 min. Pd(PPh3)4 (0.048 g, 0.042 mmol) was then added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and solvent removed under reduced pressure to afford crude product which was purified by column chromatography over silica gel to afford the title compound (0.20 g, 83.68%). LCMS: 587.40 (M+1)+; HPLC: 98.68% (@254 nm) (Rt; 4.257; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H, J=4.8 Hz), 7.56 (d, 2H, J=8 Hz), 7.38 (t, 3H, J=8 Hz), 7.19 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.82-3.85 (m, 2H), 3.57 (m, 4H), 3.48 (s, 2H), 3.23 (t, 2H, J=10.8 Hz), 2.94-3.02 (m, 3H), 2.36 (bs, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.56-1.65 (m, 4H), 1.20-1.25 (m, 2H), 0.76 (t, 3H, J=6.8 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:26]=[N:25][C:18]3[O:19][CH2:20][C:21](=[O:24])[N:22]([CH3:23])[C:17]=3[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:26]=[N:25][C:18]4[O:19][CH2:20][C:21](=[O:24])[N:22]([CH3:23])[C:17]=4[CH:16]=3)[C:10]([F:12])([F:11])[F:13])=[C:4]([Cl:28])[CH:3]=2)=[CH:31][C:30]=1[F:29])=[O:37]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1cnc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3cnc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 17, step 2, 7-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyrido[2,3-b][1,4]oxazin-2-one was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless solid. MS (m/e)=553.4 [M+H+].
Reaction SMILES: [CH3:1]N.[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([N:10]2[C:19](=[O:20])[C:18]3[CH:21]=[CH:22][C:23]([N+:24]([O-])=O)=[C:16]4[C:17]=3[C:12](=[CH:13][CH:14]=[CH:15]4)[C:11]2=[O:27])[CH2:6][CH2:5]1>C(O)(C)C>[CH3:1][NH:24][C:23]1[CH:22]=[CH:21][C:18]2[C:19](=[O:20])[N:10]([CH:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)[C:11](=[O:27])[C:12]3[C:17]=2[C:16]=1[CH:15]=[CH:14][CH:13]=3
Reactant: CN
Reactant: CN1CCC(N2C(=O)c3cccc4c([N+](=O)[O-])ccc(c34)C2=O)CC1
Solvent: CC(C)O
Product: CNc1ccc2c3c(cccc13)C(=O)N(C1CCN(C)CC1)C2=O

Procedure:
A mixture of 40% aqueous methylamine (2 mL) and 2,3-dihydro-2-(1-methylpiperidin-4-yl)-6-nitro-1H-benz[de]isoquinoline-1,3-dione (1.1 g; 3.14 mmol), prepared as in Example 3, in isopropanol (10 mL) was stirred at 65°-70° C. for six hours. Concentration of the solution followed by purification of the residue by column chromatography (silica-gel; 3% methanol in CH2Cl2 and approximately 1% aqueous NH4OH) gave 2,3-dihydro-6-methyamino-2-(1-methylpiperidin-4-yl)-1H-benz[de]isoquinoline-1,3-dione (0.63 g; 1.95 mmol) as a yellow precipitate, m.p. 251°-254° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1c[nH]nn1
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2nccn2)cc1
Yield: 66.4 %

Procedure:
4-Fluoronitrobenzene (21 g) was reacted with 1H-1,2,3-triazole (12.4 g) in the same manner as in Reference Example 9. The resultant was cooled and poured into water. The precipitated crystals were collected by filtration and purified by silica gel chromatography (eluent: dichloromethane to dichloromethane/acetone=8/1). The first eluted fraction was recrystallized from dichloromethane-diisopropyl ether to give 2-(4-nitrophenyl)-2H-1,2,3-triazole (18.8 g) as pale yellow prisms.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1F.[CH:16]([N:29]1[CH2:32][CH:31]([C:33]#[N:34])[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:16]([N:29]1[CH2:32][C:31]([C:3]2[CH:4]=[CH:5][C:6]([CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])=[CH:7][C:2]=2[Br:1])([C:33]#[N:34])[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(OCC)c1ccc(F)c(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C2(C#N)CN(C(c3ccccc3)c3ccccc3)C2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 2-bromo-4-(diethoxymethyl)-1-fluorobenzene (Preparation 15, 10.0 g, 36.0 mmol) in THF (125 mL) was added 1-benzhydrylazetidine-3-carbonitrile (13.4 g, 54.1 mmol) and KHMDS (10.8 g, 54.1 mmol). The reaction mixture is left stirring at room temperature for 1 hour. Next, the reaction mixture is concentrated to an oil under vacuum, diluted with EtOAc, and washed 2× with water. The organic phase was dried (Na2SO4) and concentrated under vacuum. The crude material was chromatographed (220 g Redi-Sep column) eluting from 100% heptane to 20:80 EtOAc:heptane to afford the intermediate (13.7 g, 75%) as a solid. 1HNMR (CDCl3) δ ppm: 7.73 (1H), 7.48-7.44 (5H), 7.37-23 (6H), 7.13 (1H), 5.47 (1H), 4.33 (1H), 4.14 (2H), 3.65-3.52 (4H), 3.41 (2H), 1.29-1.25 (6H).
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[S:13][CH:14]=2)=[CH:6][CH:5]=1.[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>>[CH3:18][S:15]([C:12]1[S:13][CH:14]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([N:28]3[CH2:29][CH2:30][CH2:31][C@H:27]3[CH2:26][N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[CH3:20])=[O:19])=[CH:9][CH:8]=2)[N:11]=1)(=[O:16])=[O:17]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: COC(=O)c1ccc(-c2csc(S(C)(=O)=O)n2)cc1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2csc(S(C)(=O)=O)n2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure N and Procedure P starting from 4-(2-Methanesulfonyl-thiazol-4-yl)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 434.12.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[C:5](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([Cl:11])[CH:10]=1)[NH2:6].[Li+].[OH-].Cl>C1COCC1.O>[Cl:11][C:9]1[CH:10]=[C:4]([C:3]([OH:15])=[O:2])[C:5]([NH2:6])=[CH:7][C:8]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a solution of 5-chloro-4-nitroanthranilic acid methyl ester (10.0 g, 43 mmol) in THF (120 mL) was added LiOH (2.7 g, 65 mmol) dissolved in water (40 mL). The reaction mixture was stirred at room temperature for 18 h and acidified to pH 4 with 1 N HCl. The aqueous layer was extracted with EtOAc (2×150 mL); the combined organic layers were dried over Na2SO4, filtered, and concentrated to give 5-chloro-4-nitroanthranilic acid (8.7 g, 88%) as an orange solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]1[C:15](=O)[CH:16]([CH3:18])[CH3:17].CCN(CC)CC.[BH4-].[Na+]>CO>[CH:16]([CH:15]1[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][C:10]([S:13][CH3:14])=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2][NH:1]1)([CH3:18])[CH3:17]
Reactant: CSc1ccc2cc(C(=O)C(C)C)n(CCN)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CSc1ccc2cc3n(c2c1)CCNC3C(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a solution of 1-(1-(2-aminoethyl)-6-(methylthio)-1H-indol-2-yl)-2-methylpropan-1-one (200 mg, 0.724 mmol) in MeOH (5 mL) was added Et3N (219.3 mg, 2.172 mmol). The reaction mixture was stirred at 60° C. for 1 h. Then NaBH4 (82.53 mg, 2.172 mmol) was added to the formed mixture. The mixture was stirred at 60° C. for another 1 h. The mixture was concentrated, treated with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative TLC on silica gel eluted with PE/EtOAc 1:1 to afford 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (80 mg, 42.46% yield, store at 0° C.) as a colorless oil. LC-MS of 1-Isopropyl-7-methylsulfanyl-3,4-dihydro-pyrazino[1,2-a]indole MS (ESI) m/z 259.1 [M+H]+. LC-MS of 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole MS (ESI) m/z 261.2 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 7.41 (d, J=8.4 Hz, 1H), 7.20 (s, 1H), 7.05 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 6.12 (s, 1H), 4.02-3.97 (m, 2H), 3.86-3.80 (m, 1H), 3.46-3.42 (m, 1H), 3.16-3.10 (m, 1H), 2.48 (s, 3H), 2.32-2.27 (m, 1H), 1.09 (d, J=6.8 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:28][OH:29]>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[N:28][OH:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(C(F)(F)F)ccc2F)CC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(C(=NO)c2cc(C(F)(F)F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 4-(2-fluoro-5-trifluromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (5 g, 0.013M) in pyridine (25 mL) was treated with hydroxylamine hydrochloride (1.11 g, 0.015 M -1.2 eq). The reaction was stirred under N2 at room temperature for 14 hours and then poured onto ice water (250 mL). The mixture was stirred at 0° C. for 1 hour, the product was then filtered off, washed with cold water (3×15 mL) and dried in a vacuum oven at 50° C. A white solid was obtained (5.03 g, 97%).
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:20]([C:22]1([OH:30])[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[C:23]1=[O:29])#[CH:21]>>[F:19][C:18]1[C:2]([C:21]#[C:20][C:22]2([OH:30])[CH2:27][CH2:26][CH2:25][N:24]([CH3:28])[C:23]2=[O:29])=[CH:3][C:4]2[C:10]3[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[S:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC1(O)CCCN(C)C1=O
Product: CN1CCCC(O)(C#Cc2cc3c(cc2F)OCCc2sc(C(N)=O)nc2-3)C1=O
Yield: 16 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-8-fluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxamide was reacted with 3-ethynyl-3-hydroxy-1-methylpiperidin-2-one (US2012/214762A1) to give the titled compound as a white solid (20 mg, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([NH:23]CCP(=O)(O)O)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.N[CH2:31][P:32](=[O:39])([O:36]CC)[O:33]CC>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([S:20]([NH:23][CH2:31][P:32](=[O:33])([OH:39])[OH:36])(=[O:21])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: CCOP(=O)(CN)OCC
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCP(=O)(O)O)c2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCP(=O)(O)O)c2)C1

Procedure:
Compound 5 was prepared in an analogous manner to that of Compound 1 using diethyl aminomethylphosphonate (Intermediate 5.3) as the amine. 1H-NMR (300 MHz, CD3OD, ppm): 7.89 (d, J=7.8 Hz, 1H), 7.74 (s, 1H), 7.63˜7.66 (m, 1H), 7.57˜7.61 (m, 2H), 6.97 (s, 1H), 4.80˜4.89 (m, 1H), 4.55˜4.67 (m, 2H), 3.83˜3.89 (m, 1H), 3.55˜3.66 (m, 1H), 3.02˜3.11 (m, 5H). MS (ES, m/z): 465 [M+H]+.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.C[Mg]Br.C1COCC1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[O:25])[CH:19]=1.O>C1COCC1>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:25])[C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)[CH:19]=1
Reactant: Ic1ncn2ccsc12
Reactant: O=Cc1cccnc1
Agent: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: OC(c1cccnc1)c1ncn2ccsc12
Reaction time: 0.33 h

Procedure:
A solution of 2.50 g of 7-iodoimidazo[5,1-b]thiazole in 50 ml of dry THF was cooled in ice, and 11.3 ml of a 0.93 M methylmagnesium bromide/THF solution was added to the cooled solution under an argon atmosphere. The mixture was stirred at that temperature for 20 min. Pyridine-3-aldehyde (1.04 ml) was then added thereto, and the mixture was stirred at that temperature for 40 min and then at room temperature for 4 hr. Water was added to the reaction solution, and the mixture was extracted five times with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and was then concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 1.925 g of 7-[(pyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[C:21]2[O:22]CC(C)(C)N=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CI.[N+](C)([O-])=[O:31]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[C:21]([OH:31])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2cc(OC)c(OC)cc2C2=NC(C)(C)CO2)cc1OC
Reactant: C[N+](=O)[O-]
Solvent: CI
Product: COc1ccc(-c2cc(OC)c(OC)cc2C(=O)O)cc1OC
Reaction time: 24 h

Procedure:
2-[2-(3,4-Dimethoxyphenyl)-4,5-dimethoxyphenyl]-4,4-dimethyl-2-oxazoline (10 g) was dissolved in nitromethane (100 ml), to which was added methyl iodide (10 ml), and the mixture was allowed to stand at room temperature for 24 hours. It was concentrated by an evaporator, and methanol (150 ml) and a 20% aqueous sodium hydroxide solution (150 ml) were added to the residue to reflux for 18 hours. The solvent was distilled off until the system becomes ununiform, and water was added until it becomes transparent. After washing with diethyl ether (200 ml), the aqueous layer was cooled in a ice-water bath and concentrated hydrochloric acid was added until it becomes acidic. The insoluble matter formed was filtered, washed with water and dried to give 7.7 g of 2-(3,4-dimethoxyphenyl)-4,5-dimethoxybenzoic acid as a white powder.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:20])([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)=[CH:5][CH:4]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:19])([CH3:20])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)cc1
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CC1=Cc2cc(Sc3ccc(O)cc3)ccc2OC1(C)C
Reaction time: 72 h
Yield: 77.7 %

Procedure:
6-(4-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (7.816 g) (see Preparation 5) was dissolved in dry 2,4,6-collidine (30 ml), anhydrous lithium iodide (10.04 g) was added and the mixture was heated under reflux under.a nitrogen atmosphere for 48 hours. A further portion of lithium iodide (9.06. g) was then added and heating was continued for another 72 hours. After cooling, the mixture was taken up in dichloromethane and washed with 2N aqueous hydrochloric acid solution (×3). The organic layer was separated, dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the residue was chromatographed on silica using dichloromethane as the eluent to yield 6-(4-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (5.799 g) as an oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][C:2]([F:10])([F:11])[CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: OC1CCC(C(F)(F)F)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a solution of 4-Trifluoromethylcyclohexanol (4.5 g, 26.7 mmol) in DCM (100 ml) was added Dess-Martin periodinane (13.6 g, 32 mmol), and stirred at rt for 2 h. After the reaction finished, the reaction mixture was concentrated in vacuo, sodium thiosulfate aqueous solution and diethylether were added and stirred at rt for 30 min, and extracted with diethylether. The organic layer was dried over MgSO4, concentrated in vacuo at rt to give the title compound (4.2 g, 94.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([C:23](OCC)=[O:24])[CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[N:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)[N:14]=[C:13]([CH2:23][OH:24])[CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(S(=O)(=O)c2ccc(F)cc2)n(-c2cccnc2F)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(F)cc1)c1cc(CO)nn1-c1cccnc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A solution of ethyl 5-[(4-fluorophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazole-3-carboxylate (170 mg) in tetrahydrofuran (2.5 mL) was cooled to −78° C., and a 1.5 mol/L solution (1.2 mL) of diisobutylaluminum hydride in toluene was added dropwise. The reaction mixture was stirred at room temperature for 1 hr, treated with 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as a yellow solid (yield 135 mg, yield 89%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:24][N:25]([CH2:27][C:28]1[O:44][C:31]([CH2:32][S:33][CH2:34][CH2:35][NH:36][CH:37](SC)[CH2:38][N+:39]([O-:41])=[O:40])=[CH:30][CH:29]=1)[CH3:26]>>[CH3:26][N:25]([CH2:27][C:28]1[O:44][C:31]([CH2:32][S:33][CH2:34][CH2:35][NH:36][C:37]([NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]2[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH3:21])=[CH:38][N+:39]([O-:41])=[O:40])=[CH:30][CH:29]=1)[CH3:24]
Reactant: CSC(C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reactant: CN(CCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NCCCN(C)CCN(Cc2ccc(F)cc2)c2ccccn2)o1

Procedure:
Preparation is effected analogously to Example 22, using 0.54 g (1.7 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of 1-[2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethyl]amino-1-methylthio-2-nitroethane as starting materials. Working up by chromatography analogously to Example 22 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=600 ([M+H]+, 12), 109 (100). For further analysis, a portion of the compound is converted into the tartaric acid salt in an ethanol/ether solvent mixture; m.p.: 63° C. (ethanol/ether).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])=[O:4].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:1][CH2:2][C:3]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])=[O:4])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@@]1(OC(=O)CO)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
The above alcohol is acetylated with acetic anhydride in pyridine to give 17α-acetoxyacetoxypregn-4-ene-3,20-dione, which shows the following significant NMR signals: δ(ppm) 0.69 (s, 3H, H-18), 1.19 (s, 3H, H-19), 2.07 and 2.17 (singlets, 3H each, 2-COCH3), ##STR28## 5.76 (broad s, 1H, H-4).