Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=O)[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([CH3:15])=[CH:4][C:3]=1[C:16]([OH:18])=[O:17].[CH2:19]([SH:22])[CH2:20][SH:21].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[C:8]3([CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:6]=2[C:5]([CH3:15])=[CH:4][C:3]=1[C:16]([OH:18])=[O:17])[S:22][CH2:19][CH2:20][S:21]3
Reactant: SCCS
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC2=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)CCC21SCCS1

Procedure:
To a mixture of 0.60 g of 3,4-dihydro-5,8-dimethyl4-oxo-2H-1-benzothiopyran-6-carboxylic acid 1,1-dioxide in 30 mL of methylene chloride was added 0.24 mL of 1,2-ethanedithiol (purchased from Aldrich Chemical Co.) and 0.35 mL of boron trifluoride diethyl etherate (purchased from Janssen Chimica). The mixture was refluxed overnight and then concentrated under reduced pressure to dryness. To the resulting residue was added 10 mL of dilute hydrochloric acid of pH 1. The mixture was extracted with ethyl acetate, and the combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 0.62 g of the title compound of Step A as an orange solid which had a melting point >250° C. 1H NMR ((CD3)2SO): δ 2.65 (s, 3H), 2.77 (s, 3H), 2.94 (m, 2H), 3.55-3.80 (m, 6H), 7.50 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]O)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: C1COCCN1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
To a solution of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (0.250 g) from Example No. 35 in DMF (14 mL) are added DMAP (13 mg), 2,4,6-collidine (0.23 mL), and methanesulfonyl chloride (0.13 mL). The reaction is stirred at rt for 1.5 h and then morpholine (0.60 mL, 6.9 mmol) is added. The reaction is stirred at rt for 18 h. The reaction mixture is poured into water (40 mL). The resulting off-white solid is filtered off and recrystallized from ethanol to yield 0.242 g (81%) of the title compound as an off-white, crystalline solid.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:42])[CH2:15][C@H:16]([C:37]1[CH:41]=[CH:40][O:39][N:38]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH:43]O.[OH-].[Li+].Cl>C1COCC1.O>[O:39]1[CH:40]=[CH:41][C:37]([C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][C:14]([OH:42])=[O:43])=[N:38]1
Reactant: O=C(C[C@@H](c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@@H](c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)c1ccon1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of the oxazolidinone 47.2 (58.0 mg, 0.1 mmol) dissolved in THF (5 mL), was added a 30%, hydrogen peroxide solution (113 μL, 1 mmol) followed by a 2 M lithium hydroxide solution (250 μL, 0.5 mmol). The resulting slurry was stirred for one hour. The reaction mixture was then diluted with water and acidified with hydrochloric acid to pH ˜3. The mixture was then extracted with EtOAc (1×20 mL), and the organic layer was washed with an acidic sodium sulfite solution (2×15 mL) and brine (1×15 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 47 (23.6 mg). MS ESI (pos.) m/e: 422.0 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.34 (1H, s), 7.53 (2H, d, J=8.6 Hz), 7.14 (2H, d, J=8.6 Hz), 7.00 (2H, d, J=8.6 Hz), 6.83 (2H, d, J=8.6 Hz), 6.16 (1H, d), 4.45 (1H, t, J=7.8 Hz), 4.25-4.31 (2H, m), 4.20-4.24 (2H, m), 3.09 (1H, dd, J=16.4, 8.2 Hz), 2.84 (1H, dd, J=16.4, 7.4 Hz).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:25]([CH3:28])([CH3:27])[CH3:26])(=O)=O>C1(C)C=CC=CC=1>[CH3:26][Si:25]([N:9]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([C:3]#[N:2])=[CH:5][CH:6]=1)[Si:25]([CH3:28])([CH3:27])[CH3:26])([CH3:28])[CH3:27]
Reactant: N#Cc1ccc(CN)cc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)N(Cc1ccc(C#N)cc1)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.2 %

Procedure:
About 5.20 g of 4-(aminomethyl)benzonitrile hydrochloride, 10.30 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 15.1 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 3 days to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding 4-[bis(trimethylsilyl)aminomethyl]benzonitrile (4-BTMSAMBZN) as a white solid (8.12 g, 95% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 7.00 (doublet, 2H, aromatic protons), 6.83 (doublet, 2H, aromatic protons), 3.72 (singlet, 2H, CH2 protons), −0.06 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26]#[C:27][CH2:28][N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:7]2
Reactant: [H][H]
Reactant: O=C1c2c(Cl)cc(C#CCN3CCCC3)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1c2c(Cl)cc(CCCN3CCCC3)cc2CN1Cc1ccc(Oc2ccccc2)cc1
Yield: 49.3 %

Procedure:
A mixture of 7-chloro-2-(4-phenoxy-benzyl)-5-(3-pyrrolidin-1-yl-prop-1-ynyl)-2,3-dihydro-isoindol-1-one (0.049 g, 0.11 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-2-(4-phenoxy-benzyl)-5-(3-pyrrolidin-1-yl-propyl)-2,3-dihydro-isoindol-1-one (0.025 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.80 (m, 6H), 2.5 (m, 6H), 2.68 (t, 2H), 4.22 (s, 2H), 4.74 (s, 2H), 6.88-7.38 (m, 11H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:8]=[C:9]([CH2:15][C:16]([OH:34])([C:30]([F:33])([F:32])[F:31])[CH2:17][C:18]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])([CH3:20])[CH3:19])[NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH3:29])=[C:21]([C:18]([CH3:19])([CH3:20])[CH2:17][C:16]([OH:34])([C:30]([F:32])([F:33])[F:31])[CH2:15][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=3[CH:8]=2)[CH:26]=1
Reactant: CCOC(=O)c1cccc2[nH]c(CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc2c(C(=O)O)cccc2[nH]1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
A solution of 2-[4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-indole-4-carboxylic acid ethyl ester (220 mg, 0.470 mmol) in 10 mL of methanol was treated with a solution of potassium hydroxide (85 mg, 1.5 mmol) in 3 mL of water. The resulting mixture was stirred at room temperature for 4 hours, refluxed for 6 hours, cooled to room temperature, and concentrated in vacuo. The residue was treated with cold 1 N sulfuric acid and extracted with three 30 mL portions of dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 190 mg of the title product as a light cream solid (89% yield).
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1[CH:13]=[N:12][CH:11]=[CH:10][N:9]=1)=O)C.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1)([O-:16])=[O:15].C(O)(=O)C>O1CCOCC1>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:6]([C:8]3[CH:13]=[N:12][CH:11]=[CH:10][N:9]=3)=[N:5][CH:4]=[N:2]2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=NC(=O)c1cnccn1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(-n2ncnc2-c2cnccn2)cc1
Temperature: 90 °C

Procedure:
10.0 g. of portion of N-(dimethylaminomethylene)-pyrazine carboxamide is added to a mixture of 10.3 g. of 4-nitrophenylhydrazine, 200 ml. of acetic acid and 50 ml. of p-dioxane. The mixture is heated at 90° C. for 5 hours and evaporated to dryness in vacuo. The residue is recrystallized from ethanol giving 9.0 g. of the desired product as tan crystals, mp. 188°-189° C.
Reaction SMILES: [CH2:1]1[CH2:6][C@@H](N)[C@H](N)C[CH2:2]1.[C:9]([O-:12])([O-])=O.[Na+].[Na+].[C:15]1(=O)[NH:19][C:18](=O)[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>C(Cl)Cl>[CH2:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][N:19]1[C@@H:6]([CH:1]=[CH2:2])[CH2:9][OH:12]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=C[C@@H](CO)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of π-allylpalladium chloride dimer 0.4 mol % (20 mg, 53 μmol), 1.2 mol % (R,R)-DACH ligand (125 mg, 158 μmol, Na2CO3 (70 mg, 0.66 mmol) and phthalimide (1.94 g, 13.2 mmol) in 100 mL of dry CH2Cl2 was purged with nitrogen for 1 h. The resulting mixture was stirred for 10 min at room temperature to which butadiene monoepoxide (FIG. 2, No. 2) (920 mg, 13.2 mmol) was added. The resulting mixture was stirred at room temperature under nitrogen for 14 h, concentrated in vacuo and purified by silica gel column chromatography using ethyl acetate/hexane (3:7) as eluent furnished 2.8 g (98%) yield of (S)-2-(Isoindolin-2-yl) but-3-en-1-ol (FIG. 2, No. 3) as a crystalline white solid. [Rf=0.21, ethyl acetate/hexane (3:7)]; [α]D25 −72.2 (c 2.02, CH2Cl2) [Lit. −72.2 (c 2.02, CH2Cl2)]; IR (CH2Cl2) v: 3467, 1773, 1698, 1467, 1383 cm−1; 1H NMR (400 MHz, CDCl3) δ: 2.7 (bs, 1H), 3.9 (m, 1H), 4.1 (m, 1H), 4.9 (m, 1H), 5.2 (m, 2H), 6.1 (ddd, J=6.4 Hz, 1H), 7.7 (dd, J=3.2, 5.48 Hz, 2H), 7.8 (dd, J=2.76, 5.48 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ: 55.9, 62.8, 118.8, 123.4, 131.7, 131.9, 134.2, 168.5. (Ref: Trost, B. M et al. J. Am. Chem. Soc. 2000, 122, 5968-597).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:5][N:4]=1.OO.[OH2:20].C(OC(=O)C)(=[O:23])C>C(O)(=O)C>[CH3:1][S:2]([C:3]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:5][N:4]=1)(=[O:23])=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: O
Reactant: CSc1nsc(Nc2ccncc2)c1C(N)=O
Agent: OO
Solvent: CC(=O)O
Product: CS(=O)(=O)c1nsc(Nc2ccncc2)c1C(N)=O
Reaction time: 1 h

Procedure:
Compound 8 (500 mg, 1.88 mmol) is slurried in acetic anhydride (1.25 mL) and acetic acid (1.25 mL). Hydrogen peroxide (30%, 0.532 mL, 4.7 mmol) is added and stirred for 1 hour. Additional hydrogen peroxide (30%, 0.532 mL, 4.7 mmol) is then added and the reaction is stirred for 1 hour. Water (about 15 mL) is added and the solids were filtered and further dried in vacuo. These solids were determined to be mainly 3-Methanesulfinyl-5-(pyridin-4-ylamino)-isothiazole-4-carboxylic acid amide. The solids are thus re-combined with the mother liquor and acetic anhydride (2.0 mL), acetic acid (2.0 mL) and hydrogen peroxide (30%, 2 mL) are added and stirred for 18 hours at room temperature. The reaction was then extracted with ethyl acetate (15 mL×3) and the combined organics were dried over sodium sulfate, then filtered and concentrated in vacuo obtain crude 3-Methanesulfonyl-5-(pyridin-4-ylamino)-isothiazole-4-carboxylic acid amide (9) (170 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([N:19](CCC=C)[CH2:20][CH2:21][CH:22]=[CH2:23])[C:13]1C=CC=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:12]([N:19]([CH2:20][CH2:21][CH:22]=[CH2:23])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: C=CCCN(CCC=C)Cc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCCN(CCC=C)C(=O)OCc1ccccc1
Temperature: 70 °C

Procedure:
11.2 mL benzylchloroformate was added to 14 g N-benzyl-N-(but-3-enyl)-but-3-en-1-amine in 100 mL toluene at 0° C. After being heated at 70° C. for 3 h, the reaction mixture was cooled to RT, basified with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate, washed with brine, dried, concentrated, and purified by chromatographie on silica gel (hexane/ethyl acetate 20:1) to yield 16.8 g of the desired product. (M+H)+: 274
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:6](=[O:8])[N:7]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH:19]1([NH:22][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[C:6](=[O:8])[N:7]=2)[CH2:21][CH2:20]1
Reactant: CSC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1N=C(NC2CC2)S/C1=C\c1c[nH]c2ncccc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
The suspension of 2-methylsulfanyl-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-thiazol-4-one (55 mg, 02 mmol, example 14a), cyclopropylamine (23 mg, 0.4 mmol) and diisopropylethylamine (DIEA) (70 uL, 0.4 mmol) in acetonitrile (1.0 mL) was stirred under at 80° C. for 12 h. After cooling to room temperature, the solid was collected by filtration, washed with a little bit of acetonitrile and dried. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 0%-10% methanol in methylene chloride in 30 min) afforded 2-cyclopropylamino-5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-meth-(Z)-ylidene]-thiazol-4-one (40 mg, 71%) as a light yellow solid. LC-MS m/e 285 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][C:32]([NH2:41])([CH3:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:40][C:32]([NH:41][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])([CH3:31])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: CC(C)(N)Cc1ccccc1
Product: CC(C)(Cc1ccccc1)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1,1-dimethyl-2-phenylethylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 82%.
Reaction SMILES: FC(F)(F)C1C=CC2NC3C=CC=CC=3N=C(N3CCN[C@@H](CCOC)C3)C=2C=1.Cl.[CH3:31][C:32]1[S:41][C:40]2[NH:39][C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[N:36]=[C:35]([NH2:46])[C:34]=2[CH:33]=1.[O:47]([CH2:54][C@H:55]1[CH2:60]N[CH2:58][CH2:57][NH:56]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[O:47]([CH2:54][C@@H:55]1[NH:56][CH2:57][CH2:58][N:46]([C:35]2[C:34]3[CH:33]=[C:32]([CH3:31])[S:41][C:40]=3[NH:39][C:38]3[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=3[N:36]=2)[CH2:60]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Reactant: c1ccc(OC[C@H]2CNCCN2)cc1
Agent: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Agent: Cl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](COc2ccccc2)C1
Yield: 39.9 %

Procedure:
By using a method similr to the coupling method for (S)-2-trifluoromethyl-11-[3-(2-methoxy-ethyl)-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine, 2-methyl-4H-3-thia-4,9-diaza-benzo[f]-azulen-10-ylamine hydrochloride (1.2 g) and (R)-2-phenoxymethyl-piperazine (2.6 g) gives the title compound as a yellow solid (728 mg): mp=64-81° C.: 1H NMR (CDCl3) δ 2.32 (s, 3H), 2.86 (dd, 1H), 3.14-2.94 (m, 3H), 3.32-3.24 (m, 1H), 3.98-3.87 (m, 2H), 4.02 (dd, 1H), 4.11 (bd, 1H), 4.96 (bs, 1H), 6.32-6.30 (m, 1H), 6.61 (dd, 1H), 7.00-6.86 (m, 5H), 7.04 (dd, 1H), 7.34-7.25 (m, 2H); MS (APCI) m/z (rel intensity) 405.4 (100).
Reaction SMILES: Cl.Cl.[F:3][C@H:4]1[C@@H:9]([CH2:10][NH:11][C:12]([C:14]2[N:15]=[N:16][C:17]([CH2:33][CH2:34][CH2:35][CH3:36])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)[CH:19]=2)=[O:13])[CH2:8][CH2:7][NH:6][CH2:5]1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[NH3:6].[F:3][C@H:4]1[C@@H:9]([CH2:10][NH:11][C:12]([C:14]2[N:15]=[N:16][C:17]([CH2:33][CH2:34][CH2:35][CH3:36])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][CH:21]=3)[CH:19]=2)=[O:13])[CH2:8][CH2:7][N:6]([CH3:39])[CH2:5]1
Reactant: CCCCc1nnc(C(=O)NC[C@H]2CCNC[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)NC[C@H]2CCN(C)C[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1
Product: N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (±)-cis-6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (3-fluoro-piperidin-4-ylmethyl)-amide dihydrochloride (220 mg, 0.47 mmol) in dichloromethane (1 mL) was added formaldehyde (1 mL) and sodium triacetoxyborohydride (1 mmol, 210 mg). The reaction was stirred at room temperature for 3 h. Reaction was diluted with dichloromethane (5 mL) and washed with saturated sodium bicarbonate solution (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified using dichloromethane:2 M ammonia in methanol to give (±)-cis-6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (3-fluoro-1-methyl-piperidin-4-ylmethyl)-amide.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[NH:7][CH:8]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1>[CH:9]([C:6]1[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[C:4]([I:3])[CH:5]=1)=[O:10]
Reactant: O=Cc1cc(I)c[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cc(I)cc1C=O
Reaction time: 0.25 h
Yield: 49 %

Procedure:
Sodium hydride (1.62 g, 60% w/w dispersion in mineral oil, 67.9 mmol) was added to a solution of 4-iodo-1H-pyrrole-2-carbaldehyde (5.0 g, 22.6 mmol) in tetrahydrofuran (30 mL) over 10 min. The reaction mixture was stirred for 15 min, then ethyl bromoacetate (7.56 g, 45.2 mmol) was added and the mixture stirred for 2 h at ambient temperature. The reaction was quenched with methanol and concentrated in vacuo. The crude compound was then extracted into ethyl acetate. The organic layer washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under in vacuo to afford the crude compound. Purification by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in petroleum ether afforded ethyl 2-(2-formyl-4-iodo-pyrrol-1-yl)acetate (3.4 g, 49%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:14][C:15]([S@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>ClCCCl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:14][C:15]([S@:18](/[N:20]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:4]([O:3][C:2]([F:13])([F:12])[F:1])=[CH:5][CH:6]=1)=[O:19])([CH3:17])[CH3:16]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCCl
Product: CC(C)(C)[S@@](=O)/N=C/c1ccc(OC(F)(F)F)cc1
Temperature: 55 °C
Yield: 102.3 %

Procedure:
To a cloudy solution of 4-(trifluoromethoxy)benzaldehyde (5 g, 26.3 mmol) and (R)-2-methylpropane-2-sulfinamide (3.51 g, 28.9 mmol) in DCE (52 mL), under N2, was added copper (II) sulfate (6.30 g, 39.4 mmol), and the resulting mixture heated in a preheated oil bath at 55° C. for 22 hours. The reaction mixture was filtered through a pad of celite, eluting with DCM. The filtrate was concentrated to afford a viscous yellow oil of (R,E)-2-methyl-N-(4-(trifluoromethoxy)benzylidene)propane-2-sulfinamide (7.9 g, 26.9 mmol, 102% yield). Material was taken onto next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (s, 9H) 7.32 (d, J=8.07 Hz, 2H) 7.91 (d, J=8.75 Hz, 2H) 8.59 (s, 1H). LCMS m/z 294.1 (M+H)+, Rt 1.01 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1.C(OCC)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([C:19]3[S:23][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=4)=[N:21][C:20]=3[CH3:34])=[O:18])[CH2:12]2)=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: Cc1ccc([C@H]2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C(N)=O
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cc1ccc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)cc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.7 %

Procedure:
(R)-2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzamide (230 mg, 0.47 mmol) was dissolved in pyridine (5 mL) and cooled to 0° C. Trifluoroacetic anhydride (0.67 mL, 4.72 mmol) was added dropwise. Stirred for 1 h at 0° C. after addition. The reaction was diluted with diethyl ether (100 mL) and washed with 1 N HCl (2×100 mL) and saturated NaHCO3 (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed with 33% ethyl acetate/hexanes to yield 262 mg (97%) of the desired 2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-benzonitrile as a clear oil.