Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:33])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N+](C)([O-])=O.Cl>CCOCC>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:33])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][CH:25]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)C(=O)Nc1nc(O)c2cc(C#Cc3ccc(C(=O)O)cc3)cnc2n1
Temperature: 0 °C
Yield: 92.6 %

Procedure:
One gram of 2-pivaloylamino-4-hydroxy-6-(4-tert.-butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine is added to 25 ml of nitromethane saturated with hydrogen chloride gas at 0° C. After stirring at 0° C., the reaction mixture is allowed to reach room temperature and stirred for an additional hour. The suspension is diluted with anhydrous ether and suction filtered. The collected solid is washed with ether, methanol, and ether again, and then dried under reduced pressure to give 0.81 g of 2-pivaloylamino-4-hydroxy-6-(4-carboxyphenylethynyl)pyrido[2,3-d]pyrimidine as a yellowish powder: m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.25 (s, 9H), 7.72 (d, 2H, J=8.02 Hz), 7.98 (d, 2H, J=8.02 Hz), 8.52 (d, 1H, J=2.01 Hz), 9.01 (d, 1H, J=2.01 Hz); IR (KBr) 3420, 3000, 1725, 1680, 1425, 1405, 1360, 1250, 1130, 1020, and 800 cm-1.
Reaction SMILES: [OH:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[C@H:12]([OH:21])[CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:22])[CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[S:24]([O:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[C@H:12]([O:21][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:22][S:24]([CH3:23])(=[O:26])=[O:25])[CH:3]=1)([CH3:23])(=[O:26])=[O:25]
Reactant: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1C[C@@H](O)C2=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4c(cc(OS(C)(=O)=O)cc4OS(C)(=O)=O)CC[C@@H]3[C@@H]1C[C@@H](OS(C)(=O)=O)C2=O
Temperature: 0 °C

Procedure:
A solution of 400 mg. of 1,3,16α-trihydroxy-8α-estra-1,3,5(10)-trien-17-one in 5 ml. of pyridine is combined at 0° C. with 1.5 ml. of methanesulfonic acid chloride and agitated for 3 days at 0°-10° C. The mixture is thereafter introduced inyo ice water (acidified with HCl), filtered off, and the residue is dissolved in methylene chloride. After chromatography on SiO2, 250 mg. of 1,3,16α-tris(mesyloxy)-8α-estra-1,3,5(10)-trien-17-one is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CO.[ClH:47]>C(O)(C)C>[ClH:47].[ClH:47].[C:1]([C:5]1[CH:6]=[C:7]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:8]([O:38][CH3:39])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:37])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COc1c(NC(=O)c2cc3cccc(CN4CCNCC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2.29 g tert-butyl 4-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperazine-1-carboxylate are dissolved in 25 ml of a 5 M solution of HCl in isopropanol and stirred for 12 hours at ambient temperature. Then the solvents are eliminated in vacuo and the residue is twice taken up with 20 ml of methanol and this is then eliminated again in vacuo.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:48]=[CH:47][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:46]=[CH:45][C:28]([C:29]([NH:31][CH2:32][C:33]([CH3:44])([CH3:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)=[O:30])=[CH:27][CH:26]=3)[CH:13]=2)=[CH:8][CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:35][CH2:34][C:33]([CH3:44])([CH3:43])[CH2:32][NH:31][C:29](=[O:30])[C:28]1[CH:45]=[CH:46][C:25]([NH:24][C:14]2[CH:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:47]=[CH:48][C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:7][CH:8]=3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2cc(NCc3ccc(OCCCBr)cc3)nc(OCC(F)(F)F)n2)cc1

Procedure:
tert-butyl (3-(4-((6-((4-(3-bromopropoxy)benzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate (100 mg, 0.14 mmol) was stirred in TFA/DCM (1:1) solution (2 mL) for 15 mins. The solution was concentrated under vacuum to give N-(3-amino-2,2-dimethylpropyl)-4-((6-((4-(3-bromopropoxy)benzyl)amino)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzamide which was carried to the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:11]([O:13][C:14](=[O:17])[CH2:15]Br)[CH3:12].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:11]([O:13][C:14](=[O:17])[CH2:15][O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[C:7]#[N:8])[CH3:12]
Reactant: N#Cc1cc(Cl)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(Cl)cc1C#N
Yield: 98.2 %

Procedure:
To a solution of 5-chloro-2-hydroxy-benzonitrile (10 g, 65.0 mmol) in acetone (100 mL) was added ethylbromoacetate (11 g, 71.4 mmol) followed by K2CO3 (19.7 g, 143 mmol). After heating at reflux for 10 h, the mixture was filtered and the filtrate was concentrated to afford the desired product (15.3 g), which was used in the next step without further purification. 1H NMR (CDCl3): 7.57 (d, J=2.5 Hz, 1H), 7.48 (dd, J=9.0, 2.5 Hz, 1H), 6.81 (d, J=9.0 Hz 1H), 4.78 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[N:31][OH:32])[CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCCC(=O)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC(=NO)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Yield: 82 %

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-(4-butyrylphenyl)isoquinoline (0.27 g) obtained in the previous Example was dissolved in ethanol (40 ml), to which was then added a solution of hydroxylamine hydrochloride (0.14 g) and sodium acetate (0.22 g) dissolved in water (10 ml), and the mixture was heated under reflux. The solvent was evaporated, and the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/methanol system), to give 0.23 g of the free compound of the title compound as a pale brown amorphous.
Reaction SMILES: C([CH:3]([C:26]([OH:28])=[O:27])[N:4]([C:19](OC(C)(C)C)=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:7]([C:17]#[N:18])[CH:6]=1)C.F[C:30](F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:19]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:7]([C:17]#[N:18])[CH:6]=1)[CH2:3][C:26]([OH:28])=[O:27])[CH3:30]
Reactant: O=C(O)C(F)(F)F
Reactant: CCC(C(=O)O)N(C(=O)OC(C)(C)C)c1ccc(OCC(C)(C)C)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN(CC(=O)O)c1ccc(OCC(C)(C)C)c(C#N)c1
Reaction time: 1 h

Procedure:
To dimethylformamide solution (240 ml) containing N-(3-cyano-4-neopentyloxyphenyl)-tert-butoxycarboxamide (24.5 g) was added sodium hydride (60% content, 1.15 g) under ice-cooling and the mixture was stirred for 30 min. The mixture was warmed to room temperature and stirred further for 1 h. The reaction mixture was ice-cooled and ethyl bromoacetate (24.5 g) was added, which was followed by stirring for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 0.1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give ethyl N-tert-butoxycarbonyl-N-(3-cyano-4-neopentyloxyphenyl)glycine (36.5 g) as an oily substance. The obtained ethyl N-tert-butoxycarbonyl-N-(3-cyano-4-neopentyloxyphenyl)glycine (8.2 g) was added to trifluoroacetic acid (24 ml) at room temperature and the mixture was stirred for 1 h. The reaction mixture was poured into an aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (5.9 g), melting point: 78° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][C:5]=3[NH:6][C:7]=2[C:8]([F:11])=[CH:9][CH:10]=1.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:4]3[CH2:15][N:14]([CH3:16])[CH2:13][CH2:12][C:5]=3[N:6]([CH2:30][CH2:31][C:32]3[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=3)[C:7]=2[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: CN1CCc2[nH]c3c(F)ccc(Cl)c3c2C1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4c(Cl)ccc(F)c42)CN(C)CC3)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (500 mg, 2.1 mmol) in DMF (5 mL), sodium hydride (252 mg, 6.3 mmol) was added. After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (1.5 g, 5.25 mmol) was added to the reaction mixture and stirred at the same temperature for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase HPLC to obtain the 9-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA) δ (ppm): 8.37 (s, 1H), 8.12 (d, 1H), 7.73 (d, 1H), 7.02 (dd, 1H), 6.86 (t, 1H), 5.1 (m, 1H), 4.57 (t, 2H), 4.56 (m, 1H), 3.85 (m, 1H), 3.6 (m, 1H), 3.27 (m, 3H), 3.2 m (2H), 3.1 (s, 3H), 2.69 (s, 3H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:17][CH2:18]O>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([SH:1])=[CH:7][CH:6]=1)[CH3:18]
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(S)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-mercapto-phenyl)-acetic acid (5.0 g, 29.8 mmol) in absolute EtOH (100 mL) at room temperature was added concentrated H2SO4 (10 mL) and the mixture was warmed to reflux. After 4 hrs, the reaction was cooled to room temperature, evaporated under reduced pressure, diluted with DCM (500 mL) and stirred over solid K2CO3. After 1 hr, the resulting mixture was filtered and concentrated to dryness to afford the title compound.
Reaction SMILES: C([O:3][C:4](=[O:32])/[CH:5]=[C:6](\[CH3:31])/[CH:7]=[CH:8]/[CH:9]=[C:10](/[C:15]1[C:24]([O:25][CH3:26])=[CH:23][C:22]2[C:21]([CH3:28])([CH3:27])[CH2:20][CH2:19][C:18]([CH3:30])([CH3:29])[C:17]=2[CH:16]=1)\[C:11]([F:14])([F:13])[F:12])C.[OH-].[Na+].Cl>CCO>[F:12][C:11]([F:13])([F:14])/[C:10](/[C:15]1[C:24]([O:25][CH3:26])=[CH:23][C:22]2[C:21]([CH3:27])([CH3:28])[CH2:20][CH2:19][C:18]([CH3:30])([CH3:29])[C:17]=2[CH:16]=1)=[CH:9]\[CH:8]=[CH:7]\[C:6](\[CH3:31])=[CH:5]\[C:4]([OH:32])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(/c1cc2c(cc1OC)C(C)(C)CCC2(C)C)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc2c(cc1/C(=C/C=C/C(C)=C/C(=O)O)C(F)(F)F)C(C)(C)CCC2(C)C
Temperature: 60 °C
Yield: 93.4 %

Procedure:
To a solution of (2E,4E,6Z)-8,8,8-trifluoro-7-(3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-3-methyl-octa-2,4,6-trienoic acid ethyl ester (Compound 1, 87 mg, 0.19 mmol) in EtOH (2 mL) was added 1M NaOH (0.68 mL). The mixture was heated to 60° C. for 2 h, was cooled to ambient temperature, acidified with 1M HCl, and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (40% EtOAc-hexane) and HPLC (20% EtOAc-hexane) to give the title compound as a white solid (75 mg, 92%).
Reaction SMILES: Cl[Si:2]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3].[Li].[CH3:11][C:12]1[CH-:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2>C(OCC)C>[CH3:11][C:12]1[CH:13]([Si:2]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:3])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: Cc1cc2ccccc2[cH-]1
Agent: [Li]
Solvent: CCOCC
Product: CC1=Cc2ccccc2C1[Si](C)(C)NC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.4 %

Procedure:
Chloro(t-butylamino)dimethylsilane (9.57 g, 0.058 moles) was stirred in diethylether (150 mL) at 0° C. as lithium-2-methylindenide (7.68 g, 0.058 moles) was added as a solid over a 15 minute period of time. The mixture was then allowed to stir for 16 hours at room temperature. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. Removal of the volatiles resulted in the isolation of the desired product as a pale yellow oil (9.99 g, 67.5 percent).
Reaction SMILES: [S:1](Cl)(Cl)=O.[NH2:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13].Cl>N1C=CC=CC=1>[CH3:13][C:7]1[C:6]2[C:11](=[N:12][S:1][N:5]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cccc2nsnc12
Temperature: 25 °C

Procedure:
Thionyl chloride (166 g, 1.4 mol) was added to a solution of 2,3-diaminotoluene (71 g, 0.58 mol) in pyridine (430 mL) dropwise at a temperature below 45° C. Concentrated HCl (300 mL) was then added dropwise while care was taken to ensure that the reaction temperature did not exceed 65° C. After cooling to room temperature, the reaction mixture was subjected to a steam distillation. The light-yellow oil suspension in the water layer was extracted with diethyl ether. The combined extracts were washed with brine and dried over Na2SO4. After removal of the solvent by rotary evaporation, 4-methyl-2,1,3-benzothiadiazole was obtained as a light-yellow liquid in 92% (80.6 g) of yield. Rf=0.62 (hexane/ethyl acetate=3:1); 1H NMR (200 MHz, CDCl3) δ2.74 (s, 3H), 7.34 (m, 1H), 7.48 (d,J1=8.7 Hz, J2=6.7 Hz, 1H), 7.83 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)=O.[C:23]([CH2:26][C:27](=O)[CH3:28])(=[O:25])[CH3:24]>CCCCCCC.C(OCC)(=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:27]([CH3:28])[C:26]=2[C:23](=[O:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)CC(C)=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1c(C)nc2ccc(OC(F)(F)F)cc2c1-c1ccc(Cl)c(Cl)c1
Yield: 59 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(3,4-dichloro-phenyl)-methanone [example A4] and acetylacetone according to the method of example 1, except that heptane/ethyl acetate (1:2). Yield: 59%. MS: m/z=414 (M).
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][OH:22])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=3)[N:11]([CH2:20][CH2:21][O:22][S:32]([CH3:31])(=[O:34])=[O:33])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCOS(C)(=O)=O
Temperature: 0 °C
Yield: 28.9 %

Procedure:
To a solution of 6-fluoro-9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (37) (460 mg, 1.4 mmol) in dichloromethane (20 mL) was added pyridine (1.11 g, 14.0 mmol, 1.1 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (722 mg, 6.3 mmol, 0.5 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×30 mL) and water (2×30 mL), dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (0-100% (B), 10 g, 45 CV, 30 mL/min) then triturated with diethyl ether to afford 166 mg (30%) of methanesulfonic acid 2-(4-diethylcarbamoyl-6-fluoro-1,2,3,4-tetrahydro-carbazol-9-yl)-ethyl ester (precursor compound 9) as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 12.9, 15.0, 21.1, 27.7, 36.1, 36.7, 40.6, 41.7, 67.8, 103.3 (d, JCF=23 Hz), 108.7, 109.0, 109.1, 109.4 (d, JCF=5 Hz), 126.9 (d, JCF=10 Hz), 132.4, 138.4, 156.1, 159.2, and 173.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[N:19](COCC[Si](C)(C)C)[CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[C:21]([C:23]#[N:24])[N:22]=2)=[O:17])=[C:11]([C:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]=2)[CH:10]=1)[C:3]([O:2][CH3:1])=[O:39]
Reactant: COC(=O)C(C(=O)OC)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C(=O)OC)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of 2-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-malonic acid dimethyl ester (as prepared in the previous step, 145 mg, 0.262 mmol) in 1.0 mL of DCM (CH2Cl2) was added 1.0 mL of TFA. After stirring at RT for 4 h, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (20-30% EtOAc-hexane) to give 93 mg (84%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C22H22N4O5, 423.1 (M+H). found 422.8.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[OH:4].[CH3:11][C:12](O)([C:15]#[N:16])[CH:13]=[CH2:14].P(=O)(O)(O)O.B(F)(F)F>C1(C)C=CC=CC=1.[N+](C)([O-])=O>[OH:4][C:3]1[C:5]([CH3:10])=[C:6]2[C:7](=[CH:8][C:2]=1[CH3:1])[O:9][C:12]([CH3:11])([C:15]#[N:16])[CH2:13][CH2:14]2
Reactant: Cc1cc(O)cc(C)c1O
Reactant: C=CC(C)(O)C#N
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: C[N+](=O)[O-]
Product: Cc1cc2c(c(C)c1O)CCC(C)(C#N)O2
Yield: 79 %

Procedure:
Using the method described in the last paragraph of Example 1, 23.3 g (0.169 mole) of 2,6-dimethylhydroquinone were reacted with 16.6 g (0.169 mole) of methyl vinyl ketone cyanohydrin, stabilized with 1 g of phosphoric acid, in 125 ml of toluene and 17 ml of nitromethane in the presence of 11.5 g (0.169 mole) of BF3. Conventional working up gave 6-hydroxy-2,5,7-trimethyl-2-cyanochromane in the form of colorless crystals, in 79% yield; melting point 135° C.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:10]=1[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:37]([CH2:44][C:45](=O)[CH3:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(O)(=O)C>O1CCCC1>[CH3:7][O:8][C:9]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:10]=1[CH:11]=[C:45]([CH3:46])[CH2:44][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: COc1ccc(OC)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(OC)c(C=C(C)CCc2ccccc2)c1

Procedure:
A solution of n-butyl lithium (29 ml. of 2.2 M) is added dropwise to 2,5-dimethoxybenzyl triphenylphosphonium bromide (31.5 g.) in tetrahydrofuran (200 ml.) with stirring and the resulting deep red solution is stirred for one-half hour. Benzyl acetone (9.4 g.) is added dropwise and the reaction mixture stirred for 12 hours. It is then adjusted to pH 7 by addition of acetic acid and concentrated under reduced pressure. The residue is extracted with methylene chloride and the extract evaporated to give crude 1-(2,5-dimethoxyphenyl)-2-methyl-4-phenyl-1-butene as an oil. It is purified by chromatography on silica gel and elution with benzene.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.[F:13][C:14]1([C:18]2[CH:23]=[CH:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH:19]=2)[CH2:17][O:16][CH2:15]1>>[F:13][C:14]1([C:18]2[CH:23]=[CH:22][C:21]([C:2]3[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=3)=[CH:20][CH:19]=2)[CH2:17][O:16][CH2:15]1
Reactant: CC1(C)OB(c2ccc(C3(F)COC3)cc2)OC1(C)C
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Product: NC(=O)c1cc(-c2ccc(C3(F)COC3)cc2)sc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the general procedure in Intermediate 10 Step 5 using 5-bromo-2-nitrothiophene-3-carboxamide (Intermediate 10, Step 4) (0.31 g, 1.23 mmol) and 2-[4-(3-fluorooxetan-3-yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.378 g, 1.36 mmol) as the starting materials.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[S:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)[CH:21]=3)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([S:7]([NH:6][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:8])=[O:9])[CH:18]=2)[C:14]([C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:21]=2)=[CH:15]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4cc(-c5ccncc5)cc(C(F)(F)F)c4)cn(C)c3c2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cc(-c3ccncc3)cc(C(F)(F)F)c2)c2ccc(S(=O)(=O)Nc3ncns3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.7 %

Procedure:
N-(2,4-dimethoxybenzyl)-1-methyl-3-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.050 g, 0.075 mmol) was dissolved in 0.5 mL of DCM and TFA (0.5 ml, 6.49 mmol) was added. The reaction was stirred for 15 minutes at room temperature. The reaction was concentrated, dissolved in acetonitrile, and passed through a PEAX ion exchange column (purchased from Biotage, LLC, Charlotte, N.C.). The column was flushed several times with acetonitrile, then the product was liberated by flushing several times with an 1M HCl solution in 15% MeOH/EtOAc. The solution was concentrated to afford 1-methyl-3-(3-(pyridin-4-yl)-5-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (0.029 g, 0.056 mmol, 75% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.94-8.84 (m, 2 H), 8.46 (s, 1 H), 8.41 (s, 1 H), 8.32 (s, 1 H), 8.30 (d, J=6.1 Hz, 2 H), 8.14-8.09 (m, 3 H), 8.05 (d, J=1.3 Hz, 1 H), 7.62 (dd, J=1.6, 8.6 Hz, 1 H), 3.98 (s, 3 H). m/z (ESI). 516.0 (M+H)+.