Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[N:10]([CH2:31][OH:32])[N:9]=1.C(NC(C)C)(C)C.CN(C1C=CC=CN=1)C.[C:49]1(=[O:55])[O:54][C:52](=[O:53])[CH2:51][CH2:50]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][C:13]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[N:14][C:15]=2[NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[N:10]([CH2:31][O:32][C:49](=[O:55])[CH2:50][CH2:51][C:52]([OH:54])=[O:53])[N:9]=1
Reactant: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2CO
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccccn1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)CNc1nc(Oc2ccc(F)cc2F)nc2c1c(-c1ccccc1Cl)nn2COC(=O)CCC(=O)O
Temperature: 25 °C
Yield: 25.7 %

Procedure:
1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-hydroxymethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (2.0 g, 4.3 mmol) was dissolved in 80 mL THF, and diisopropylamine (0.78 g, 5.6 mmol), dimethyamino pyridine (52 mg, 0.4 mmol) and succinic anhydride (703 mg, 7.0 mmol) were added while stirring at room temperature. The reaction mixture was stirred for 16 hours at room temperature, then partitioned between water and ethyl acetate, and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc and purified by flash chromatography (silica gel, hexanes/EtOAc 1:1 to EtOAc/AcOH 100:1) to give 0.62 g of succinic acid mono-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2-hydroxy-propylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl]ester, MS (M+H)=562
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](Cl)=[O:34])=[CH:28][CH:27]=1)([O-:25])=[O:24]>C(Cl)Cl>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[O:34])=[CH:30][CH:31]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: NCCN1CCN(c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)NCCN1CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 89 %

Procedure:
To a stirred solution of 2-(4-Phenyl-piperazin-1-yl)-ethylamine 4a (0.5 g, 2.44 mmol) and Et3N (0.34 g, 3.41 mmol) in 40 mL of dry CH2Cl2 under nitrogen at 0° C. was added a solution (4-Nitro-phenyl)-acetyl chloride (0.58 g, 2.92 mmol). The temperature was allowed to rise to room temperature, the mixture was stirred for 2 h, and then washed with water. The aqueous layer was extracted with dichloromethane. The combined organic phase was washed with saturated sodium chloride, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography over silica gel (EtOAc) to produce 26a: 0.8 g, (89% yield) as a white solid (mp: 138-139° C.). 1H NMR (CDCl3, 400 MHz): δ2.52 (2H, t, J=5.6, CH2—CH2NH), 2.57 (4H, t, J=5.2, (CH2)2N—), 3.11 (4H, t, J=5.2, (CH2)2—NPh), 3.36−3.34 (2H, m, CH2—NHCO), 3.65 (2H, s, CH2Ar), 6.19 (1H, bs, NHCO), 6.86-6.91(3H, m, ArH), 7.25-7.29 (2H, m, ArH), 7.47 (2H, d, J=8.8, ArH), 8.16-8.19 (2H, m, ArH).
Reaction SMILES: C([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([S:23]([Cl:26])(=[O:25])=[O:24])[C:19]([O:21][CH3:22])=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=O)C.[OH-].[NH4+:28].Cl>>[ClH:26].[CH3:22][O:21][C:19]1[C:18]([S:23](=[O:25])(=[O:24])[NH2:28])=[CH:17][C:8]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][NH:4][CH2:5][CH2:6][C:7]=2[CH:20]=1
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)C(c1ccccc1)CN(C(C)=O)CC2
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: COc1cc2c(cc1S(N)(=O)=O)C(c1ccccc1)CNCC2

Procedure:
By the procedure of Example 2, 3-acetyl-8-chlorosulfonyl-7-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine is treated with ammonium hydroxide followed by hydrochloric acid to give 7-methoxy-1-phenyl-8-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [Li+].[BH4-].CO.C([O:7][C:8]([C:10]1[CH:18]=[C:13]2[CH2:14][S:15][CH2:16][CH2:17][N:12]2[N:11]=1)=O)C>C1COCC1>[N:11]1[N:12]2[C:13]([CH2:14][S:15][CH2:16][CH2:17]2)=[CH:18][C:10]=1[CH2:8][OH:7]
Reactant: CCOC(=O)c1cc2n(n1)CCSC2
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc2n(n1)CCSC2
Temperature: 40 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
LiBH4 (cont. 90%) (536 mg) and MeOH (0.9 mL) was added to the THF (59 mL) solution of 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]thiazine-2-carboxylic acid ethyl ester (3.13 g) under a nitrogen atmosphere at room temperature and stirred for 3 h at 40° C. The mixture was quenched with 1 mol/L HCl at pH 1 and stirred for 1 h at room temperature. Solid K2CO3 was added to the solution to adjust pH to 8 and the mixture was extracted with AcOEt. The organic layer was dried (K2CO3) and filtered. The filtrate was concentrated under reduced pressure to afford titled compound as pale yellow oil (2.51 g, quant.).
Reaction SMILES: [N:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)=[C:2]=[O:3].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1>>[C:4]12([NH:1][C:2]([N:34]3[CH2:33][CH2:32][C:31]4[C:36](=[CH:37][C:28]([C:26]5[CH:27]=[C:22]([N:19]6[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]6)[N:23]=[C:24]([NH2:38])[N:25]=5)=[CH:29][CH:30]=4)[CH2:35]3)=[O:3])[CH2:13][CH:8]3[CH2:7][CH:6]([CH2:12][CH:10]([CH2:9]3)[CH2:11]1)[CH2:5]2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)NC35CC6CC(CC(C6)C3)C5)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 5 starting from 1-isocyanatoadamantane (Aldrich, Cat. #375073) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=502.3.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][NH:2]1.CO[C:14]1[CH:19]=[CH:18][CH:17]=[C:16](OC)[CH:15]=1.FC(F)(F)C(O)=O>C(O)(=O)C>[C:14]1([C:9]2[C:8]([OH:11])=[CH:7][CH:6]=[C:5]3[C:10]=2[CH2:1][NH:2][CH2:3][CH2:4]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(OC)c1
Reactant: Oc1ccc2c(c1)CNCC2
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2c(c1-c1ccccc1)CNCC2

Procedure:
Scheme 1 (FIG. 1): Protection of the hydroxyl group in vanillin with benzyl bromide yielded aldehyde 1 is shown in Scheme 1. Henry reaction between aldehyde 1 and nitromethane gave nitrostyrene 2. Reduction of compound 2 with lithium aluminum hydride in tetrahydrofuran (THF) afforded amine 3. The reaction of amine 3 with an excess amount of methyl formate provided formamide 4. Cyclization of amide 4 using phosphorus oxychloride (POCl3) via Bischler-Napieralski reaction obtained 3,4-dihydroisoquinoline 5. Alkylation of compound 5 with iodopropane followed by NaBH4 reduction produced tetrahydroisoquinoline 6 in high yield. Catalytic hydrogenation over Pd/C removed the protective groups of 6 to afford 1,2,3,4-tetrahydroisoquinolin-7-ol 7 in quantitative yield. Treatment of compound 7 with Pb(OAc)4 in acetic acid followed by acid-catalyzed aromatic substitution with 1,3-dimethoxybenzene using trifluoroacetic acid (TFA) furnished 8-phenyl-tetrahydroisoquinolin-7-ol 8.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=C/CCCCCCC.[C:13]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:26][CH2:25]1)(=[O:23])/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:13]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][C:32]([O:34][CH2:1][CH3:2])=[O:33])[CH2:26][CH2:25]1)(=[O:23])/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCC/C=C/C(=O)N1CCN(CCC(=O)O)CC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCN(CCC(=O)OCC)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and ethyl 3-piperazin-1-yl propionate dihydrochloride (ethyl ester of Compound 21) as starting raw materials, to produce ethyl 3-[4-((E)-2-decenoyl)piperazin-1-yl]propionate, and subjected to alkali saponification, to obtain an intended compound as white crystals. White crystals, mp 53°-55° C., C17H30N2O3 MW 310.4, EIMS: m/z 311 [M+H]+, 1H-NMR (500 MHz, DMSO-d6) δ: 0.86 (t, J=7.0 Hz, 3H), 1.19-1.31 (m, 8H), 1.35-1.44 (m, 2H), 2.12-2.20 (m, 2H), 2.32-2.43 (m, 6H), 2.55-2.61 (m, 2H), 3.43-3.57 (m, 4H), 6.45 (d, J=15.0 Hz, 1H), 6.65 (dt, J=15.0, 7.0 Hz, 1H), 11.70-12.70 (brs, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]([CH3:11])=[O:10])[CH:3]=1.[C:12](Cl)(=[O:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:12]([C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:10])[CH3:11])=[CH:3][C:2]=1[CH3:1])(=[O:14])[CH3:13]
Reactant: CC(=O)Cl
Reactant: CC(=O)Nc1cccc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1ccc(C(C)=O)c(C)c1
Reaction time: 1 h

Procedure:
The reaction was run in a 500 mL 3 neck round bottom (RB) fitted with a mechanical stirrer and reflux condenser. To 45 g (301.6 mmol) of 3-methylacetanilide in 240 mL of carbon disulfide under argon at RT was added 38.6 mL (542.8 mmol) of acetyl chloride with stirring. To the solution was then added 145 g (1.09 mol) of aluminum chloride in small portions over a 1 h period. After addition was complete the mixture was refluxed for 1 h and then allowed to cool and stand for 1 h. The supernatant carbon disulfide layer was decanted off and the very dark viscous lower layer was poured into a mixture of cracked ice and hydrochloric acid. The precipitate was collected and washed with 1 L of water. The solid was dried under high vacuum for 30 h at RT no provide 52.17 g (90%) of title amide in the form of a light tan solid which is used as the crude material in the following reaction.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.[NH2:13][OH:14]>CO>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:3]=1[C:4](=[N:13][OH:14])[NH2:5]
Reactant: N#Cc1ccc(CO)cc1F
Reactant: NO
Agent: Cl
Solvent: CO
Product: NC(=NO)c1ccc(CO)cc1F
Temperature: 50 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
To a solution of 2-fluoro-4-hydroxymethylbenzonitrile (CAS 222978-02-1) (2.5 g, 16.5 mmol) in methanol (30 mL) was added hydroxylamine hydrochloride (3 mL, 50 mmol). After heating to 50° C. with stirring for 16 h, the reaction mixture was cooled to RT and concentrated to afford 1.3 g of Intermediate 5.
Reaction SMILES: C(O)(=O)CC[C@H](NC(C1C=CC(NCC2N=C3C(N=C(NC3=O)N)=NC=2)=CC=1)=O)C(O)=[O:6].ON1C(=O)CCC1=O.ON1C2C=CC=CC=2N=N1.[CH:51]1([N:57]=[C:58]=[N:59][CH:60]2[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]2)[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1>CS(C)=O>[C:58]([NH:57][CH:51]1[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]1)([NH:59][CH:60]1[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1)=[O:6]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Nc1nc2ncc(CNc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)nc2c(=O)[nH]1
Agent: O=C1CCC(=O)N1O
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Folic Acid (Sigma Chemical Co., St. Louis, MO. 1 g, 2.1 mmol) was dissolved in 10 ml of dimethyl sulfoxide (Fluka) pre-dried with a molecular sieve. To this solution, N-hydroxysuccinimide (NHS) (Pierce, 0.242 g., 2 mmol) or N-hydroxybenzotriazole (Fluka, 0.270 g., 2 mmol) was added. At this point 1,3-dicyclohexylcarbodiimide (Fluka, 0.872 g., 4 mmol) dissolved in a small volume of dimethyl sulfoxide was then slowly added to this solution. The reaction was allowed to proceed overnight in the dark at room temperature under stirring. Dicyclohexylurea formed as a white precipitate was removed by filtering twice the reaction mixture through 40 mesh filter paper. The DMSO was then removed by distillation under vacuum at 45° C. until the solution became viscous gel. The product (NHS-folate or benzotriazole-folate) was then crystallized in an excess volume of anhydrous ether. A small amount of methanol was added to accelerate the crystallization process. A fine yellow powder of NHS-folate or benzotriazole-folate formed at this point was subsequently washed twice with anhydrous ether. The product was then dried under vacuum and stored at 4° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl.[Cl:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O.O>[ClH:21].[N:24]1([CH2:23][CH2:22][O:1][CH2:2][C:3]2[C:11]3[O:10][C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:8][C:7]=3[CH:6]=[CH:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ClCCN1CCCCC1
Reactant: OCc1cccc2cc(-c3ccccc3)oc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(-c2cc3cccc(COCCN4CCCCC4)c3o2)cc1
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
7-Hydroxymethyl-2-phenylbenzofuran (1.57 g) is dissolved in dimethylsulfoxide (10 ml), and sodium hydride (60% oil dispersion) (0.57 g) is added thereto. After the mixture is stirred for 10 minutes, N-(2-chloroethyl)piperidine hydrochloride (1.35 g) is added to the mixture and the mixture is stirred at room temperature for 4 hours. The mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is converted to its hydrochloride and recrystallized from ethyl acetate, whereby 7-[(2-piperidinoethoxy)methyl]-2-phenylbenzofuran hydrochloride (1.32 g) is obtained. Yield: 51%.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([NH2:10])=[CH:8][N:7]=[CH:6][N:5]=1.[CH3:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=O.P(Cl)(Cl)(Cl)=O>C(O)C>[CH3:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][CH:8]=2)[N:3]=1
Reactant: Nc1cncnc1N
Reactant: COc1cc(SC)ccc1C(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(SC)ccc1-c1nc2ncncc2[nH]1

Procedure:
A mixture of 4.1 g of 4,5-diamino-pyrimidine dihydrochloride, 7.1 g of 2-methoxy-4-methylmercapto-benzoylchloride, and 50 ml of phosphorus oxychloride was refluxed for three hours. The reaction mixture was evaporated until one-half of the original volume remained, and then the remaining mixture was poured into water. The precipitate that formed was dissolved in boiling ethanol, precipitated by addition of ether, and purified by chromatography on silicagel (eluate: methylene chloride/ethanol in a volume ratio of 19:1).
Reaction SMILES: [F-].[K+].[C:3]([C:7]1[C:8](=[O:18])[C:9](=[O:17])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].C(O)(=O)C.C([Si](CC)(CC)[C:26]([F:29])([F:28])[F:27])C>C(#N)C>[C:13]([C:11]1[CH:12]=[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[C:8](=[O:18])[C:9]([OH:17])([C:26]([F:29])([F:28])[F:27])[CH:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC[Si](CC)(CC)C(F)(F)F
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Agent: [F-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)C1=CC(O)(C(F)(F)F)C(=O)C(C(C)(C)C)=C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
A mixture of 100 mg (1.7 mmol) of potassium fluoride, 132 mg (0.60 mmol) of 3,5-di-tert-butyl-1,2-benzoquinone, and 2 mL of acetonitrile was treated successively with 40 μL (0.70 mmol) of glacal acetic acid and 129 mg (0.70 mmol) of triethyltrifloromethylsilane, and stirred vigorously at room temperature for 15 minutes. The mixture was filtered and the filter cake was washed with dichloromethane. Concentration of the combined filtrates afforded a residue which was purified by PTLC (one 2 mm silica gel plate eluted with 20% dichloromethane--80% petroleum ether) to give 27 mg (16% yield) of 4,6-di-tert-butyl-2-hydroxy-2-trifluoromethyl-3,5-cyclohexadiene-one.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17](O)=[O:18])=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:29][NH2:30].Cl>ClCCl.CN(C)C=O>[OH:29][NH:30][C:17](=[O:18])/[CH:16]=[CH:15]/[C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:20])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)O)c2)cc1
Reactant: C[Si](C)(C)ON
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc(/C=C/C(=O)NO)c2)cc1
Reaction time: 1.5 h
Yield: 20.6 %

Procedure:
0.231 g of (E)-3-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid (compound A1) are dissolved in 8 ml of dichloromethane at room temperature. Then 50 μl of N,N-dimethylformamide (DMF) are added, 0.275 g of oxalic acid chloride dissolved in 2 ml of dichoromethane are added dropwise and stirred for 1.5 hour. To the solution are added 0.439 g of O-(trimethylsilyl)hydroxylamine and stirred for 15 minutes. Then 20 ml of aqueous hydrochloric acid (1 M strength) are added and extracted with ethyl acetate. The combined organic phase is dried over sodium sulfate. Afterwards it is filtered and evaporated under vacuo. The crude product is purified by silica gel flash chromatography using a gradient of dichloromethane and methanol from 98:2 to 6:4 to yield 0.050 g of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:20](=[O:21])[C:19]3[C:18]4[C:13](=[CH:14][C:15]([C:22]#[N:23])=[CH:16][CH:17]=4)[NH:12][C:11]=3[C:10]([CH3:25])([CH3:24])[C:9]=2[CH:26]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:25][C:10]1([CH3:24])[C:11]2[NH:12][C:13]3[C:18](=[CH:17][CH:16]=[C:15]([C:22]#[N:23])[CH:14]=3)[C:19]=2[C:20](=[O:21])[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]3)=[CH:26][C:9]1=2
Reactant: O=C1CNCCN1
Reactant: CC1(C)c2cc(OCCBr)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)c2cc(OCCN3CCNC(=O)C3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 80 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To DMF solution (5 mL) of 8-(2-bromo-ethoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A7-24, 30 mg, 0.07 mmol), piperazin-2-one (44.9 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.061 mL, 0.35 mmol) were added at room temperature and stirred at 80° C. for 18 hr. After cooling to room temperature, the mixture was extracted with ethyl acetate washed with saturated brine. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by preparative TLC (dichloromethane/methanol) to obtain the title compound (white solid, 24 mg, 80%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:31].[Na+]>O.C(OCC)(=O)C.C(OCC)(=O)C.O.[Ru](=O)=O>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([O:26][CH3:27])[CH:24]=[CH:25][C:20]=3[O:19][CH2:18][C:17]2=[O:28])[C:12](=[O:31])[CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1=O)C(=O)CO2
Temperature: 25 °C
Reaction time: 53 h
Yield: 24.5 %

Procedure:
A mixture of tert-butyl{1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 47, 1.39 g, 3.4 mmol) in water/ethyl acetate (40 mL, 4:1) was treated with sodium periodate (2.8 g, 21.4 mmol) and ruthenium (IV) oxide hydrate (50 mg, 0.34 mmol) at room temperature. After 53 hours, the reaction was diluted with ethyl acetate, the aqueous phase was extracted with ethyl acetate (6×25 mL), and the combined organic layers were mixed with 2-propanol (20 mL) and stirred for 2 hours at room temperature. The reaction mixture was then filtered through celite, dried over sodium sulfate, and concentrated in vacuo. Chromatography on silica gel with dichloromethane/methanol (95:5) gave 350 mg (25%) of the product as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.[CH:10]1([C:14]([C:16](=[CH:22]OCC)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])[CH2:13][CH2:12][CH2:11]1>>[CH:10]1([C:14]([C:16](=[CH:22][NH:9][C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])[CH2:11][CH2:12][CH2:13]1
Reactant: COc1ccc(N)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)C1CCC1
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)C1CCC1

Procedure:
Ethyl 2-(cyclobutanecarbonyl)-3-((6-methoxypyridin-3-yl)amino)acrylate was prepared with conditions described in Example 99 using 2-methoxy-5-aminopyridine and ethyl 2-(cyclobutanecarbonyl)-3-ethoxyacrylate.
Reaction SMILES: [CH2:1]([O:8][C@@:9]1([C:36]([F:39])([F:38])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][NH2:35])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:41][CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45].[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C@@:9]1([C:36]([F:38])([F:39])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=5)[C:24]=4[CH:25]=3)[C@:12]2([CH2:34][N:35]2[CH2:41][CH2:42][CH2:43][S:44]2(=[O:46])=[O:45])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Reactant: O=S(=O)(Cl)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=S1(=O)CCCN1C[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 50 °C
Yield: 64.2 %

Procedure:
A solution of ((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methanamine (34, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rg=Benzyl) (82 mg, 0.153 mmol) in DCM (3 mL) was treated with TEA (0.021 mL, 0.153 mmol) and 3-chloro-propane-1-sulfonyl chloride (0.023 mL, 0.19 mmol) at rt under nitrogen for about 1 h. The organic layer was washed with 2N aq. HCl (2 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and added dropwise to a suspension of sodium hydride (60 wt % in oil, 7.6 mg, 0.30 mmol) in DMF (1 mL). The reaction was heated at about 50° C. for 2 h and then cooled to rt and concentrate under reduced pressure. The residue was purified on silica gel (4 g) using a gradient of 0-30% EtOAc in DCM. Product fractions were combined and concentrated to yield 2-(((3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-12b-yl)methyl)isothiazolidine 1,1-dioxide (35, R1=4-Fluorophenyl, R3=Trifluoromethyl, Rg=Benzyl) (63 mg, 64%) as an oil. LC/MS, method 3, Rt=3.01 min, MS m/z 642 (M+H)+. The oil was used in step #2 without further purification.