Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[C:16]2[C:17](=[O:31])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:15]=2[NH:14][N:13]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[C:16]2[C:17](=[O:31])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[N:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:15]=2[NH:14][N:13]=1
Reactant: O=c1c2c(CCc3ccccc3[N+](=O)[O-])n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccccc1CCc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Reaction time: 8 h
Yield: 8.7 %

Procedure:
To a solution of 3-[2-(2-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (420 mg, 11.0 mmol, prepared in Example 16) in DMF (45 ml) and methanol (20 ml) was added activated carbon-palladium (45 mg), and the mixture was stirred overnight under hydrogen atmosphere, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-[2-(2-aminophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (364 mg, 94%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:32])=[C:16]([N:21]4[C:29](=O)[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22]4=O)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:33])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:32])=[C:16]([N:21]4[CH2:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:29]4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]=2[CH3:33])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1oc2c(C)c(C)c(N3C(=O)c4ccccc4C3=O)c(C)c2c1-c1ccc(C(C)C)cc1
Solvent: CCO
Product: Cc1oc2c(C)c(C)c(N3Cc4ccccc4C3)c(C)c2c1-c1ccc(C(C)C)cc1
Yield: 70 %

Procedure:
By using 2-[3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione, the title compound was synthesized according to Example 2a. Yield: 70%. Melting point: 126-129° C. (Ethanol)
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15].C(N(CC)CC)C.[C:23](Cl)(=[O:27])[C:24]([CH3:26])=[CH2:25]>CN(C1C=CN=CC=1)C.CN(C)C=O>[F:1][C:2]1[C:7]([S:8]([NH:11][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25])(=[O:10])=[O:9])=[C:6]([F:12])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: NS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=C(C)C(=O)NS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Yield: 61.9 %

Procedure:
Using 24.7 g (0.1 mol) of pentafluorobenzene-sulfonamide, 1.2 g (0.01 mol) of 4-(N,N-dimethylamino)pyridine, 22.3 g (0.22 mol) of triethylamine, 13.5 g (0.12 mol) of methacryloyl chloride, and 100 ml of dimethylformamide, reaction was conducted in the same manner as in Synthesis Example 1. As a result, 19.5 g of N-(pentafluorobenzene-sulfonyl)methacrylamide was obtained (yield, 61.9%; light-yellow crystals; m.p., 133-133.5° C.).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][Si:12](Cl)([CH3:14])[CH3:13]>C(OCC)C>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:7]1[S:6][CH:10]=[CH:9][N:8]=1
Reactant: c1cscn1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1nccs1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a mixture of 40.6 ml n-butyl lithium (1.6M in hexane) and 18 ml diethylether is added dropwise at −70° C. a solution of 5.03 g thiazole dissolved in 59 ml diethylether. After 30 min 6.41 g trimethylsilylchloride dissolved in 59 ml diethylether is added at −70° C. The reaction mixture is stirred at −70° C. for 1 h and allowed to warm up to room temperature. The mixture is washed with saturated NaHCO3 solution, dried over Na2SO4 and the solvent is evaporated. The residue is distilled, to yield the desired product.
Reaction SMILES: [CH2:1]([N:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:5](=[O:18])[C@@H:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:7]C=C)[CH:2]=[CH2:3]>C(Cl)CCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[O:18]=[C:5]1[C@@H:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:7][CH:3]=[CH:2][CH2:1][N:4]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC=C)c1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC=CCN(c2ccccc2)C1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A solution of (S)-tert-butyl 1-(allyl(phenyl)amino)-1-oxopent-4-en-2-ylcarbamate (0.98 g, 2.97 mmol) in ClCH2CH2Cl (400 mL) was degassed with argon for 5 min. Then, Grubbs II catalyst (0.126 g, 0.148 mmol) was added. The reaction was stirred at 60° C. under argon for 16 hr. The reaction mixture was cooled to rt and concentrated to dryness. The brownish residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex to give (S,Z)-tert-butyl 2-oxo-1-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (0.787 g, 2.60 mmol, 88% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.42-7.34 (m, 2H), 7.30-7.24 (m, 1H), 7.24-7.19 (m, 2H), 6.06-5.66 (m, 2H), 5.23-5.10 (m, 1H), 4.79 (dd, J=21.1, 17.3 Hz, 1H), 3.85-3.71 (m, 1H), 2.85-2.70 (m, 1H), 2.43-2.29 (m, 1H), 1.55-1.43 (m, 10H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.C([Si](C)(C)[O:16][CH:17]([CH2:42][C:43](=[O:54])[NH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[CH2:18][CH:19]([OH:41])[CH2:20][CH2:21][CH:22]1[CH:31]2[C:26](=[CH:27][CH:28]([CH3:39])[CH2:29][CH:30]2[O:32][C:33](=[O:38])[CH:34]([CH3:37])[CH2:35][CH3:36])[CH:25]=[CH:24][CH:23]1[CH3:40])(C)(C)C.CCN(CC)CC>C(Cl)Cl>[OH:16][CH:17]([CH2:42][C:43](=[O:54])[NH:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[CH2:18][C:19](=[O:41])[CH2:20][CH2:21][CH:22]1[CH:31]2[C:26](=[CH:27][CH:28]([CH3:39])[CH2:29][CH:30]2[O:32][C:33](=[O:38])[CH:34]([CH3:37])[CH2:35][CH3:36])[CH:25]=[CH:24][CH:23]1[CH3:40]
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(O)CC(CC(=O)NCc3ccc(OC)cc3)O[Si](C)(C)C(C)(C)C)C21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(=O)CC(O)CC(=O)NCc3ccc(OC)cc3)C21
Reaction time: 2 h

Procedure:
A solution of 0.18 ml oxalyl chloride in 10 ml CH2Cl2 is slowly treated at −60° C. with 0.33 ml DMSO. After 15 minutes stirring at −60° C. a cold solution (−78° C.) of 2-methyl-butyric acid 8-[5-(tert-butyl-dimethyl-silanyloxy)-3-hydroxy-6-(4-methoxy-benzylcarbamoyl)-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester in 5 ml CH2Cl2 is added. After 2 hours at −60° C., 0.80 ml of NEt3 is added and the temperature is slowly rised to room temperature. After 2 hours at room temperature the reaction is quenched with H2O. The phases are separated and the organic phase dried and concentrated. The crude product is purified by silica gel chromatography (CH2Cl2/MeOH). The resulting compound is dissolved in THF and treated with AcOH and Bu4NF.3H2O. After 30 hours the reaction mixture is concentrated, diluted with AcOEt and washed with H2O, sat. NaHCO3, brine, then dried (Na2SO4) and concentrated. The crude product is purified by silica gel chromatography. Pure fractions are combined and evaporated to afford 2-methyl-butyric acid 8-[5-hydroxy-6-(4-methoxy-benzylcarbamoyl)-3-oxo-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester as foam.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:12])=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(Cl)Cl.CC([O-])=O.[K+].Br[C:22]1[S:23][C:24]2[C:30]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[C:29]([C@H:38]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:28]([CH3:49])=[CH:27][C:25]=2[N:26]=1.C([O-])([O-])=O.[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.O1CCOCC1>[NH2:12][C:6]1[C:5]2[C:9](=[CH:10][C:2]([C:22]3[S:23][C:24]4[C:30]([C:31]5[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=5)=[C:29]([C@H:38]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:28]([CH3:49])=[CH:27][C:25]=4[N:26]=3)=[CH:3][CH:4]=2)[N:8]([CH3:11])[N:7]=1
Reactant: Cn1nc(N)c2ccc(Br)cc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(N)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A vessel was charged with 6-bromo-1-methyl-1H-indazol-3-amine (191 mg, 0.846 mmol), bis-pinacolatodiboron (236 mg, 0.930 mmol), PdCl2(dppf).DCM (69 mg, 85 μmol), glacial KOAc (273 mg, 2.79 mmol), and dioxane (3.2 mL). The reaction was heated to 100° C. for 1 h. To this reaction was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (420 mg, 0.846 mmol), 2 M aq K2CO3 (800 μL), and Pd(PPh3)4 (98 mg, 85 mmol). The reaction was heated for another 1 h at 100° C. The reaction was diluted with water and extracted with EtOAc (3×). Combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was treated with benzene and purification by flash column chromatography on silica gel (hexanes/ethyl acetate eluent) gave the title compound in semi-pure form. The mixture was treated with DCM and purification by flash column chromatography on silica gel (DCM/MeOH eluent) giving the title compound. LCMS-ESI+: calc'd for C30H31ClN4O3S: 563.2, 565.2 (M+H+); Found: 563.3, 565.3 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: O=C1CCCCc2ccc([N+](=O)[O-])cc21
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)C(=O)CCCC2
Temperature: 70 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture of 3-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (10.0 g, 48.73 mmol), tin(II) chloride dihydrate (49.48 g, 219.3 mmol) and ethanol (200 ml) was stirred at 70° C. for 2 hours. The reaction mixture was poured into ice water, adjusted to pH 10 with sodium hydroxide, and then extracted with toluene. The extract solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to obtain 8.08 g of 3-amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH2:32])([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:21][CH:20]=4)[CH:14]=3)[CH:9]=2)[CH2:4][O:3]1.CO.Cl.O>>[NH2:32][C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[CH:14]=2)[CH:9]=1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: CC1(C)OCC(N)(c2ccc3cc(Oc4ccc(Oc5ccccc5)cc4)ccc3c2)CO1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(CO)(CO)c1ccc2cc(Oc3ccc(Oc4ccccc4)cc3)ccc2c1
Temperature: 90 °C
Yield: 78.2 %

Procedure:
2,2-Dimethyl-5-[6-(4-phenoxy-phenoxy)-naphthalen-2-yl]-1,3-dioxinan-5-ylamine (0.1241 g, 0.0002811 mol) was dissolved in methanol (3 mL, 0.07 mol) and a solution of 1 M of hydrogen chloride in water (5 mL, 0.005 mol) in a 40 mL reaction vial equipped with a magnetic stir bar. The vial was capped and heated at 90° C. overnight. TLC analysis showed that the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure. The resulting solid was dissolved in methylene chloride (5 mL) and washed with water then aqueous sodium carbonate. The combined organic layer was dried over magnesium sulfate, then concentrated under vacuum and purified by HPLC to give 88.3 mg of the title compound (78% yield). MS: m/z=424.45 [M+Na+]. 1H NMR (DMSO-d6) δ: 8.00 (s, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.62-7.68 (m, 1H), 7.39-7.44 (m, 2H), 7.35-7.39 (m, 2H), 7.30 (dd, J=8.9, 2.5 Hz, 1H), 7.00-7.17 (m, 6H), 3.73 (d, J=3.8 Hz, 4H)
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:20]1([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccccc4)c3c2s1
Yield: 67 %

Procedure:
Prepared from VII and aniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 67%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3395, 3057, 2228, 1731, 1644, 1608, 1577, 1491, 1459, 1378, 1352, 1301, 1255, 1214, 1147, 1128, 1106, 1071, 967, 896, 827; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.11 (s, 1H), 7.78 (d, 1H, J=9.0 Hz), 7.40 (t, 2H, J=7.5 Hz), 7.20 (m, 2H), 7.11 (t, 1H, J=7.5 Hz); HRMS calcd for C16H10N5S (M+H+): 304.0657, found 304.0657.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:10]([CH2:11][C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[O:13])[C:9]2[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:6](=[O:36])[CH2:5]1.Br[CH2:38][C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:41]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[N:40]=1.O>CN(C=O)C>[C:51]([O:50][C:48]([N:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]([CH2:38][CH:5]2[C:4](=[O:3])[N:10]([CH2:11][C:12]([N:14]([CH:23]([CH3:25])[CH3:24])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)=[O:13])[C:9]3[CH:26]=[CH:27][CH:28]=[CH:29][C:8]=3[N:7]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:6]2=[O:36])=[N:40]1)=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: COc1cccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
52 mg of Sodium hydride (60% in oil, 1.31 mmol) is added to a solution of 2-(-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(3-methoxy-phenyl) acetamide, prepared as in Part D, (500 mg, 1.09 mmol) in DMF (10 mL ) and the resultant mixture stirred at RT for 0.5 h prior to the addition of 3-Bromomethyl-1-tert-butoxycarbonyl-1H-indazole (339 mg, 1.09 mmol) to the reaction mixture. After stirring 18 h at RT, water (50 mL) is added and the resultant mixture extracted into ethyl acetate (3×50 mL). The combined organics were washed with water (3×20 mL), brine (20 mL), dried (MgSO4) and concentrated in vacuo to afford the crude product which is purified by silica gel flash column chromatography using 5% methanol in methylene chloride as eluent to give the desired product (252 mg) as a cream foam: 1H NMR (300 MHz, CDCl3) δ8.07 (d, 1H, J=8.6), 7.91 (d, 1H, J=8.5), 7.5-6.8 (m, 15H), 5.03 (m, 1H, J=6.9), 4.39 (m, 3H), 3.94 (m, 2H), 3.84 (s, br, 4H), 3.60 (dd, 1H, J=10.1, 2.1), 1.6 (s, 9H), 1.16 (d, 6H, J=6.9).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH3:12])=[CH:4][C:3]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H][H]>CO.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)([C:13]([F:16])([F:15])[F:14])[CH3:12])=[CH:4][C:3]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [H][H]
Reactant: COc1ccc(C(C)(C=CCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Agent: [Ni]
Solvent: CO
Product: COc1ccc(C(C)(CCCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Yield: 61.9 %

Procedure:
1-(4-Fluoro-3-phenoxyphenyl)-4-(4-methoxyphenyl)-4-trifluoromethyl-2-pentene (15.12 g; 37.76 mmol) was hydrogenated in methanol (200 ml) with hydrogen using Raney nickel (5 g) at room temperature and under atmospheric pressure. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the solvent removed under reduced pressure. After chromatography on silica gel using ethyl acetate/hexane as eluant, there was obtained a 10.1 g of product (=61.8% of theory).
Reaction SMILES: [C:1]([N:4]1[CH2:28][CH2:27][C:7]2([N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:19])[C@H:9]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:8]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O.C[Si]([Cl:34])(C)C>CC(CC)=O>[ClH:34].[C:1]([N:4]1[CH2:5][CH2:6][C:7]2([N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:19])[C@H:9]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:8]2)[CH2:27][CH2:28]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Agent: CC(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
8-acetyl-1,3-(S)-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one (1.25 g, 3.3 mmol) was dissolved in ethyl methyl ketone (10 mL), and water (33 μL) and TMSCl (461 μL) were added and the mixture was stirred overnight. The precipitated solid matter was isolated by filtration, washed with diethyl ether, and dried in vacuo. The product 8-acetyl-1,3-(S)-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 939 mg (69%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl.[NH2:14][OH:15].[OH-].[Na+].C(O)C>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[N:14][OH:15])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2=O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cnc2c(c1)CCCC2=NO

Procedure:
The quinolinone (30g), hydroxylamine hydrochloride (14g), sodium hydroxide (9g), ethanol (165ml) and water (65ml) were stirred and refluxed for 2 hours. Water (100 ml) was added and the product was allowed to crystallise overnight. The crystals were removed by filtration and washed with water and dried to give 3-methyl-8-oximino-5,6,7,8-tetrahydroquinoline (27.5g) mp 188° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[S:9][C:10]([Br:13])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[N:7]([C:8]1[S:9][C:10]([Br:13])=[CH:11][N:12]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ncc(Br)s2)cc1
Reaction time: 8 h

Procedure:
To a single necked round bottom flask (5-Bromo-thiazol-2-yl)-carbamic acid tert-butyl ester (1.4 g, 5.01 mmol) was dissolved in 25 ml dry DCM. To it 1,8-Diazabicyclo[5.4.0]undec-7-ene(DBU) (2.24 ml, 15.03 mmol) was added followed by 1-Chloromethyl-4-methoxy-benzene (1.02 ml, 7.52 mmol) addition was done and reaction mixture was stirred for overnight. Reaction was quenched by addition of water (20 ml), extracted with DCM (25 ml), Organic layer was separated and washed with brine (30 ml) and dried over anhydrous sodium sulfate, sodium sulfate was filtered and washed with DCM (20 ml) and solvent was evaporated on rotavapour to get required product. The crude material was purified by silica-gel column chromatography, eluting with 4% acetone in hexane. (1.4 g).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH:34]([C:37]1[CH:38]=[C:39]([CH:43]([CH3:47])[CH2:44][CH:45]=O)[CH:40]=[CH:41][CH:42]=1)([CH3:36])[CH3:35]>>[CH:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]([CH2:44][CH:45]=[CH:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:47])[CH:38]=1)([CH3:36])[CH3:35]
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)c1cccc(C(C)CC=CCc2ccccc2)c1
Yield: 81.5 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (5.00 g, 11.2 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 7.0 mL, 11.2 mmol, 1.0 equiv.) and 3-(3-isopropylphenyl)butanal (3.20 g, 16.8 mmol, 1.5 equiv.), 2.54 g (82%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 997:3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:12]2[C:8](=[C:9]([CH3:16])[N:10]([CH3:15])[N:11]=2)[C:7]=1[C:17]([O:19][CH3:20])=[O:18]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]2[C:8](=[C:9]([CH3:16])[N:10]([CH3:15])[N:11]=2)[C:7]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)/C=C/c1ccc2nn(C)c(C)c2c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc2nn(C)c(C)c2c1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
To a solution of methyl 5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-2,3-dimethyl-2H-indazole-4-carboxylate (726 mg, 2.52 mmol) in methanol (25 mL) was added palladium-carbon powder (145 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (666 mg, yield 91%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+]>[Pt]=O.C(O)C>[OH:1][CH:2]1[CH2:10][CH2:9][CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=[Pt]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCC(O)CC1
Reaction time: 32 h

Procedure:
A mixture of 42 parts of p-hydroxybenzoic acid, 2 parts of platinum oxide, 1 part of 10% aqueous potassium hydroxide and 150 parts by volume of ethanol was charged to a hydrogenation flask. The mixture was hydrogenated at 50 psi for 32 hours. The reaction mixture was filtered and the solvent evaporated. The solid product was slurried in 500 parts by volume of hot cyclohexane to remove cyclohexane carboxylic acid, filtered, and the solids recrystallized from 100 parts of water. The solid, unreacted p-hydroxybenzoic acid, was filtered off and the water evaporated yielding 16 parts of 4-hydroxycyclohexane carboxylic acid having a melting point of 110°-130° C.