Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:35][C@@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[CH2:31]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:40][O:41][C:42]1[CH:61]=[CH:60][C:45]([C:46](Cl)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:44][CH:43]=1.CO>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:35][C@@H:34]([CH2:36][O:37][C:46]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:45]3[CH:44]=[CH:43][C:42]([O:41][CH3:40])=[CH:61][CH:60]=3)[C@@H:32]([OH:33])[CH2:31]2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:38][CH:39]=1
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](CO)O2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Yield: 71.9 %

Procedure:
Compound 6 (0.62 g, 1.24 mmol) in dry pyridine (25 mL) was treated with 4-monomethoxytrityl chloride (0.46 g, 1.49 mmol) at room temperature for 16 h. After addition of methanol (5 mL), the mixture was concentrated to dryness. The residue was dissolved in dichloromethane (60 mL) and washed successively with water (40 mL), a saturated aqueous solution of NaHCO3 (40 mL) and water (3×40 mL). The organic layer was dried, filtered, concentrated and co-evaporated with toluene and methanol. The residue was purified by silica gel column chromatography (0-10% MeOH in dichloromethane) to give 7 (0.71 g, 72%) as a foam: 1H NMR (DMSO-d6): δ 2.21 (d, 1H, H-2′ J2′,2″=14.3 Hz), 2.6-2.7 (m, 1H, H-2″), 3.1-3.3 (2m, 2H, H-5′ and H-5″), 3.64 and 3.65 (2s, 6H, 2×OCH3), 4.1-4.2 (m, 1H, H-4′), 4.2-4.3 (m, 1H, H-3′), 5.68 (d, 1H, OH-3′, JH,OH=5.2 Hz), 6.24 (d, 1H, H-1′, J1′,2″=7.0 Hz), 6.7-6.8 and 7.1-7.3 (2m, 29H, 2 MMTr and NH-6), 7.83 and 8.21 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 796 [M+H]+, 408 [BH2]+, (FAB−) m/z 794 [M−H]−, 406 [B]−; UV (95% ethanol): λmax 275 nm (ε 30900), λmin 246 nm (ε 12800); [α]D20=+14 (c 1.03, DMSO).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[Cl:26][CH2:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29]>C(OCC)(=O)C>[Cl-:26].[F:25][C:21]1[CH:20]=[C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[O:10][C:8]([CH:5]2[CH2:4][CH2:3][N+:2]([CH3:1])([CH2:27][C:28](=[O:29])[C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[CH2:7][CH2:6]2)=[O:9])[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CCl)c1cccs1
Reactant: CN1CCC(C(=O)OC(c2cccc(F)c2)c2cccc(F)c2)CC1
Solvent: CCOC(C)=O
Product: C[N+]1(CC(=O)c2cccs2)CCC(C(=O)OC(c2cccc(F)c2)c2cccc(F)c2)CC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.3 %

Procedure:
To a solution of bis(3-fluorophenyl)methyl 1-methylpiperidine-4-carboxylate (150 mg, 0.43 mmol) in ethyl acetate (5 ml), 2-chloro-1-(thiophen-2-yl)ethanone (69.8 mg, 0.43 mmol) was added, and the mixture was stirred at room temperature overnight. The solvent was removed under vacuum, and the residue was taken up in diethyl ether, filtered, and purified by flash chromatography (DCM/MeOH=95/5) to obtain 4-((bis(3-fluorophenyl)methoxy)carbonyl)-1-methyl-1-(2-oxo-2-(thiophen-2-yl)ethyl)piperidinium chloride (18 mg).
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[CH2:5][CH2:6][C:7](N)=[S:8])[CH3:2]>[Re](=S)(=S)(=S)(=S)(=S)(=S)=S.C(O)C>[SH:8][CH2:7][CH2:6][CH2:5][Si:4]([O:13][CH2:14][CH3:15])([O:3][CH2:1][CH3:2])[O:10][CH2:11][CH3:12]
Reactant: CCO[Si](CCC(N)=S)(OCC)OCC
Agent: S=[Re](=S)(=S)(=S)(=S)(=S)=S
Solvent: CCO
Product: CCO[Si](CCCS)(OCC)OCC
Temperature: 25 °C

Procedure:
Into a clean, dry 300 cubic centimeter high pressure reactor were added 58 grams (0.23 moles) of beta-triethoxysilylthiopropionamide product (Example II pilot plant lot containing 5% beta-cyanoethyltriethoxysilane starting material), 1.45 grams (2.5 weight percent) of rhenium heptasulfide catalyst (Re2S7.2H2O), and 12 grams ethanol rinse. The reactor was sealed, initially pressurized to 800 psig with hydrogen, and placed in a rocker. The vessel was heated with agitation for 4 hours to a maximum pressure of 1000 psig. After cooling to ambient temperature, the pressure was 0 psig, indicating that hydrogen was consumed by the reaction. The reaction had produced gamma-mercaptopropyltriethoxysilane.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C([Li])(C)(C)C.[B:23](OC)([O:26]C)[O:24]C.CCCCCC>C1COCC1.CC(=O)OCC>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([B:23]([OH:26])[OH:24])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: COB(OC)OC
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(B(O)O)c(C)nc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In an oven dried nitrogen purged 3 neck 50 mL round bottom flask, 1.00 g (2.91 mmol) of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine in 60 mL of dry THF is cooled to −78° C. 4.12 mL (7.00 mmol) of 1.7 M tert-butyllithium in hexanes is added and reaction is stirred at −78° C. for 1 hour. 0.818 mL (7.30 mmol) of trimethyl borate is added and reaction is followed by MS and TLC (1:1 Hexane:EA) Indication of product is observed by mass spectrum. The reaction is allowed to stir for an additional hour, quenched with 1 N hydrochloric acid, and diluted with ethyl acetate. The organic layer is separated, and the aqueous layer is extracted three times with 100 mL of ethyl acetate. The extracts are combined, dried over MgSO4, filtered, and concentrated. The reaction residue is triturated in hexanes and a solid is filter off. MS, ES+=262.2 (M+1).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14](=[O:25])[C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14](=[O:25])[C:15](=[CH:21][NH:4][CH:1]1[CH2:3][CH2:2]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: NC1CC1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Solvent: CCO
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)cc1Cl
Reaction time: 1 h

Procedure:
A 3.9 ml portion of cyclopropylamine was added dropwise to a solution of 16.25 g of 2-chloro-α-(ethoxymethylene)-4,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester in 45 ml of ethanol, producing an exotherm. The solution was stirred for 1 hour, evaporated to dryness and the residue crystallized from hexane, giving 14.6 g of the desired compound, mp 55°-58° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:14][O:13][C:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][CH:2]=[N+:1]2[O-:20])=[CH:6][CH:7]=1)=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc2ccc[n+]([O-])c2c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of the methyl quinoline-7-carboxylate from above in DCM (10 mL) was added 3-chlorobenzoperoxoic acid (1.991 g, 11.54 mmol). The reaction was stirred for 21 h at rt. The mixture was then diluted with saturated aqueous NaHCO3 (40 mL) and the mixture was extracted with DCM (2×30 mL). The organic layers were combined, washed with saturated aqueous NaCl (40 mL), dried (MgSO4), and concentrated. The N-oxide was isolated as an orange solid which was used without purification in the next step.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2.C(N(CC)CC)C>C(Cl)Cl.O>[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:1](=[O:3])[CH3:2])[CH2:9]2
Reactant: CC(=O)Cl
Reactant: Fc1ccc2c(c1)CCN2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)C1Cc2cc(F)ccc2N1
Reaction time: 2 h

Procedure:
Acetyl chloride (3 ml) was added dropwise to a solution of 7 grams of crude 5-fluoro-2,3-dihydro-1H-indole and 3 ml of triethylamine in 100 ml of CH2Cl2 at 0° C. After two hours, the reaction was diluted with water. The methylene chloride layer was seperated, dried and evaporated to afford 7.3 grams of crude product which was purified on silica gel eluting with hexane/ethyl acetate to give 3.3 grams of the titled compound.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]([SH:11])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-:12].[Na+].ClCCl.[CH2:17]([OH:19])C>>[CH2:1]([CH:5]1[CH2:6][CH2:7][CH:8]([S:11][O:12][CH2:17][O:19][S:11][CH:8]2[CH2:9][CH2:10][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7]2)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCC(S)CC1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCC1CCC(SOCOSC2CCC(CCCC)CC2)CC1
Yield: 107.4 %

Procedure:
Synthesis was conducted as in Synthesis Example 2 using 44.6 g (0.23 mol) of the 4-n-butylcyclohexylmercaptan prepared above, 10.7 g (0.26 mol) of sodium hydroxide, 92 g of ethanol and 16.1 g (0.19 mol) of dichloromethane. There was obtained 48.0 g of the desired formaldehyde bis(4-n-butylcyclohexylthio)acetal.
Reaction SMILES: C(OC(=O)[NH:10][C:11]([CH3:32])([CH3:31])[C:12](=[O:30])[N:13]1[CH2:25][C:24]2[NH:23][C:22]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:26](=[O:29])[NH:27][N:28]=[C:15]([C:16]=2[C:17]=34)[CH2:14]1)C1C=CC=CC=1.C1NCC2NC3C=CC=C4C(=O)NN=C1C=2C=34>[Pd]>[NH2:10][C:11]([CH3:32])([CH3:31])[C:12]([N:13]1[CH2:25][C:24]2[NH:23][C:22]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:26](=[O:29])[NH:27][N:28]=[C:15]([C:16]=2[C:17]=34)[CH2:14]1)=[O:30]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Agent: [Pd]
Agent: O=C1NN=C2CNCc3[nH]c4cccc1c4c32
Product: CC(C)(N)C(=O)N1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1

Procedure:
Compound 62 was prepared from benzyl(2-methyl-1-oxo-1-(8-oxo-8,9-dihydro-2,4,9,10-tetraazacyclohepta[def]fluoren-2(1H,3H,4H)-yl)propan-2-yl)carbamate and Pd/C (10%) according to the procedure similar to that for Compound 42. 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 9.99 (s, 1H), 7.48 (d, 1H, J=8.0 Hz), 7.43 (d, 1H, J=7.2 Hz), 7.13 (dd, 1H, J=8.0, 7.2 Hz), 5.29-5.31 (m, 2H), 4.69-4.75 (m, 2H), 1.26 (s, 6H). MS (ESI) m/e [M+1]312.
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15](I)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:20][CH:21]2[CH2:24][CH:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22]2)=[CH:3][CH:2]=1.B(O)(O)[C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:41][CH:42]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:40]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:41]=[CH:42][C:37]([C:15]2[C:14]([F:19])=[CH:13][C:12]3[N:8]([CH2:7][C:4]4[CH:5]=[CH:6][C:1]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:2][CH:3]=4)[C:9]([O:20][CH:21]4[CH2:22][CH:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:24]4)=[N:10][C:11]=3[C:16]=2[F:17])=[CH:38][CH:39]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C1CC(Oc2nc3c(F)c(I)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Temperature: 120 °C

Procedure:
A solution of ethyl 3-{[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-1H-benzimidazol-2-yl]oxy}cyclobutanecarboxylate (0.350 g, 0.595 mmol), biphenylboronic acid (0.130 g, 0.654 mmol), and Pd(PPh3)4 (0.027 g, 0.024 mmol) in 6 mL of DMF was treated with a 1 M solution of K2CO3 (1.20 mL). The resulting yellow solution was heated at 120° C. for 45 min, and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting residue by flash chromatography (0-15% then 15-20% then 20% EtOAc/hexanes) provided the desired product as a white solid. LCMS: calculated for C39H32F2N2O3 614.68, observed ink 615.1 (M+H)+ (Rt 2.79/4 min).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@@H:11]3[CH2:28][N:14]4[C:15](=[O:27])[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[ClH:29]>CO.ClCCl.O1CCOCC1>[ClH:29].[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@@H:11]3[CH2:28][N:14]4[C:15](=[O:27])[CH2:16][CH2:17][NH:18][CH2:19][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N2C[C@@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: O=C1CCNC[C@@H]2C[C@H](Oc3cnc(C4CC4)cn3)CN12
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To tert-butyl (8S,9aS)-8-[(5-cyclopropylpyrazin-2-yl)oxy]-5-oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepine-2(3H)-carboxylate (254 mg, 0.654 mmol, Part C) in methanol/dichloromethane (1:1, 1 mL) was added 4 N HCl solution in dioxane (3 mL). The mixture was stirred at room temperature for three hours and then concentrated to give 212 mg (100% yield) of the title compound as a solid which was used without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (m, 2H), 0.96 (m, 2H), 2.10 (m, 2H), 2.66 (m, 1H), 3.10 (m, 3H), 3.40 (m, 2H), 3.65 (m, 2H), 4.22 (m, 1H), 4.40 (m, 1H), 5.38 (m, 1H), 8.15 (d, J=1 Hz, 1H), 8.19 (d, J=1 Hz, 1H), 9.38 (br s, 1H), 9.50 (br s, 1H); MS (ESI) m/z 289.0 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>IC1C=CC(C)=CC=1.[Cu]>[CH3:18][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)c1cccc(I)c1
Agent: [Cu]
Agent: Cc1ccc(I)cc1
Product: COC(=O)c1cccc(-c2ccc(C)cc2)c1
Temperature: 205 °C
Reaction time: 6 h
Yield: 29 %

Procedure:
To a mixture of methyl 3-iodobenzoate (26.1 g) in 4-iodotoluene (21.9 g) was added copper powder (31.8 g) gradually at 180°-190° C. The mixture was then stirred for 6 hours at 200-210° C. The reaction mixture was cooled to room temperature, to which was added toluene. Insoluble materials were filtered off, and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel to afford the title compound as a colorless oil (6.61 g, 29%).
Reaction SMILES: BrC1C(C)(C)CC2C(C=1)=CC=C(OC)C=2.BrC1C=CC(OC)=CC=1[N+]([O-])=O.[CH3:28][O:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=3[N+:50]([O-])=O)[C:36]([CH3:41])([CH3:40])[CH2:37]2)=[CH:32][CH:31]=1>>[CH3:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([C:35]2[C:36]([CH3:40])([CH3:41])[CH2:37][C:38]3[C:33](=[CH:32][CH:31]=[C:30]([O:29][CH3:28])[CH:39]=3)[CH:34]=2)=[C:43]([NH2:50])[CH:44]=1
Reactant: COc1ccc2c(c1)CC(C)(C)C(c1ccc(OC)cc1[N+](=O)[O-])=C2
Agent: COc1ccc(Br)c([N+](=O)[O-])c1
Agent: COc1ccc2c(c1)CC(C)(C)C(Br)=C2
Product: COc1ccc(C2=Cc3ccc(OC)cc3CC2(C)C)c(N)c1
Yield: 75.1 %

Procedure:
Synthesized from 3-bromo-7-methoxy-2,2-dimethyl-1,2-dihydronaphthalene and 4-bromo-3-nitroanisole according to an analogous synthetic method to Preparation Example 107 described below, 7-methoxy-3-(4-methoxy-2-nitrophenyl)-2,2-dimethyl-1,2-dihydronaphthalene (1.9 g) was used according to an analogous synthetic method to Example 57 to provide the title compound (1.3 g).
Reaction SMILES: [CH3:1][C:2]1[C:13](C(O)=O)=[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1>ClCCl.CO.O>[CH3:1][C:2]1[CH:13]=[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Cc1nn2ccc(C(=O)O)cc2c1C(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1cc2cc(C(=O)O)ccn2n1
Temperature: 150 °C
Yield: 54.8 %

Procedure:
A mixture of 2-methylpyrazolo[1,5-a]pyridine-3,5-dicarboxylic acid (1.39 g) and polyphosphoric acid (13.9 g) was stirred at 150° C. with heating for 2 hr, and ice (14 g) was added under ice-cooling, which was followed by shaking to give a homogeneous solution. The reaction mixture was adjusted to pH 4 at the same temperature and diluted with dichloromethane/methanol (4:1) and water. The precipitate was collected by filtration to give the objective compound (610 mg) as a pale-brown powder. The organic layer of the mother liquor was taken, and the aqueous layer was extracted with dichloromethane/methanol (4:1). Both organic layers were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was washed with ether to give second crystals (200 mg) as a pale-brown powder.
Reaction SMILES: O1CCOCC1.CCCCCC.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:23]2[CH2:28][CH2:27][C:26]([C:32]([OH:34])=[O:33])([C:29]([OH:31])=[O:30])[CH2:25][CH:24]=2)=[C:15]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)C>[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]2[CH2:28][CH2:27][C:26]([C:32]([OH:34])=[O:33])([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)=[C:15]1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cn1c(-c2ccccc2)c(C2=CCC(C(=O)O)(C(=O)O)CC2)c2ccccc21
Solvent: CCCCCC
Solvent: CCO
Solvent: C1COCCO1
Product: Cn1c(-c2ccccc2)c(C2CCC(C(=O)O)(C(=O)O)CC2)c2ccccc21
Yield: 50.3 %

Procedure:
Using the method of Example 11, except that dioxane replaced ethanol as solvent and product was recrystallized from acetone:hexane one time, 7.5 g (0.020 mol) of 4-(1-methyl-2-phenyl-1H-indol-3-yl)-3-cyclohexene-1,1-dicarboxylic acid (Example 3) was hydrogenated to give 3.8 g (51%) of 4-(1-methyl-2-phenyl-1H-indol-3-yl)cyclohexane-1,1-dicarboxylic acid, m.p. 230° C.(decompn.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1.O>C1COCC1.C([Li])CCC.C(OCC)(=O)C>[OH:16][C:13]1([C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)cc(C2(O)CCOCC2)c1
Reaction time: 1 h
Yield: 63.1 %

Procedure:
Under an atmosphere of argon, to a solution of 5-bromo-m-xylene (5.55 g) in THF (60 mL), n-butyl lithium (17.8 mL) was added at −78° C. The mixture was stirred for 1 hour. Tetrahydropyran-4-on (2.0 g) was added to the reaction mixture, and the mixture was stirred for 3 hours. Water was added to the reaction mixture, and the solution was diluted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3) to give the title compound (2.6 g) having the following physical data.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[S:17][C:16](Br)=[CH:15][C:12]=32)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:19][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.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]>[CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[S:17][C:16]([CH3:19])=[CH:15][C:12]=32)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2Cc3sc(Br)cc3C2C1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC2Cc3sc(C)cc3C2C1
Yield: 59 %

Procedure:
A solution of the product from step b) (863 mg, 2.62 mmol) in dioxane (13.1 ml) was treated with Pd(dppf)2Cl2 (128 mg, 0.157 mmol) and a 2M solution of dimethylzinc in toluene (2.62 ml, 5.24 mmol) at 102° C. for 1 h. The reaction was cooled to 220C and carefully quenched with sat. NH4Cl (3 ml). After the effervescence subsided, the reaction was extracted with EtOAc (3×50 ml). The combined organic extracts were dried (MgSO4), concentrated and eluted through a plug of silica-gel using 50:50 hexanes:EtOAc to give 411 mg (59%) of the subtitle compound. MS calculated for C14H19NO2S+H 266, observed 266.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>>[OH:21][C:18]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)[CH2:19][CH2:20][C:15]2([O:11][CH2:12][CH2:13][O:14]2)[CH2:16][CH2:17]1
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Product: NC(=O)c1ccc(C2(O)CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared as a white solid from 4-bromobenzamide (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:26][S:27]([C:30]1[CH:37]=[CH:36][C:33](CBr)=[CH:32][CH:31]=1)(=[O:29])=[O:28].Cl>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:33]1[CH:36]=[CH:37][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)cc1

Procedure:
Use a method similar to the Example 380, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 4-methylsulfonylbenzyl bromide to give, after hydrochloride formation by the General Procedure 2-2, the title compound as a white solid. MS (ES+) m/z: 382 (M+H)+.
Reaction SMILES: [C:1]([N:4]([CH3:25])[NH:5][C:6]([C@H:8]1[CH2:14][CH2:13][C@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[O:16]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]([CH3:25])[NH:5][C:6]([C@H:8]1[CH2:14][CH2:13][C@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[OH:16])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 101.4 %

Procedure:
To a solution of (2R,5S)—N′-acetyl-6-(benzyloxy)-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 213 (0.20 g, 0.57 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)—N′-acetyl-6-hydroxy-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 214 (0.15 g, 99%) as a colorless foam.