Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([OH:18])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:17][CH2:16][CH2:15][CH2:14]2.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)Cl>[OH:18][C:4]1([CH2:3][CH2:2][NH:1][C:27](=[O:28])[O:29][CH2:30][CH3:31])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]21[CH2:14][CH2:15][CH2:16][CH2:17]2
Reactant: NCCC1(O)CCc2ccccc2C12CCCC2
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCCC1(O)CCc2ccccc2C12CCCC2
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A solution of the product from Example 9 (1.05 g, 4.28 mmol) and triethylamine (0.44 g, 4.35 mmol) in 10 mL of CH2Cl2 was cooled to 0° C. and ethyl chloroformate (0.47 g, 4.33 mmol) in 5 mL CH2Cl2 was added dropwise. The reaction was warmed to room temperature and washed with water. The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by chromatography (silica gel, 1:1 heptane/ethyl acetate) to give the title compound (1.33 g, 98%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[NH:11][C@H:10]2[CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][C:27]=2[CH3:36])=[CH:22][C:21]=1[C:37]1[C:38]([CH2:45]OS(C)(=O)=O)=[N:39][C:40]([S:43][CH3:44])=[N:41][CH:42]=1>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C@H:9]2[O:13][C:12](=[O:14])[N:11]([CH2:45][C:38]3[C:37]([C:21]4[CH:22]=[C:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][C:27]=5[CH3:36])[CH:24]=[CH:25][C:20]=4[O:19][CH3:18])=[CH:42][N:41]=[C:40]([S:43][CH3:44])[N:39]=3)[C@H:10]2[CH3:15])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(SC)nc3COS(C)(=O)=O)c2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(Cl)cc(Cl)c4)[C@@H]3C)c2)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To (4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE XX—see table 18, 202 mg, 0.821 mmol) in THF (6 mL) at 0° C. was added sodium hydride (60 wt %, 37.3 mg, 0.933 mmol). The reaction was stirred at 0° C. for 1 hour and a solution of methyl 4′-methoxy-2-methyl-3′-[2-(methylsulfanyl)-4-{[(methylsulfonyl)oxy]methyl}pyrimidin-5-yl]biphenyl-4-carboxylate (364 mg, 0.746 mmol) in THF (500 μL) was added. The reaction was allowed to warm to room temperature overnight. The reaction was cooled to 0° C. and was quenched with HCl (1 N, 373 μL) and the reaction was poured into saturated aqueous NaHCO3 and ethyl acetate. The organic was washed with brine, was dried (Na2SO4), filtered, and concentrated. The resultant residue was purified by column chromatography to yield methyl 3′-[4-{[(4S,5R)-5-(3,5-dichlorophenyl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-2-(methylsulfanyl)pyrimidin-5-yl]-4′-methoxy-2-methylbiphenyl-4-carboxylate (295 mg, 0.462 mmol). LCMS calc.=638.1. found=638.2.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC(C(F)(F)F)=O.[NH:21]1[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[O:27])[CH2:22]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:21]3[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=4)=[O:27])[CH2:22]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
A solution of 4-phenyl-cyclohexanone (Aldrich, 1.5 g, 8.62 mmol) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide TFA salt (as prepared in the previous step, 3.89 g, 12.9 mmol) in DCM (20 mL) was treated with TEA (6 mL, 43 mmol) for 10 min followed by NaBH(OAc)3 (Aldrich, 3.65 g, 17.2 mmol) for another 4 hours at room temperature. The reaction was quenched with saturated sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the two title compounds as white solids.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:13](=[O:30])([O:22][CH2:23][C:24]2C=CC=CC=2)[O:14][CH2:15][C:16]2C=CC=CC=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(OP([O-])OCC)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([P:13](=[O:30])([O:22][CH2:23][CH3:24])[O:14][CH2:15][CH3:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(P(=O)(OCc2ccccc2)OCc2ccccc2)cc(OC)c1OC
Agent: CCOP([O-])OCC
Product: CCOP(=O)(OCC)c1cc(OC)c(OC)c(OC)c1

Procedure:
Compound 11 is synthesized following the procedure for Compound 2, using diethylphosphite.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1c(F)cccc1F
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1c(F)cccc1F
Reaction time: 0.25 h
Yield: 65.3 %

Procedure:
40% Methanolic Triton B (0.49 mL, 1.07 mM) was added to a solution of the 9-[(2,6-difluorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (290 mg, 0.82 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (259 mg, 1.65 mM) was added and the resultant mixture stirred at room temperature for 24 hours. The mixture was diluted with H2O and the resultant white precipitate collected by filtration, triturated with diethyl ether/hexanes, and dried in vacuo to afford 228 mg (65%) of the {9-[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ 7.65 (d, 1H, J=8 Hz), 7.45-7.2 (m, 5H), 6.85 (t, 2H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.0 (br s, 1H), 5.5 (s, 2H), 4.9 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 3432, 3170, 1762, and 1675. MS (ES) m/e 425.
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[C:6]([CH:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[CH:7][C:8]([NH:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:9][CH:10]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(OCC)(=O)C.CCCCCC>[Cl:4][C:5]1[C:6]([CH:20]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[CH:7][C:8]([N:11]([S:47]([CH3:46])(=[O:49])=[O:48])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)NNc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NN(c1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a methylene chloride (5 ml) solution of t-butyl N′-[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]hydrazine carboxylate (178 mg, 0.327 mmol) and triethylamine (43 μl, 0.392 mmol) was added methanesulfonyl chloride (30 μl, 0.392 mmol) at 0° C. The resulting mixture was stirred at room temperature for 16 hours. To the reaction mixture were added triethylamine (43 μl, 0.392 mmol) and methanesulfonyl chloride (30 μl, 0.392 mmol). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was diluted with ethyl acetate. The diluted solution was washed sequentially with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=4:1) eluate was concentrated under reduced pressure to give the title compound (174 mg, 0.280 mmol, 85%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9].[CH2:13]1[S:18](=[O:20])(=[O:19])[O:17][CH2:16][CH2:15][CH2:14]1.CC(C)=O.CO>C(#N)C>[S:18]([CH2:13][CH2:14][CH2:15][CH2:16][N+:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9])([CH3:12])[CH3:1])([O-:17])(=[O:20])=[O:19]
Reactant: C=C(C)C(=O)NCCCN(C)C
Reactant: O=S1(=O)CCCCO1
Solvent: CO
Solvent: CC(C)=O
Solvent: CC#N
Product: C=C(C)C(=O)NCCC[N+](C)(C)CCCCS(=O)(=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
In 380 ml of acetonitrile were dissolved 130 g (0.764 mol) of N-[3-(dimethylamino)propyl]methacrylamide, 104 g of butanesultone and 234 mg of 4-hydroxy-2,2,6,6-tetramethylpiperidinoxy and the solution was heated at 70° C. for 6 hours. After allowing to cooling, to the reaction mixture were added 1,350 ml of acetone and 150 ml of methanol and the mixture was stirred at room temperature for one hour. The crystals deposited were collected by filtration and thoroughly washed with acetone to obtain 200.0 g (yield: 85%) of 4-sulfonatobutyl[3-(methacryloylamino)propyl]dimethylammonium.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[CH3:30][CH:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:33]([CH:31]([CH3:32])[CH3:30])(=[O:35])=[O:34])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Nc1cccc(C2CC(C)(C)c3cc(C(F)(F)F)ccc3N2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.47 mmol) in pyridine (0.23 mL, 2.81 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of propane-2-sulfonyl chloride (200 mg, 1.40 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford propane-2-sulfonic acid [3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide (155 mg, 77.8%) as a white solid. MS (ESI+APCI) M+1=427.2.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([O:24]C(C)(C)C)=[O:23])=[CH:12][CH:11]=2)[C:7]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(O)=O>O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([OH:24])=[O:23])=[CH:12][CH:11]=2)[C:7]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=CO
Solvent: O
Product: CCCc1ccc(C(=O)OCC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 79.9 %

Procedure:
Ethyl 5-n-propyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]pyrrole-2-carboxylate (600 mg, 1.34 mmol) was stirred with formic acid (6 ml) at room temperature for 4 hours (slowly dissolved to a homogenous yellow solution). The mixture was diluted to about 50 ml with water to give a white precipitate which was filtered and subsequently purified by flash chromatography on silica gel (10% EtOAc/hexanes) to give 419 mg (80%) of the compound; m.p. 111°-115° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[O-]CC.[Na+]>C(O)C>[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:27](/[CH:28]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CCCCCOc1c(C=O)cccc1OC
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)cccc1OC
Yield: 45.9 %

Procedure:
The title compound was synthesized by condensation of Intermediate 15 (350 mg, 1.071 mmol) with 3-methoxy-2-pentyloxybenzaldehyde (333 mg, 1.501 mmol) in presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure of Example 24 to give 261 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.91 (t, J=6.6 Hz, 3H), 1.33-1.42 (m, 4H), 1.50-1.58 (m, 2H), 3.77 (s, 3H), 3.83 (t, J=6.3 Hz, 2H), 6.85-6.90 (m, 2H), 6.96-7.02 (m, 2H), 7.40-7.47 (m, 4H), 7.51-7.90 (m, 1H), 7.95-8.02 (m, 1H), 8.06-8.12 (m, 1H); ESI-MS (m/z) 531.26 (M+H)+.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[CH2:6]([N:8]1[C:16](OC)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[C:9]1[CH:19]=[CH:20][C:21]1[S:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[N+:25]=1[CH2:26][CH3:27])[CH3:7].[CH2:32]([N:34]1[C:38](=[O:39])[CH2:37][S:36][C:35]1=[S:40])[CH3:33].C(N(CC)CC)C>CO>[CH2:32]([N:34]1[C:38](=[O:39])[C:37](=[C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[CH:19][CH:20]=[C:21]3[N:25]([CH2:26][CH3:27])[C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[S:22]3)[N:8]2[CH2:6][CH3:7])[S:36][C:35]1=[S:40])[CH3:33]
Reactant: CCn1c(C=Cc2sc3ccccc3[n+]2CC)c2ccccc2c1OC
Reactant: CCN1C(=O)CSC1=S
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(=c2c3ccccc3c(=CC=C3Sc4ccccc4N3CC)n2CC)SC1=S

Procedure:
2-[2-(2-Ethyl-3-methoxyisoindol-1-yl)vinyl]-3-ethylbenzothiazolium perchlorate (0.5 g) and 3-ethylrhodanine (0.3 g) were dissolved in a 1:1 acetronitrile/methanol solution. Triethylamine was added and the reaction mixture heated to reflux for 10 minutes. The dyes which separated out was dissolved in chloroform and passed through a column of silica gel. After recrystallization from a mixture of chloroform and methanol the dye melted at 252°-253° C. pyridine/methanol λ max 661 nm.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](I)[C:9]=1[O:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:5]=[O:6].[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][O:15][CH2:14][CH2:13][O:12][CH2:11][O:10][C:9]1[C:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[C:2]1[CH:3]=[CH:4][CH:7]=[CH:8][CH:9]=1
Reactant: COCCOCOc1c(I)cc(C=O)cc1I
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: COCCOC
Product: COCCOCOc1c(-c2ccccc2)cc(C=O)cc1-c1ccccc1
Yield: 57 %

Procedure:
The tile compound was prepared according to the procedure in Example 2, step 3 using 3,5-diiodo-4-(2-methoxyethoxymethoxy)benzaldehyde (4.029 g, 8.721 mmol), phenylboronic acid (2.339 g, 19.19 mmol), palladium(II) acetate (39.16 mg, 0.174 mmol) in DME:H2O. Purification on Biotage KP-Sil eluting with 15% EtOAc/pet. ether gave 1.803 g, (57%) of the title compound. 1H NMR (DMSO-d6) δ2.78-2.82 (m, 2 H), 2.89-2.92 (m, 2 H), 3.01 (s, 3 H), 4,42 (s, 2 H), 7.40-7.54 (m, 6 H), 7.62∝7.65 (m, 4 H), 7.91 (s, 2 H), 10.06 (s, 1 H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[N+]=[N-].[H][H]>[Pd].CCO>[NH2:1][CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1n[nH]c2ncccc12
Agent: [Pd]
Solvent: CCO
Product: NCc1n[nH]c2ncccc12
Reaction time: 2 h

Procedure:
A mixture of 286 mg (1.64 mmol) of 1-2 and 35 mg of 10% palladium on carbon catalyst in 2 mL of absolute EtOH was hydrogentated at 1 atmosphere pressure using a hydrogen filled balloon. After approximately 2 hours, the reaction was determined to be complete by LC-MS analysis. The reaction was filtered through a Celite pad, and the filtrate concentrated in vacuo to give the title product as a pale yellow oil. MS M+1=149.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:23](OC(ON=C(C#N)C(OCC)=O)=O)[CH:24]([CH3:26])[CH3:25]>O1CCCC1>[CH2:23]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:24]([CH3:26])[CH3:25]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C#N)=NOC(=O)OCC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)COC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 142.7 %

Procedure:
To a solution of N-benzyloxycarbonylglycine (1.05 g) and triethylamine (0.7 ml) in dry tetrahydrofuran (15 ml), ethyl 2-isobutoxycarbonyloxyimino-2-cyanoacetate (2.42 g) is added, and the resulting mixture is stirred at room temperature for 2 hours. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine isobutyl ester (1.9 g) as an oil.
Reaction SMILES: Cl.C1(C)C=CC(S(O[CH:12]2[CH2:18][CH2:17][CH:16]3C[N:13]2[CH2:14][CH2:15]3)(=O)=O)=CC=1.C1(C)C=C[C:24]([S:27](Cl)(=[O:29])=[O:28])=CC=1.CS(Cl)(=O)=O>C(Cl)(Cl)Cl.[OH-].[Na+]>[CH3:24][S:27]([N:13]1[CH2:12][CH2:18][CH:17]=[CH:16][CH2:15][CH2:14]1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3CCN2C3)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCC=CCC1

Procedure:
15.9 g (0.05 mol) of endo-4-(p-toluenesulphonyl-oxy-1-azabicyclo[3.2.1]octane hydrochloride with a melting point of 146°-148°, which, according to W. Kunz, Thesis, University of Basel 1973, 6349, page 92, can be obtained by reacting endo-1-azabicyclo[3.2.1]octan-4-ol, which is described in this thesis and in J. Org. Chem. 33, 4376-4380 (1968), with the approximately 1.2-fold molar amount of p-toluenesulphonyl chloride in absolute chloroform at room temperature for a reaction period of about 48 hours, precipitating the crude product with pentane and recrystallising the product from chloroform, and 23.0 g (0.2 mol) of methanesulphonyl chloride are stirred in 1,400 ml of 0.75 N sodium hydroxide solution for 4 hours at room temperature and the mixture is then heated at 90° for 20 minutes, while stirring. After cooling, the reaction mixture is extracted four times with methylene chloride. The combined extracts are washed with 0.1 N hydrochloric acid, dried over potassium carbonate and evaporated and 1-methylsulphonyl-2,3,6,7-tetrahydro-1H-azepine is obtained; melting point 95°-96° (from ethyl acetate/benzene).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].B(F)(F)F.[CH3:34]COCC>CO>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:34])=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: CCOCC
Agent: FB(F)F
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Yield: 95 %

Procedure:
To a solution of cholic acid (300 g, 0.73 mol) in 1.1 L methanol is added boron trifloride etherate. The mixture is refluxed for 1 h. After cooling, a solid precipitate 2 is collected by filtration. The mother liquor is kept in a refrigerator to give another crop of product The combined product (295 g, 95%) is dried under vacuum and used for the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:21]=[C:20]([CH3:22])[C:19]3[N:18]([CH3:23])[C:17]4[CH2:24][CH:25]5[NH:29][CH:28]([C:16]=4[C:15]=3[C:14]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:13]2[CH:21]=[C:20]([CH3:22])[C:19]3[N:18]([CH3:23])[C:17]4[CH2:24][CH:25]5[NH:29][CH:28]([C:16]=4[C:15]=3[C:14]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: Cc1cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(S(=O)(=O)c2ccc(N)cc2)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
To a solution of the product of step A (43 mg, 0.08 mmol) in ethanol (5 mL) was added 5% palladium on carbon (60 mg). The reaction flask was purged with hydrogen and the reaction mixture was stirred at ambient temperature for 4 h before it was filtered through a celite bed. The filtrate was concentrated in vacuo to give tert-butyl 2-(4-amino-phenyl)sulfonyl-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (29 mg, 72%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.00 (s, 1H), 7.71 (dd, J=6.9, 1.8 Hz, 2H), 7.29 (s, 1H), 6.62 (dd, J=6.9, 1.8 Hz, 2H), 5.22 (br s, 1H), 4.69 (br s, 1H), 4.04 (s, 2H), 3.82 (s, 3H), 3.34 (br s, 1H), 2.72 (s, 3H), 2.44 (d, J=15.9 Hz, 1H), 2.08-2.37 (m, 2H), 1.86-1.97 (m, 1H), 1.52-1.65 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[CH3:15][Si:16]([CH3:42])([CH3:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>COCCOC>[CH3:42][Si:16]([CH3:15])([CH3:41])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:37])=[CH:39][CH:40]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 16.9 g. of 4-[14-(trimethylsilyl)tetradecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate and evaporated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is evaporated and the residue is recrystallized to yield the title product.