Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][C@H:12]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[C@H:26]1[O:55][C@H:54]([CH2:56][O:57]CC2C=CC=CC=2)[C@@H:45]([O:46]CC2C=CC=CC=2)[C@H:36]([O:37]CC2C=CC=CC=2)[C@@H:27]1[O:28]CC1C=CC=CC=1)[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[H][H]>C(O)C.[OH-].[Pd+2].[OH-].[C]>[NH2:11][C@H:12]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[C@H:26]1[O:55][C@H:54]([CH2:56][OH:57])[C@@H:45]([OH:46])[C@H:36]([OH:37])[C@@H:27]1[OH:28])[C:13]([OH:15])=[O:14]
Reactant: O=C(N[C@H](Cc1c([C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N[C@H](Cc1c([C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]2O)[nH]c2ccccc12)C(=O)O
Yield: 62.4 %

Procedure:
To a solution of (2R*)-2-[N-(carbobenzyloxy)amino]-3-[2-(2,3,4,6-tetra-O-benzyl-α-D-mannopyranosyl)indole-3-yl]propionic acid [compound (XII-1) wherein R1 to R4 are benzyl and Ar is phenyl](181 mg (0.210 mmol)) in ethanol (45 ml) was added 20% palladium hydroxide-carbon catalyst (150 mg) and the mixture was stirred at about 60° C. for about 11 hours under atmospheric pressure in the presence of hydrogen. The reacted solution was filtrated on Celite and the filtrate was concentrated. The residue was fractionated by high performance liquid chromatography [column: YMC-Pack ODS-AM SH-365-10AM, 500×30 mm, S-10, 120 Å; temperature: room temperature; migrating layer: 5% acetonitrile-water; flow rate: 40 ml/min.; detection: 278 nm (UV)] and then freeze-dried to give 48 mg (yield 62%) of (2R*)-2-amino-3-[2-(α-mannopyranosyl)indole-3-yl]propionic acid [compound (XIII-1)].
Reaction SMILES: [Br:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:22]>CCOCC>[Br:1][C:2]1[C:19]([O:20][CH3:21])=[N:18][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[C:3]=1[OH:22]
Reactant: COc1nc2c(c(O)c1Br)CCN(C(=O)OC(C)(C)C)CC2
Solvent: CCOCC
Product: COc1nc2c(c(O)c1Br)CCNCC2
Reaction time: 10 h
Yield: 88.2 %

Procedure:
NBS (0.668 mmol, 119 mg) was added in one portion to a stirred solution of tert-butyl 4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (0.607 mmol, 170 mg) in DCM (3 ml) at room temperature. After 3 h of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried, concentrated in vacuo and purified purified by column chromatography to provide 180 mg (83%) of tert-butyl 3-bromo-4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate. Ag2CO3 (0.42 mmol, 116 mg) was added to a solution of tert-butyl 3-bromo-4-hydroxy-2-oxo-1,2,5,6,8,9-hexahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (75.0 mg, 0.21 mmol) in DCM (1.5 ml) at room temperature. After 10 min of stirring, Mel (0.23 mmol, 15 μl) was added. After 5 h of stirring, sat. aq. NH4Cl was added and the mixture was extracted with DCM. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to provide 52 mg (67%) of tert-butyl 3-bromo-4-hydroxy-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate. The correct regioselectivity was confirmed by NOESY. 1H-NMR (CDCl3) δ 13.21 (1H), 3.85 (3H), 3.65 (2H), 3.55 (2H), 3.05 (2H), 2.85 (2H), 1.49 (9H) ppm. To a solution of tert-butyl 3-bromo-4-hydroxy-2-methoxy-5,6,8,9-tetrahydro-7H-pyrido[2,3-d]azepine-7-carboxylate (51 mg, 0.137 mmol) was added HC1 (2 N in Et2O, 3 ml) at room temperature. After 10 h of stirring, the reaction was quenched with sat. aq. NaHCO3 and extracted with DCM. The organic layer was dried and concentrated in vacuo to provide 33 mg (89%) of 3-bromo-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-4-ol. 1H-NMR (CDCl3) δ 12.02 (br s, 1H), 9.21 (br s, 1H), 3.79 (3H), 3.25 (m, 2H), 3.15 (m, 2H), 3.06 (m, 2H), 2.92 (m, 2H) ppm.
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)C(OCOC(=O)CC)=O)(=O)C.[C:36](Cl)(=[O:46])[O:37][CH2:38][O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42]>ClCCl>[O:34]=[S:30]1(=[O:33])[CH2:29][CH2:28][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:36]([O:37][CH2:38][O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:46])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:32][CH2:31]1
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Reactant: CC(C)(C)C(=O)OCOC(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 85 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (472.0 mg, 1.38 mmol) in dichloromethane (13 mL) and 2,2-dimethyl-propanoyloxymethyl carbonochloridate (7f) gave the titled product in 85% yield (585.6 mg, 1.17 mmol).
Reaction SMILES: C([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][CH2:18][NH2:19])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:22]1[N:29]=[CH:28][CH:27]=[CH:26][C:23]=1[C:24]#[N:25].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[C:24]([C:23]1[C:22]([N:19]([CH2:13][CH2:14][CH2:16][CH2:17][CH2:18][CH2:31][CH3:32])[CH2:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:20])[S:12][CH:13]=2)=[N:29][CH:28]=[CH:27][CH:26]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN)cs1
Reactant: N#Cc1cccnc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCCc1csc(SC(C)(C)C(=O)O)n1)c1ncccc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-{[4-(3-aminopropyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 33 and 2-chloronicotinonitrile as starting materials and by operations similar to those of Example 265-1 and Example 265-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17]C)=[O:16])[C:7](=[CH:13][CH:14]=1)[CH2:8][C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].[H-].[Na+].[Br:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>C1COCC1>[Br:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[C:8]([C:7]1[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:15]([OH:17])=[O:16])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=Cc1ccccc1Br
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccccc1Br)c1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 0 °C
Yield: 70.1 %

Procedure:
Dimethyl 4-nitrohomophthalate (Ghosh, C. K.; Mukherjee, K. K. J. Ind. Chem. Soc. 1976, 53, 662) (5 g, 0.02 tool) in THF (20 mL) was added to a suspension of sodium hydride (0.85 g of 60% disp., 0.021 mol) in THF (30 mL) with stirring at 0° C. under nitrogen. The resulting solution was stirred for 5-10 min and 2-bromobenzaldehyde (2.3 mL, 0.02 mol) was added in one portion. The cooling bath was removed after 10 min and the reaction was stirred at room temperature until the mixture solidified. The solid was dissolved in water and extracted with dichloromethane (2×). The aqueous phase was acidified and reextracted 3× with fresh portions of dichloromethane. The latter extracts were combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue crystallized on standing to give 5.62 g (70%) of off-white product: 1H NMR (300 MHz, CDCl3) δ 3.90 (3H, s), 6.66 (1H, d), 7.09 (1H, t), 7.16-7.23 (3H, m), 7.69 (1H, d), 7.86 (1H, s), 8.24 (1H, dd), 8.68 (1H, d); MS m/e 423-425 (M+NH4+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)C(OC(C)(C)C)=O)[CH2:10][C:9]=2[CH:30]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:10][C:9]=2[CH:30]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)CC(N(Cc1ccccc1)C(=O)OC(C)(C)C)CCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CC(NCc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
To a solution of 8-(N-benzyl-N-tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (10.07 g) in dichloromethane (100 ml) was added trifluoroacetic acid (9.47 ml), and the mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo and partitioned between ethyl acetate and an aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1) to afford 8-benzylamino-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid methyl ester (7.78 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49](O)=[O:50].CCN(C(C)C)C(C)C.[NH2:61][CH2:62][CH2:63][N:64]1[CH2:68][CH2:67][CH2:66][CH2:65]1>CN(C=O)C>[CH3:25][C:26]1[C:34]2[C:33]([NH:35][C:36]3[C:37]([O:42][CH:43]4[CH2:44][CH2:45][O:46][CH2:47][CH2:48]4)=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:32][CH:31]=[N:30][C:29]=2[S:28][C:27]=1[C:49]([NH:61][CH2:62][CH2:63][N:64]1[CH2:68][CH2:67][CH2:66][CH2:65]1)=[O:50]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)NCCN2CCCC2)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
HATU (0.105 g, 0.28 mmol) was added into a mixture of 5-methyl-4-(2-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-ylamino)thieno[2,3-d]pyrimidine-6-carboxylic acid (0.097 g, 0.25 mmol) and Hünig's base (44 μL, 0.25 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 1-(2-Aminoethyl)-pyrrolidine (157 μL, 1.25 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The solvent was concentrated in vacuo, the crude material added into water (10 mL) and the aqueous layer extracted into DCM. The product was purified by flash-column chromatography (DCM→10% ammonia/MeOH/DCM) to yield the title compound as off-white solid (0.051 g, 42% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[N:10][C:9]=2[C:19]2[C:20]([F:26])=[C:21]([NH:22][S:33]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cccnc1
Yield: 71.5 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14, using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (3 g, 7.7 mmol) and pyridine-3-sulfonyl chloride (1.49 g, 8.4 mmol) the title compound of Step A was obtained (2.9 g, 71.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.55-10.60 (br, 1H), 8.82-8.86 (m, 1H), 8.72-8.76 (m, 1H), 8.30 (d, J=5.3 Hz, 1H), 8.07-8.13 (m, 1H), 7.51-7.52 (m, 1H), 7.39-7.47 (m, 1H), 7.27-7.40 (m, 2H), 6.47 (d, J=5.3 Hz, 1H), 3.47-3.57 (m, 4H), 3.67-3.75 (m, 4H). MS (ES+): 533 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]2[N:13]=[C:12](O)[C:11]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)=[CH:10][N:9]=2)[CH2:5][C@@H:4]([CH3:22])[O:3]1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:12]1[C:11]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:10][N:9]=[C:8]([N:6]2[CH2:7][C@H:2]([CH3:1])[O:3][C@H:4]([CH3:22])[CH2:5]2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2O)ccn1
Product: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2Cl)ccn1
Temperature: 110 °C
Reaction time: 3 h
Yield: 7.1 %

Procedure:
To solid 2-(cis-2,6-dimethylmorpholino)-5-(2-methylpyridin-4-yl)pyrimidin-4-ol (8.3 g, 27.6 mmol) at 20° C. was added neat phosphorus oxychloride (79 ml, 848 mmol). The reaction mixture was stirred at 110° C. for 3 hours. After cooling to 30° C., most of the phosphorus oxychloride was removed and 20 ml of dichloromethane was added. The solution was added into ice-water. The pH was adjusted to 8 using sodium bicarbonate. The dichloromethane layer was separated, washed with water, dried and evaporated. The crude product was added to a silica gel column and was eluted with dichloromethane and then dichloromethane/methanol (5:1). Collected fractions were evaporated to give the title compound (680 mg, 1.960 mmol, 7.09% yield). LC/MS [M+H]+=319/321.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23]([OH:25])=O)[NH:18]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][C:30]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)([OH:33])[CH2:29][CH2:28]1>>[OH:33][C:30]1([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][C@H:39]([OH:42])[C@@H:38]([CH3:43])[CH2:37]2)[CH2:31][CH2:32][CH:27]([NH:26][C:23]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[C:14]([O:13][CH2:12][C:8]2[C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=4[O:10][CH:9]=2)[CH:22]=[CH:21][CH:20]=3)=[O:25])[CH2:28][CH2:29]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: COc1cccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc12
Product: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc12

Procedure:
This compound is synthesized analogously to example 1 from 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (synthesis described in WO2005077932A2, cmpd 119) and amine 14.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:31]=[C:32]([Cl:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([NH:34][C:35]([NH:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[O:36])[CH:31]=[C:32]([Cl:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(Cl)cc(NC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(Cl)cc(NC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-chloro-6-(cyclohexylaminocarbonylamino)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C:16]3[C:15]4[CH:14]=[CH:13][C:12]([OH:19])=[CH:11][C:10]=4[CH:9]=[CH:8][C:7]=3[C@@H:6]1[CH2:5][CH:4]=[CH:3]2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([O:19][C:12]1[CH:13]=[CH:14][C:15]2[C:16]3[CH2:17][CH2:18][C@@:2]4([CH3:1])[C@@H:6]([CH2:5][CH:4]=[CH:3]4)[C:7]=3[CH:8]=[CH:9][C:10]=2[CH:11]=1)(=[O:28])[CH3:27]
Reactant: C[C@@]12C=CC[C@H]1c1ccc3cc(O)ccc3c1CC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c3c(ccc2c1)[C@@H]1CC=C[C@@]1(C)CC3

Procedure:
A solution of estra-1,3,5(10),6,8,16-hexaen-3-ol Q8, 148.8 mg, 0.5944 mmol) in anh. pyridine (2.0 ml, 25 mmol) and acetic anhydride (0.28 ml, 3.0 mmol) was stirred 6 h, after which ethyl acetate (20 ml) was added. See FIG. 159. The mixture was washed with three 10 ml portions of 1 N hydrochloric acid+10 ml of saturated sodium bicarbonate+10 ml of brine, dried over sodium sulfate, and filtered. The residue was washed with 5 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Recrystallization from 95% ethanol gave lustrous white platelets (99.4 mg, 0.340 mmol, 55%, m.p. 9596° C. TLC (2% ethyl acetate/hazanes on silica gel) showed product (Rf 0.1) contained a trace contaminant at the origin.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)=[O:5])[CH3:2].O1CCCC1>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-n2cnc3ccc(C=CCCOCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1sc(-n2cnc3ccc(CCCCOCc4ccccc4)cc32)nc1-c1cccc(Cl)c1
Yield: 76.1 %

Procedure:
A mixture of 0.568 g of 2-[6-(-benzyloxy-but-1-enyl)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (I.41b), 5 mL of tetrahydrofuran, 5 mL of ethanol, and 0.30 g of 10% palladium on carbon catalyst was hydrogenated at 50 psi overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-2:98) to give 0.434 g of 2-[6-(4-benzyloxy-butyl)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (I.41c) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=[O:6].N1C=CC=CC=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].[OH-].[Na+]>ClCCl.CO.O>[CH3:18][S:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(C(=O)O)c1
Reaction time: 2 h

Procedure:
To a solution of methyl 3-amino-benzoate (2.0 g, 13.2 mmol) and pyridine (2.30 g, 29.1 mmol) in dichloromethane (50 ml) at −10° C. under a nitrogen atmosphere was slowly added methanesulfonyl chloride (2.25 ml, 29.1 mmol) by syringe. After 2 hours, water was added and the volatiles were removed by spin evaporation in vacuo. A solution of the residue and sodium hydroxide (3.175 g, 79.4 mmol) in methanol (50 ml) and water (50 ml) was stirred for 18 hours. The residue after removal of the volatiles by spin evaporation in vacuo was dissolved in 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and the volatiles were removed by spin evaporation in vacuo to give 3-[(methylsulfonyl)amino]benzoic acid as an oil. (1.32 g, 46%). 1H-NMR (400 MHz, DMSO-d6): δ 7.83-7.78 (m, 2H), 7.55-7.50 (m, 1H), 7.50-7.46 (m, 1H), 3×80 (s, 3H). ES-LCMS m/z 216 (M+H).
Reaction SMILES: C(OC([C:6]([C:35](=[O:38])[CH2:36][CH3:37])([CH2:18][CH2:19][CH2:20][CH:21]([O:31]C(=O)C)[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=O)C.C(C(C(OCC)=O)(CCCC(OC(=O)C)COC1C=CC(F)=CC=1)CC#CCCCC(OC)=O)(=O)C>>[C:35]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([OH:31])[CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:38])[CH2:36][CH3:37]
Reactant: CCOC(=O)CCCCCCC(CCCC(COc1ccc(F)cc1)OC(C)=O)(C(=O)CC)C(=O)OCC
Agent: CCOC(=O)C(CC#CCCCC(=O)OC)(CCCC(COc1ccc(F)cc1)OC(C)=O)C(C)=O
Product: CCC(=O)C(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1

Procedure:
The synthesis of this compound is carried out by the procedure of Example 4, Step D except that an equivalent quantity of ethyl 8-ethoxycarbonyl-8-propionyl-12-acetoxy-13-(4-fluorophenoxy)tridecanoate is substituted for the methyl 8-acetyl-8-ethoxycarbonyl-12-acetoxy-13-(4-fluorophenoxy)-5-tridecynoate of Example 4, Step D.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[CH:4]([CH3:9])[CH:5]([CH3:8])[CH2:6][CH:7]=1.O=O>[Cu]=O>[CH3:9][C:4]1[C:5]([CH3:8])=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[OH:10]
Reactant: CC1=CCC(C)C(C)C1=O
Agent: O=[Cu]
Agent: O=O
Product: Cc1ccc(C)c(O)c1C

Procedure:
If the reaction mixture comprising 2,5,6-trimethylcyclohex-2-en- 1-one, alkanol, the catalytic amount of copper oxide and hydrogen halide gas, as described above, is allowed to react for a longer time with air or oxygen, 4-halo-2,3,6-trimethylphenol is obtained in addition to 2,3,6-trimethylphenol. If, instead of isolating this product, the reaction mixture is treated, as described above, with an alkali metal alcoholate, and the oxidation with air or oxygen is continued, the 4-halo-2,3,6-trimethylphenol is also converted to 2,3,5-trimethyl-p-benozoquinone. After the reaction products obtained in step A have been treated with an alkali metal alcoholate, they can also be oxidized with tert.-butyl hydroperoxide instead of air or oxygen. Depending on whether trimethylphenol or halotrimethylphenol is the predominant product, subsequent oxidation with tert.-butyl hydroperoxide gives 2,3,5-trimethyl-p-benzoquinone in a yield of from 65 to 80% of theory.
Reaction SMILES: [S:1](=[O:4])([OH:3])[O-:2].[Na+:5].[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1>O.C(O)C>[F:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[C:12]([S:1]([O-:3])(=[O:2])=[O:4])[NH:13]2)=[CH:9][CH:8]=1.[Na+:5]
Reactant: O=S([O-])O
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1cc2ccc(F)cc2[nH]1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
To a solution of 23.4 g sodium bisulfite in 80 ml water a solution of 13.5 g 6-fluoro indole in ethanol is added drop wise. The obtained suspension is stirred at room temperature over night. The precipitate is filtered and washed with cold water, cold methanol and diethyl ether. 7.0 g (29%) of the title compound are obtained as a colourless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(I)cc1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (90 mg, 0.48 mmol) and iodo-4-methylbenzene (0.07 mL, 0.55 mmol) according to the general procedure IB to give 18 mg (15%) of an orange oil after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:30→1:10). Rf: 0.42 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.45-7.39 (m, 4H), 7.18-7.13 (m, 4H), 3.67 (s, 3H), 2.98-2.93 (t, 2H, J=7.8 Hz), 2.66-2.60 (t, 2H, J=7.8 Hz), 2.36 (s, 3H); 13CNMR (CDCl3) δ 173.1, 140.6, 138.3, 131.7, 131.4, 129.1, 128.3, 121.4, 120.2, 89.3, 88.6, 51.6, 35.4, 30.8, 21.5; EI-MS m/z 278 (M+).