Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([NH:29][C@H:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[C:22]([O:26][C:27](=[O:28])[NH:29][C@@H:30]([C:31](=[O:32])[NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccccc1
Yield: 142 %

Procedure:
Preparation of example 117 from the the title compound of Example 7 (hydrochloride) (44 mg, 0.141 mmol), (R)-tert-butoxycarbonylamino-phenyl-acetic acid (42 mg, 0.169 mmol), triethylamine (0.059 mL, 0.423 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (64 mg, 0.169 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (102 mg) as a yellow powder contaminated with an unknown impurity. The compound was an intermediate and carried on without further purification to Example 91.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH:16](O)([CH3:18])[CH3:17]>O>[CH:16]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=1)([CH3:18])[CH3:17]
Reactant: CC(C)O
Reactant: O=C(O)c1cccc(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)c1cccc(Br)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 3-bromo benzoic acid (Aldrich, 2.4 g, 11.9 mmol) in isopropanol (20 mL) was treated with 1 mL of concentrated sulfuric acid and the resulting reaction mixture was refluxed overnight. The reaction mixture was then cooled to ambient temperature and diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to an oil that was subjected to flash column chromatography over silica gel (230–400 mesh) using 10% ethyl acetate in hexane as the eluent to afford the title compound as an oil (2.54 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.CC1(C)C(C)(C)OB(/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])O1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[Cl:1][C:2]1[C:7](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CCOC(=O)/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccc(I)c(Cl)n1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(Cl)nc1Cl
Reaction time: 2 h

Procedure:
To a solution of 2,6-dichloro-3-iodopyridine (3.0 g, 10.95 mmol), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2.476 g, 10.95 mmol), and Dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium (II) (0.357 g, 0.548 mmol) in THF (81 mL) was added 1M (aq) K2CO3 (54.8 mL, 54.8 mmol). A steady stream of N2 was bubbled through the resultant mixture for 5 minutes. Stirring was continued at ambient temperature for 2 h then the mixture was diluted with EtOAc and the organic layer washed successively with water (1×) and brine (1×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-30% EtOAc/Hexanes as eluent to give the title compound as a tan solid. 1H NMR δ (ppm) (CHCl3-d): 7.95 (1H, d, J=16 Hz), 7.90 (1H, d, J=8.1 Hz), 7.35 (1H, d, J=8.1 Hz), 6.47 (1H, d, J=16 Hz), 4.32 (2H, q, J=7.15 Hz), 1.38 (3H, t, J=7.14 Hz). MS (M+H)+: 245.
Reaction SMILES: [Cl-].[NH+]1C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20]C)[CH:15]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1
Reactant: COc1cccc(C=Cc2cccc(Cl)c2)c1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: Oc1cccc(C=Cc2cccc(Cl)c2)c1
Temperature: 180 °C
Reaction time: 3 h

Procedure:
An excess of triethyl phosphite was added to 3-chlorobenzyl chloride (a), and the mixture was heated with stirring at 130° C. until the generation of ethyl bromide stopped. Diethylchlorobenzyl phosphonate (b) was obtained by the removal of excess triethyl phosphite. Dried dimethylformamide and an excess of sodium methylate were added thereto as a solvent and as a base, respectively, followed by cooling at 0° C. on an ice bath. An equivalent of m-anisaldehyde (c) was added thereto, and the mixture was stirred at room temperature for 1 hour. Then, after stirring at 90° C. for 1 hour, the temperature was lowered to room temperature and stirring was continued overnight. The reaction solution was extracted with ethyl acetate to obtain an ethyl acetate extract. This extract was purified by silica gel chromatography (solvent: hexane/ethyl acetate=9.5/0.5 (V/V)) to obtain 3'-chloro-3-methoxystilbene (d). Subsequently, an excess of pyridinium chloride was added to 3'-chloro-3-methoxystilbene (d), and heated with stirring at 180° C. for 3 hours. The reaction solution was extracted with ethyl acetate, and the resulting ethyl acetate extract was purified by silica gel chromatography (solvent: hexane/ethyl acetate=8.5/1.5 (V/V)) to obtain 3'-chloro-3-hydroxystilbene (compound 4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+].[CH3:23][S:24](Cl)(=[O:26])=[O:25].[OH-].[Na+]>C(#N)C.O>[CH3:23][S:24]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Yield: 29.2 %

Procedure:
A suspension of 1.15 g (5 mmol) of 6-(3-aminophenyl)-1,2-dihydro-2-oxonicotinic acid, 200 ml of water, and 0.42 g (5 mmol) of sodium bicarbonate is stirred at 0°-5° and a solution of 3.6 ml (30 mmol) of methanesulfonyl chloride and 30 ml of acetonitrile is added over a 2 hr. period. During the addition, the pH of the reaction is maintained at 6.9-7.3 with 1 N sodium hydroxide. After the addition, the reaction is stirred at 0°-5° for 2 hrs. The precipitated solid is filtered and dried to give 0.45 g of 6-[3-(methylsulfonylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid.
Reaction SMILES: [Br:1][C:2]1(Br)[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:16])=[C:9]([Cl:15])[CH:10]=3)[NH:5][C:4]=2[C:3]1=[O:17].[Li+].[Br-]>CN(C=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:16])=[C:9]([Cl:15])[CH:10]=3)[NH:5][C:4]=2[C:3]=1[OH:17]
Reactant: O=C1c2[nH]c3cc(Cl)c(Cl)cc3c2CCC1(Br)Br
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Oc1c(Br)ccc2c1[nH]c1cc(Cl)c(Cl)cc12
Temperature: 110 °C
Yield: 37.8 %

Procedure:
2,2-Dibromo-6,7-dichloro-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.1 g, 0.24 mmol) was dissolved in DMF (2 mL) and LiBr (0.02 g, 0.26 mmol) followed by Li2CO3 (0.01 g, 0.25 mmol) were added. The reaction mixture was heated to 110° C. for 2 h, cooled to room temperature and quenched with saturated NH4Cl (10 mL), extracted with EtOAc (2×15 mL) and the combined organic extracts were concentrated in vacuo to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (1:9) as eluant] to provide the title compound as light red solid (30 mg, 37%). 1H NMR (500 MHz, CDCl3, δ in ppm): 8.28 (bs, 1H), 8.07 (s, 1H), 7.57 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 5.72 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:15]#[N:16])(=[O:3])[CH3:2].[CH2:17]([OH:19])[CH3:18].[ClH:20].C(OCC)C>>[ClH:20].[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:15](=[NH:16])[O:19][CH2:17][CH3:18])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: COc1ccc2c(c1)CC(C#N)N2C(C)=O
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)C1Cc2cc(OC)ccc2N1C(C)=O

Procedure:
To a solution of intermediate (23) (0.0154 mole) and ethanol (0.0231 mole) in 1M HCl/diethylether (200 ml), cooled in an ice bath was bubbled HCl (gas) for 60 minutes. The ice bath was maintained for 45 minutes, and the mixture was concentrated at room temperature under vacuum to 200 ml of an oily precipitate. The residue was triturated to a brown solid that became an oil after decanting off the diethylether. The residue was washed with diethylether twice, dissolved in methanol, and used without further purification for further synthesis, yielding ethyl 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carboximidate monohydrochloride (intermediate 24).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NC1C=CC=CC=1>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3ccccc3)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and aniline (9.1 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (18 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9](C)([C:13](O)=O)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(=O)=O>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(Cc1ccc(Cl)nc1)(C(=O)O)C(=O)O
Agent: O=C=O
Product: CC(Cc1ccc(Cl)nc1)C(=O)O
Temperature: 185 °C
Yield: 90.8 %

Procedure:
The solid 2-[(6-chloropyridin-3-yl)methyl]-2-methylmalonic acid (8.70 g, 37.5 mmol) in a 500 mL round bottom flask was immersed in an oil bath heated to 185° C. As the solid melted carbon dioxide evolution occurred. After heating for 30 min, the reaction was deemed complete. Upon cooling there was obtained an amber gum (6.8 g, 95% yield). [M+H]+=200, 202; IR: 1703 (C═O). The product was about 85% pure and was used for the next step reaction directly.
Reaction SMILES: [C:1]([Cu])#[N:2].N[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([NH2:16])=[O:15])=[C:10]2[S:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=[O:19])=[O:18].N(OC(C)(C)C)=O>CS(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([NH2:16])=[O:15])=[C:10]2[S:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)(=[O:19])=[O:18])#[N:2]
Reactant: N#C[Cu]
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Agent: CC(C)(C)ON=O
Solvent: CS(C)=O
Product: N#Cc1cccc2c(S(=O)(=O)N3CCOCC3)c(C(N)=O)[nH]c12
Reaction time: 18 h

Procedure:
To a stirring suspension of CuCN (35 mg, 0.39 mmol, 1.25 equiv) and 7-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (100 mg, 0.31 mmol, 1.0 equiv) in 3 mL of DMSO was added dropwise tert-butyl nitrite (110 μL, 0.92 mmol, 3.0 equiv). After stirring for 18 hours, the title compound was obtained by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 335.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15](OC)=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH2:21][NH2:22].O>CCO>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15]([NH:21][NH2:22])=[O:16])[O:12][N:11]=2)=[CH:6][CH:5]=1
Reactant: NN
Reactant: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)no1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To a solution of methyl 3-(4-(trifluoromethoxy)phenyl)isoxazole-5-carboxylate (3.0 g, 10.5 mmol) in EtOH (80 mL) was added NH2NH2.H2O (3.3 mL, 52.3 mmol). The resulting mixture was stirred at RT for 16 h and then concentrated under reduced pressure. The residue was crystallized from CHCl3 and petroleum ether to afford the title compound (2.7 g, 90%). MS (ES+) C11H8F3N3O3 requires: 287. found: 288 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1.[NH:12]1[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]1=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:10][C:7]1([CH3:11])[O:8][CH2:9][CH:4]([CH2:3][CH2:2][N:12]2[CH:19]=[CH:18][C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:5][O:6]1
Reactant: CC1(C)OCC(CCBr)CO1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCn2ccc(=O)[nH]c2=O)CO1
Temperature: 25 °C
Reaction time: 120 h
Yield: 29.2 %

Procedure:
To a solution of 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxane (15) (M. R. Harnden et al, J. Med. Chem., 30, 1636, 1987) (12.0 gm, 53.81 mmol) in dry DMF (150 ml) were added uracil (7.0 gm, 62.4 mmol) and potassium carbonate (14.0 gm). The reaction mixture was stirred at 25° C. for 5 days. The resulting solution was filtered and the solvent removed. The residue obtained was purified by column chromatography on silica gel eluting with chloroform-methanol (90:10, v/v) to afford 17 (4.0 gm, 25.2%).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[CH:21](O)[CH2:22][CH2:23][C:24]1([C:41]([O:43][CH3:44])=[O:42])[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][S:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[CH2:26][CH2:25]1)=[CH:18][C:17]([O:46][CH3:47])=[CH:16][CH:15]=2.C(=O)([O-])O.[Na+]>ClCCl>[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[CH:21]([F:7])[CH2:22][CH2:23][C:24]1([C:41]([O:43][CH3:44])=[O:42])[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][S:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[CH2:28][CH2:29]1)=[CH:18][C:17]([O:46][CH3:47])=[CH:16][CH:15]=2
Reactant: COC(=O)C1(CCC(O)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCSc2cc(F)ccc2F)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(CCC(F)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCSc2cc(F)ccc2F)CC1
Temperature: 5 °C

Procedure:
0.1 cm3 of diethylaminosulfur trifluoride was added to a solution of 0.25 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-4-carboxylate in 10 cm3 of dichloromethane, with stirring and under an inert atmosphere, at a temperature in the region of 5° C. After stirring for 7 hours at a temperature in the region of 20° C., saturated sodium hydrogen carbonate solution was added to the reaction mixture. The aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200μ; mass: 15 g), eluting with 60 cm3 of dichloromethane, then with 45 cm3 of a mixture of ethyl acetate/dichloromethane (1/9 by volume), then with 30 cm3 of a mixture of ethyl acetate/dichloromethane (2/8 by volume) and then with 210 cm3 of a mixture of ethyl acetate/dichloromethane (3/7 by volume) and then with ethyl acetate. Fractions 24 to 26 were combined and then concentrated to dryness according to the same conditions as above. 0.08 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-4-carboxylate was obtained in the form of a thick yellow oil.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH3:4].[NH2:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([NH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCI
Reactant: COC(=O)c1sccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1ccsc1C(=O)OC
Temperature: 120 °C
Reaction time: 10 h
Yield: 47.8 %

Procedure:
34.1 ml (0.300 mol) of n-butyl iodide was added to a solution of 15.7 g (0.100 mol) of methyl 3-aminothiophene-2-carboxylate and 15.2 g (0.110 mol) of potassium carbonate in 200 ml of N,N-dimethylformamide at 25° C., and the mixture was stirred at 120° C. for 10 hours. After cooling, the solvent was evaporated under reduced pressure and 200 ml of ethyl acetate was added to the residue to remove inorganic salts by filtration. The filtrate was again concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=1/9 v/v) to give 10.2 g (yield: 48%) of methyl 3-(n-butyl)aminothiophene-2-carboxylate (Compound a-1)
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=1.[F:15][C:16]([F:34])([F:33])[C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.C(OC(=O)C)(=O)C>>[CH3:12][N:11]1[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:14])[N:3]=[C:2]1[CH:1]=[CH:27][C:26]1[CH:29]=[CH:30][C:23]([C:21](=[O:22])[C:20]2[CH:31]=[CH:32][C:17]([C:16]([F:15])([F:33])[F:34])=[CH:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: Cc1cccc2nc(C)n(C)c(=O)c12
Reactant: O=Cc1ccc(C(=O)c2ccc(C(F)(F)F)cc2)cc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc2nc(C=Cc3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)n(C)c(=O)c12
Temperature: 140 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a mixture of 2,3,5-trimethyl-4(3H)-quinazolinone (508 mg) and 4-(4-trifluoromethylbenzoyl)benzaldehyde (751 mg) was added acetic anhydride (1.0 ml) and the mixture was stirred at 140° C. for 2 hours. This reaction mixture was concentrated and the residue was washed with n-hexane-diethyl ether and dried to provide 898 mg of yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][C:12]=1[C:13](O)=O>>[CH3:9][O:10][C:11]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][CH:6]=2
Reactant: COc1ccc(NS(C)(=O)=O)cc1C(=O)O
Reactant: Nc1cccnc1N
Product: COc1ccc(NS(C)(=O)=O)cc1-c1nc2ncccc2[nH]1

Procedure:
Prepared analogously to Example 14 from 2,3-diaminopyridine and 2-methoxy-5-methanesulfonylamino-benzoic acid,
Reaction SMILES: [SH2:1].Br[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1>>[C:3]1([S:1][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:8]=[CH:9][CH:10]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: S
Reactant: Brc1cccc2ccccc12
Product: c1ccc2c(Sc3cccc4ccccc34)cccc2c1

Procedure:
By a procedure similar to that described in Example 14, hydrogen sulphide is passed into 20 g (0.1 mole) of molten 1-bromonaphthalene at a temperature of 220°-230° C for seven hours to obtain by distillation in vacuum (1 mm Hg) 7.5 g (52 percent by weight) of di(1-naphthyl)sulphide. The conversion is 82.5 percent by weight.
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C)C=O>[C:26]([O:25][C:24]([N:23]([CH2:22][C:9]1[CH:8]=[C:7]([C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)[N:11]([S:12]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=2)[O:21][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])(=[O:13])=[O:14])[CH:10]=1)[CH3:31])=[O:30])([CH3:27])([CH3:28])[CH3:29]
Reactant: CN(Cc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2C2=CCCCC2)c1
Reaction time: 3 h

Procedure:
tert-Butyl ((5-(cyclohex-1-en-1-yl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 7d (100 mg, 0.22 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of cesium carbonate (146 mg, 0.45 mmol) and ethyl bromoacetate (102 mg, 0.67 mmol), and then the reaction solution was stirred for 3 h. The reaction solution was concentrated under reduced pressure, 50 mL of water was added, and the reaction solution was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product ethyl 2-(3-((4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-(cyclohex-1-en-1-yl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)acetate 8a (99 mg, a light yellow oil) in 81% yield.
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[CH2:5]([C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:27])[CH2:11][CH:10]=1)[CH3:6]>CO.ClCCl>[CH2:5]([C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C@@H:12]([OH:27])[CH2:11][CH:10]=1)[CH3:6]
Reactant: CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)C(=O)CC=C3[C@H]12
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
ix)—A solution of sodium borohydride (0.21 g) and sodium hydroxide (0.44 g) in methanol (50 ml) was added dropwise to a solution of (7α)-7-ethyl-3-methoxyestra-1,3,5(10),14-tetraen-17-one (4.31 g) in dichloromethane (12 ml) and methanol (20 ml), cooled to 0° C. The reaction mixture was stirred for 1.5 h, quenched with acetone (4 ml), and then poured into a saturated aqueous solution of ammonium chloride. The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure, to give (7α,17β)-7-ethyl-3-methoxyestra-1,3,5(10),14-tetraen-17-ol (4.28 g). The product was used in the following step without further purification.
Reaction SMILES: [CH2:1]([CH:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[OH:5])[CH:2]=[CH2:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH:2]=[CH2:3]
Reactant: C=CCC(O)c1cccc2ccccc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=CCC(=O)c1cccc2ccccc12

Procedure:
Allyl-1-naphthylcarbinol (205 mg) and pyridinium chlorochromate (230 mg) were reacted in dichloromethane (2 mL) at room temperature for 4 hours.