Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1>CN(C=O)C.[Pt]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][C:3]=1[O:12][C:13]([F:16])([F:14])[F:15]
Reactant: Nc1cc(Cl)c(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(OC(F)(F)F)cc1N

Procedure:
5-Chloro-2-nitro-4-trifluoromethoxy-phenylamine (180 g, 0.7 mol, 1.0 equiv.) was dissolved in dry DMF (1 L) and then 5% Pt/C containing 50.2% water (4.0 g) was added. The reaction solution was hydrogenated (50 psi) at room temperature for 16 hours. HPLC analysis indicated complete reaction. MS [M+H]+ found 225.2. The reaction solution was used on the next step without isolation.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][N:9]([CH3:21])[CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=2)[CH2:11]1.C1([O:28][C:29](=O)[NH:30][C:31]2[CH:36]=[C:35]([C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH:34]=[C:33]([CH2:43][CH3:44])[CH:32]=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH2:43]([C:33]1[CH:32]=[C:31]([NH:30][C:29]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[CH2:8][N:9]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[CH2:11]2)[CH3:21])=[O:28])[CH:36]=[C:35]([C:37]2[N:41]([CH3:42])[N:40]=[N:39][N:38]=2)[CH:34]=1)[CH3:44]
Reactant: CN(C[C@@H]1CCCC[C@H]1N)C1CCc2cc(F)ccc2C1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1cc(NC(=O)N[C@@H]2CCCC[C@H]2CN(C)C2CCc3cc(F)ccc3C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
A mixture of N-(2RS)-{[(1S,2R)-2-aminocyclohexyl]methyl}-6-fluoro-N-methyl-1,2,3,4-tetrahydronaphthalen-2-amine (60 mg, 206 μmol), phenyl[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]carbamate (52 mg, 206 μmol), triethylamine (57 μL, 412 μmol) and acetonitrile (2 mL) was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was dissolved in ethyl acetate. The solution was washed with aqueous sodium hydroxide (1.0 N), dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonia, to provide an amorphous solid (40 mg, 37%) which was a mixture of two diastereomers by NMR.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][N:14]([C@@H](C3C=CC(OC)=CC=3)C)[C:13](=[O:26])[CH2:12]2)[CH3:10])[C:5]2[N:27]([CH3:30])[CH:28]=[N:29][C:4]=2[CH:3]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:26])[CH2:12]2)[CH3:10])[C:5]2[N:27]([CH3:30])[CH:28]=[N:29][C:4]=2[CH:3]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cc4ncn(C)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Temperature: 57.5 °C

Procedure:
(R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.05 (32 mg, 0.075 mmol) was dissolved in trifluoroacetic acid (1.1 mL) at room temperature and mixture was heated between 55-60° C. overnight. After cooling to room temperature, mixture was concentrated under reduced pressure, taken up in ethyl acetate, washed with saturated NaHCO3 (aq), and layers separated. Aqueous layer was extracted with ethyl acetate (3×) and combined organic layers were washed with 1:1 saturated NaHCO3 (aq): brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to yield (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06, which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:43]=[C:42]([N+:44]([O-])=O)[CH:41]=[CH:40][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])=[CH:8][C:7]=1[P:26](=[O:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>[Pd].C(O)C>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:43]=[C:42]([NH2:44])[CH:41]=[CH:40][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[C:22]([F:25])([F:24])[F:23])=[CH:8][C:7]=1[P:26](=[O:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Oc3ccc([N+](=O)[O-])cc3C(F)(F)F)c(P(=O)(c3ccccc3)c3ccccc3)c2)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Oc2ccc(Oc3ccc(N)cc3C(F)(F)F)c(P(=O)(c3ccccc3)c3ccccc3)c2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a 250 mL Parr hydrogenation flask was charged [2,5-bis(2-trifluoromethyl-4-nitrophenoxy)phenyl]diphenylphosphine oxide (2.55 g, 0.0037 mol), ethanol (25 mL), and 10% Pd/C (0.27 g). The mixture was degassed prior to the introduction of hydrogen gas. The mixture was agitated under a hydrogen atmosphere for ˜24 hours at room temperature. After degassing the solution, the Pd/C was removed by filtration and the solution added to stirred water to afford an off white solid. The crude solid was collected via filtration, washed with water, and dried at room temperature to afford 1.23 g (53% crude yield). The solid exhibited no melting peaks as determined by DSC at a heating rate of 10° C./min.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)=[O:12])=[C:6]([O:20][CH3:21])[CH:5]=1.O.O.[OH-].[Li+]>CO>[CH3:21][O:20][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([NH:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)=[O:12])[C:3]([OH:22])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)Nc2cnccn2)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1NC(=O)Nc1cnccn1
Temperature: 65 °C
Yield: 92.6 %

Procedure:
To a stirred suspension of 3-methoxy-4-(3-pyrazin-2-yl-ureido)-benzoic acid methyl ester (6.07 g, 20 mmol) in 200 mL 3:1 MeOH:H2O at room temperature under nitrogen was added lithium hydroxide monohydrate (8.4 g, 200 mmol) and the reaction heated to 65 ° C. overnight. The reaction was then cooled to room temperature and most of the methanol removed by rotary evaporation. The remaining suspension was neutralized to pH about 4 with concentrated HCl. The formed precipitate was isolated by filtration and rinsing with H2O and then drying under high vacuum to give the desired acid as a white solid (5.34 g, 93%). 1H-NMR (400 MHz, d6-DMSO) δ 8.89 (br s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 8.16 (d, 1H), 8.16 (d, 1H), 7.56 (s, 1H), 7.50 (d, 1H), 3.91 (s, 3H)
Reaction SMILES: [NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:3]=1.[N:28]#[C:29]Br>CCO.C(OCC)C>[NH:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:5]3[C:4]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:3][C:2]4[NH:1][C:29]([NH2:28])=[N:20][C:19]=4[CH:18]=3)=[O:7])[CH:17]=2)[CH:13]=[N:14]1
Reactant: N#CBr
Reactant: CN1CCN(c2cc(N)c(N)cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Solvent: CCO
Solvent: CCOCC
Product: CN1CCN(c2cc3[nH]c(N)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1

Procedure:
To a solution of 4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide (2 mmol; see Example 181) in 10% aqueous EtOH (6 mL) was added cyanogen bromide (2.2 mmol), and the mixture was heated at reflux for 4 h. The reaction mixture was then concentrated in vacuo, and the residue obtained was suspended in diethyl ether with vigorous stirring. The solid obtained was collected by filtration, washed with diethyl ether, and dried in vacuo to afford 2-amino-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a hydrobromide salt. MS: m/z 391 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[OH-].[Li+].C(OCC)(=O)C.Cl>O1CCCC1.O>[CH2:18]([O:17][C:15]([NH:14][C@H:4]([CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])[C:3]([OH:25])=[O:2])=[O:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To (R)-2-Benzyloxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propionic acid methyl ester (1.450 g, 3.95 mmol) in tetrahydrofuran/water (2/1) is added lithium hydroxide (250 mg, 5.92 mmol). After stirred at rt during 16 h, the solution is treated with ethyl acetate and the pH is decrease to 2 with aqueous 1N HCl. The organic phase is dried and evaporated to yield the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1CC.[SH:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[S:22][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCCl
Reactant: Sc1ncccn1
Product: Nc1nc2ccccc2c2c1ncn2CCCCSc1ncccn1

Procedure:
Using the general method of Example 20 Part A, 1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.30 mmol) was reacted with 2-mercaptopyrimidine (0.59 g, 5.3 mmol) to provide 1.0 g of 2-ethyl-1 μm-[4-(pyrimidin-2-ylthio)butyl]-1H-imidazo[4,5-c]quinolin-4-amine as an off white powder, m.p. 182-185° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH2:14][CH3:15])[C:4]1=[O:5])[CH3:2].Cl[CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22]>>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[CH3:22])[CH:9]=[N:8][C:7]=2[N:6]([CH2:14][CH3:15])[C:4]1=[O:5])[CH3:2]
Reactant: CC(=O)CCCCCl
Reactant: CCn1c(=O)c2[nH]cnc2n(CC)c1=O
Product: CCn1c(=O)c2c(ncn2CCCCC(C)=O)n(CC)c1=O

Procedure:
1,3-Diethyl-7-(5-oxohexyl)xanthine (melting point 68-69° C.) is prepared from 1,3-diethylxanthine and 1-chloro-hexan-5-one.
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([OH:11])[CH2:5][C:4]1([CH3:13])[CH3:12].C[O:15][C:16]([Cl:18])=O>>[Cl:18][C:16]([O:11][CH:6]1[CH2:7][C:8]([CH3:9])([CH3:10])[N:3]([O:2][CH3:1])[C:4]([CH3:13])([CH3:12])[CH2:5]1)=[O:15]
Reactant: COC(=O)Cl
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Product: CON1C(C)(C)CC(OC(=O)Cl)CC1(C)C

Procedure:
The title compound is prepared by reacting 1-methoxy-2,2,6,6-tetramethylpiperidin-4-ol (1 mole) with methylchloroformate (1 mole).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([CH3:15])[CH3:14]>>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH:20][C:19]2[CH:21]=[CH:22][C:16]([CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)F)cc1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NCc2ccc(OC(F)F)cc2)cc1

Procedure:
Following the procedure described in Example 1A, step 1, 4-(difluoromethoxy)benzaldehyde and 4-isopropylaniline gave the title compound as a pale yellow oil.
Reaction SMILES: [S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3I)[O:6]1)[NH2:2].CCN(C(C)C)C(C)C.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:44]([F:47])([F:46])[F:45])#[CH:37]>CN(C=O)C.C(Cl)Cl.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:1](=[O:26])(=[O:25])([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10]([CH3:14])([CH3:13])[O:11]2)[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[C:37]#[C:36][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]([F:45])([F:46])[F:47])[O:6]1)[NH2:2]
Reactant: C#Cc1ccccc1C(F)(F)F
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(I)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COS(N)(=O)=O)O[C@H]2n1cnc2c(C#Cc3ccccc3C(F)(F)F)ncnc21
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 85.3 %

Procedure:
To a solution of [(3aR,4R,6R,6aR)-6-(6-iodo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl sulfamate (0.200 g, 0.402 mmol) in DMF (7 mL) was added DIPEA (0.176 mL, 1.01 mmol), 1-ethynyl-2-trifluoromethyl-benzene (0.224 mL, 1.61 mmol), CuI (0.0191 g, 0.101 mmol), and Pd(PPh3)2Cl2 (0.0282 g, 0.0402 mmol). The mixture was stirred at r.t. for 50 min, diluted with DCM (25 mL) and washed with saturated aq EDTA.Na2 (3×25 mL). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (15 to 50% EtOAc/DCM) to isolate the title compound (0.185 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:20]N1C(=O)CCC1=O>O1CCOCC1>[NH2:1][C:2]1[C:7]2[C:8](=[O:19])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[O:11][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:20]
Reactant: Nc1ccc(-c2cc(=O)c3c(N)cccc3o2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Product: Nc1ccc(-c2cc(=O)c3c(N)c(Cl)ccc3o2)cc1
Yield: 18.3 %

Procedure:
2.0 g (7.93 mmol) of 5-amino-2-(4-aminophenyl)-4H-1-benzopyran-4-one (EP-A-374789) was dissolved in 50 ml of dioxane, 1.06 g (7.93 mmol) of N-chlorosuccinimide was added and the mixture was stirred under heating at reflux for 19 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:acetone=4:1) to give 710 mg (31%) of crude product. Further recrystallization from chloroform/methanol afforded 415 mg (18%) of Compound 1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:40])[NH:12][C:13]([C:15]1[S:16][C:17]([S:38][CH3:39])=[C:18]([S:20]([C:23]2[CH:24]=[C:25]([C:29]3[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:36][OH:37])[CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:19]=1)=[NH:14])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.CCOC(C)=O>C1COCC1>[C:6]([O:10][C:11]([NH:12][C:13](=[NH:14])[C:15]1[S:16][C:17]([S:38][CH3:39])=[C:18]([S:20]([C:23]2[CH:24]=[C:25]([C:29]3[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:36][O:37][S:2]([CH3:1])(=[O:4])=[O:3])[CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:19]=1)=[O:40])([CH3:8])([CH3:9])[CH3:7]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2COS(C)(=O)=O)c1
Reaction time: 18 h
Yield: 14.8 %

Procedure:
Methanesulfonyl chloride (0.027 g, 0.241 mmol) was added to a solution of {[4-(2′-hydroxymethyl-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.100 g, 0.188 mmol) [example 213, step b] and triethylamine (0.048 g, 0.470 mmol) in THF [3 mL] at room temperature and stirred for 18 hours. Column chromatography (25% EtOAc in hexanes) of the residue yielded the title compound (0.017 g, 14%). ESI-MS (m/z): Calcd. for C26H30N2O7S4: 610.09; found: 611.8.
Reaction SMILES: C([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]([O:23]CC)=[O:22])=[CH:14][C:13]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:12][CH:11]=2)C1C=CC=CC=1.[OH-].[K+]>C(O)C.O>[CH2:16]([N:9]1[C:10]2[C:15](=[CH:14][C:13]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:12][CH:11]=2)[C:16]([CH:17]=[CH:18][CH:19]=[CH:20][C:21]([OH:23])=[O:22])=[CH:8]1)[C:15]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=CC=Cc1c(Cc2ccccc2)[nH]c2ccc(OCc3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C=CC=Cc1cn(Cc2ccccc2)c2ccc(OCc3ccccc3)cc12

Procedure:
In a manner similar to Example 2, 1 g (2.4 mmol) of ethyl 5-(benzyl-5-benzyloxyindol-3-yl)-2,4-pentadienoate was treated with 0.5 g (8.6 mmol) of potassium hydroxide in ethanol-water to give, after powders, m.p. 202-203. MS(EI): 365 (M+--CO2), 274 (M+--CO2 --CH2C6H5); NMR (DMSO-d6): δ5.14 (s, 2), δ5.36 (s, 2), δ5.89 (d, J=15 Hz, 1).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl[S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>N1C=CC=CC=1.CCOCC>[CH3:34][O:33][C:31](=[O:32])[CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=2)(=[O:21])=[O:22])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(N)cc1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (200 mg, 0.80 mmol) in anhydrous pyridine (4 mL) was added dropwise methyl 3-(4-chlorosulfonylphenyl)propionate (251 mg, 0.96 mmol) at rt. After 60 min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 200 mg) was added and the resulting mixture was stirred for 1 hr at rt. After filtration and rinsing the resin, water (100 mL) was added into the filtrate. Extraction with EtOAc (100 mL), washing with HCl (1N, 60 mL) and an aqueous saturated solution of NaHCO3 (50 mL), drying over MgSO4 and evaporation under vacuo gave a yellow oil. The residue was taken up in Et2O and a white solid precipitated out. Filtration and washing with Et2O gave the title compound (214 mg) was obtained as a white solid (56%) in 99.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=O)[CH2:6]2.C(N1CC=[C:18]([Sn:21](C)([CH3:23])[CH3:22])CC1)(C)(C)C>>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]([Sn:21]([CH3:23])([CH3:22])[CH3:18])[CH2:6]2
Reactant: CC(C)(C)N1CC=C([Sn](C)(C)C)CC1
Reactant: CN1C2CCC1CC(=O)C2
Product: CN1C2C=C([Sn](C)(C)C)CC1CC2

Procedure:
The compound was prepared from 8-methyl-8-azabicyclo[3.2.1]octan-3-one as described above for 1-tert-Butyl-1,2,3,6-tetrahydro-4-(trimethylstannyl)pyridine.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=O)[CH2:3][CH2:2]1.[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][NH2:23]>CO.C(O)(=O)C>[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22]/[N:23]=[C:4](/[CH:1]1[CH2:3][CH2:2]1)\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=C(c1ccccn1)C1CC1
Reactant: Cn1c(NN)nc2ccccc21
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(N/N=C(\c2ccccn2)C2CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of cyclopropyl-(2-pyridyl)-methanone (1,00 g, 7,40 mmol) and 1-methyl-2-hydrazinobenzimidazole (1.20 g, 7.40 mmol) in 20 ml of methanol is stirred for 3 days at room temperature after the addition of 6 drops of glacial acetic acid. Monitoring is effected by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored in the refrigerator at approximately 5° C. for 24 hours. The precipitate is filtered, washed several times with 50% methanol, and dried. The product is recrystallized from a mixture of methanol and water. Yield: 0.97 g (45% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]2=[O:23])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:24]1([CH:27](O)[CH3:28])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[N:13]([CH3:22])[C:12]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][CH:27]([CH:24]1[CH2:26][CH2:25]1)[CH3:28])=[O:5]
Reactant: CC(O)C1CC1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C(=O)O)c2)c1=O
Product: CC(OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl)C1CC1

Procedure:
In an analogous manner, starting from 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoic acid via its acid chloride and 1-cyclopropylethanol there is obtained 1-cyclopropylethyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoate, m.p. 118°-119° C.;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.[F:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.CCN(C(C)C)C(C)C>CC#N>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:15]2[CH2:16][CH2:17][C@H:13]([F:12])[CH2:14]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: F[C@H]1CCNC1
Reactant: N#Cc1cc(Br)cnc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Br)cnc1N1CC[C@H](F)C1

Procedure:
5-Bromo-2-chloro-nicotinonitrile (6) (5.0 g, 23.0 mmol) was dissolved in MeCN (100 mL). (S)-3-Fluoropyrrolidine hydrochloride (5.7 g, 53.0 mmol) and DIPEA (12.0 mL, 68.9 mmol) were added and the mixture was stirred at reflux for 1 hour. The solvent was evaporated in vacuo and the residue partitioned between EtOAc (100 mL) and H2O (50 mL). The layers were separated and the organic phase washed with saturated brine solution (50 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo. The title compound was obtained as an off-white solid (6.2 g, 100%); LCMS, Rt=2.91 min (MeOH-FA method), m/z 270, 272 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH2:34][OH:35])[CH2:21][CH2:22][C@@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:9]1.[C:50]1([CH3:60])[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1>N1C=CC=CC=1>[CH3:60][C:50]1[CH:55]=[CH:54][C:53]([S:56]([O:35][CH2:34][C@@H:20]([C@@H:19]2[C@:36]3([CH3:42])[C@H:16]([C@H:15]4[C@H:39]([CH2:38][CH2:37]3)[C@:40]3([CH3:41])[C:12]([CH2:11][C@@H:10]([O:43][CH:44]5[CH2:49][CH2:48][CH2:47][CH2:46][O:45]5)[CH2:9][C@@H:8]3[O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:13][CH2:14]4)[CH2:17][CH2:18]2)[CH2:21][CH2:22][C@@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])(=[O:58])=[O:57])=[CH:52][CH:51]=1
Reactant: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 3.99 g. (0.0058 mole) of [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol, 15 ml. of pyridine and 2.20 g. (0.0115 mole) of p-toluenesulfonyl chloride was stirred at 0° C. for 18 hr. The mixture was quenched with ice chips. The mixture was then poured into water and extracted with methylene chloride. The organic phase was washed with 10% aqueous sulfuric acid and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield oily [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate), [α]D20 +8° (c 1, CHCl3).