Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[N+:14]([O-])=O.Cl.[Sn]>C(O)C>[NH2:14][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1cc(-c2ccccc2)ccc1Cl
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Nc1cc(-c2ccccc2)ccc1Cl
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of 62.0 g (0.266 mole) of 4-chloro-3-nitro-biphenyl, 400 ml of concentrated hydrochloric acid and 100 ml of absolute ethanol was heated at reflux while 93 g (0.785 mole) of 20 mesh granular tin metal was added in portions over a 1 hr period. Heating was continued for 2 hr. The white slurry which resulted was cooled and filtered. The white precipitate (filter cake) was partitioned between dilute sodium hydroxide and methylene chloride. The methylene chloride layer was dried over magnesium sulfate and concentrated under reduced pressure to give a solid residue. Recrystallization of the residue from cyclohexane gave 47.5 g (88%) of the title compound as white powder, m.p. 91.0°-92.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>C(Cl)(Cl)Cl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)cc1

Procedure:
A round bottom flask was charged with 4-bromobenzoic acid (2.0 g, 9.95 mmol) in chloroform (150 mL). To the solution was added thionyl chloride (3 mL) in chloroform (10 mL), 2-3 drops of dimethylformamide (DMF). The slurry was heated at reflux for 3 hr. while monitoring the reaction through a bubbler. A clear solution of 4-bromobenzoyl chloride was obtained, the volatiles were removed and a light yellow oil was obtained which solidified upon cooling.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)(=[O:21])=[O:20])=[CH:15][C:14]=2[C:29]([OH:31])=[O:30])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:24]1[CH:23]=[C:22]([S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[C:14]([CH:15]=2)[C:29]([OH:31])=[O:30])(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(S(=O)(=O)c3cccc(F)c3)cc2C(=O)O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(S(=O)(=O)c2cccc(F)c2)ccc1C1CCNC1
Reaction time: 4 h
Yield: 101.1 %

Procedure:
3-[2-Carboxy-4-(3-fluoro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (75 mg, 0.167 mmol) was dissolved in 3 ml of CH2Cl2. TFA (0.5 ml) was added and the mixture was stirred for 4 hours. The solution was concentrated under reduced pressure. The residue was crystallized from MeOH to give 59 mgs (quantitative) of 5-(3-Fluoro-benzenesulfonyl)-2-pyrrolidin-3-yl-benzoic acid as a white powder, MS (M+H)=350.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32]I)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Clc1ccc(OCCCI)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCOc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 150 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione and 1-chloro-4-(3-iodopropoxy)benzene and conditions outlined in procedure V. M.p.=130-132° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.92-7.87 (m, 1H), 7.82-7.74 (m, 2H), 7.6-7.52 (m, 1H), 7.36-7.18 (m, 2H), 7.0-6.92 (m, 2H), 4.1-3.95 (m, 2H), 3.07 (s, 2H), 2.83-2.72 (m, 2H), 2.55-2.48 (m, 2H), 2.4-2.25 (m, 2H), 2.05-1.75 (m, 6H); LCMS: 470 [M+H].
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]#[N:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH2:27][OH:28]>C(O)C>[OH:28][NH:27][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:8]3[CH:25]=[CH:26][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=3)=[N:12][CH:13]=2)[CH2:18][CH2:19]1)=[NH:24]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(OCc2ccc(C3CCN(C#N)CC3)cn2)cc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(OCc2ccc(C3CCN(C(=N)NO)CC3)cn2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
To a solution of 4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidin-1-carbonitrile (92 mg, 0.248 mmol) in ethanol (0.8 mL) was added 50% hydroxylamine solution (0.2 mL). The mixture was stirred at 60° C. for 4 hours, allowed to cool to room temperature and concentrated under reduced pressure to give the title compound (98 mg, yield 98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K24) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as an orange foam (314 mg, 80%).
Reaction SMILES: [Cl:1][CH2:2][C:3]#[C:4][CH2:5][OH:6].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.O>[Cl:1][CH2:2][C:3]#[C:4][CH2:5][O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: OCC#CCCl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: ClCC#CCOC1CCCCO1
Yield: 97.5 %

Procedure:
A solution of 4-chloro-but-2-yn-1-ol (2.16 g, 20.66 mmol), 3,4-dihydro-2H-pyran (2.83 mL, 30.99 mmol, 1.5 eq), and pyridinium p-toluenesulfonate (528.0 mg, 0.21 mmol, 0.10 eq) in anhydrous dichloromethane (50 mL) was stirred at room temperature under N2 for 17 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give 3.80 g (97.4%) of the desired product as clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.80 (t, J=4.0 Hz, 1H), 4.39-4.22 (m, 2H), 4.19 (t, J=2.0 Hz, 2H), 3.88-3.80 (m, 1H), 3.57-3.51 (m, 1H), 1.89-1.70 (m, 2H), 1.68-1.50 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:19][CH2:18][C:17]2([CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[O:20]2)[CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:19][CH2:18][C:17]4([CH2:23][C:22]5[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=5[O:20]4)[CH2:16]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: c1ccc2c(c1)CC1(CCNC1)O2
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(N3CCC4(Cc5ccccc5O4)C3)nn2)n1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (39 mg) obtained in Example 43(2), 3H-spiro[1-benzofuran-2,3′-pyrrolidine] hydrochloride (42 mg) and potassium carbonate (55 mg) was stirred in DMF (5 mL) at 120° C. overnight. After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The residue was washed with a small amount of acetic acid to give the object product (35 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[OH-].[Na+].[Cl:14][C:15]1[N:20]=[C:19](Cl)[N:18]=[C:17]([NH2:22])[N:16]=1>CC#N.O>[NH2:22][C:17]1[N:16]=[C:15]([Cl:14])[N:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[N:18]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: Nc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cccc(Nc2nc(N)nc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.4 %

Procedure:
Methyl 3-aminobenzoate (0.69 g, 4.55 mmol) and a 1N NaOH aqueous solution (0.91 mL, 0.91 mmol) were added to a solution of 4,6-dichloro-1,3,5-triazin-2-amine (0.75 g, 4.55 mmol) in a 1:1 MeCN/water mixture (40 mL) at 0 C. The mixture was stirred at 0 C for 1 h and room temperature for 3 days. The acetonitrile was removed under vacuum and the resulting white solid in water was filtered and dried under vacuum to provide the title compound (1.1 g, 87%). Method B HPLC-MS: MH+ requires m/z=280/282 Found: m/z=280/282, Rt=1.69 min (95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([CH:28]=[CH2:29])[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:30])=[C:4]([CH:28]2[CH2:29][O:39]2)[C:5]([O:26][CH3:27])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH3:9])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1c(C)c(Cl)cc(C(C)Nc2ncnc3c2ncn3C2CCCCO2)c1OC
Solvent: ClCCl
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1C1CO1
Reaction time: 8 h

Procedure:
N-[1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (740 mg, 1.7 mmol) was stirred in methylene chloride (5.7 mL) and m-chloroperbenzoic acid (2.1 g, 8.7 mmol) was added. The mixture was stirred overnight. The suspension was filtered and the solids were washed with dichloromethane. Evaporation of the filtrates gave the desired compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=1)(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:15]([F:16])([F:17])[F:18])[CH:8]=[C:9]([C:11]([F:13])([F:14])[F:12])[C:10]=1[N+:19]([O-:21])=[O:20])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-acetamido-3,5-bis(trifluoromethyl)benzene (400 mg, 1.37 mmol) in concentrated H2SO4 (3 mL) at 0° C. was added dropwise 70% HNO3 (0.4 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 3 h and it was poured into ice water (10 g). The precipitate was collected by filtration, affording 400 mg of crude product which contained two compounds by 1H NMR. It was separated on a column of silica gel, eluted with chloroform, to afford 134 mg of pure 1-acetamido-2-nitro-3,5-bis(trifluoromethyl)benzene as white long needles. mp: 190°-2° C., 1H NMR (CDCl3): δ2.226 (s, 3H), 7.765 (s, 1H), 7.978 (s, 1H); 8.918 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[N:20]=2)=[CH:12][C@@H:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[N:20]=2)[CH2:12][C@@H:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: COc1nc(C(=C[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: [Pd]
Solvent: CO
Product: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
5% palladium-activated carbon (30 mg) was added to a solution of (5R)-5-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (E:Z=2:8) (150 mg) in methanol in a hydrogen gas stream, and the mixture was stirred at room temperature for seven hours. The reaction solution was filtered through celite, and the solvent was evaporated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (chloroform) and further purified by preparative TLC (chloroform) to give (5R)-5-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethyl]pyrrolidin-2-one as a pale brown amorphous (110 mg, 73%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[N+:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([O-:24])=[O:23].CO.[OH-].[Na+]>O>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol), 3-nitrobenzaldehyde (96 mg, 0.633 mmol), methanol (5 ml) and saturated NaOH (50 ul). The mixture was diluted with water (5 ml). The resulting yellow precipitate was collected by filtration, wash with water and dried under vacuum to give yellow solid (129 mg, 45%). 1H NMR (CDCl3): 8.48 (s, 1H), 8.28-8.24 (m, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.74 (d, J=15.9 Hz, 1H), 7.61 (d, J=16.2 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.36 (d, J=3.0 Hz, 1H), 7.18 (dd, J=3.3, 9.0 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.49-4.36 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=O)[CH2:21][C:22](=[O:24])[CH3:23])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=[S:35])[CH2:21][C:22](=[O:24])[CH3:23])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)CC(C)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192 g, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as red solid. MS (ESI): m/z=404.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14].[OH-].[NH4+]>S(=O)(=O)(O)O>[N+:13]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:4]=1[O:3][C:2]([F:11])([F:12])[F:1])[NH2:8])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
20 g (112.9 mmol) 4-(trifluormethoxy)-aniline were dissolved in to 50ml conc. sulfuric acid and treated at −5° C. with a mixture of 24 ml conc. sulfuric acid and 6 ml nitric acid. After stirring the mixture at 0° C. for 3 h, the reaction mixture was poured on 1 L ice water and made alkaline with 200 ml conc. aqueous ammonium hydroxide. The resulting solution was extracted with ethyl acetate, the combined organic phases were dried and evaporated to dryness. The residue was purified by flash chromoatography (Silica gel, methylene chloride:methanol=98: 2) and subsequent recrystallization from methylenchoride/heptane. Yield: 14.8 g
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:28]#[N:29])([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:28]#[N:29])([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:10]([CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(F)cc1
Yield: 94 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 55b (1.6 g, 3.3 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-4-(4-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.7 g, 94%).
Reaction SMILES: [C:1]([CH:3]([CH:9]([CH3:11])[CH3:10])[C:4]([O:6]CC)=O)#[N:2].[CH2:12]([NH:14][C:15]([NH2:17])=[O:16])[CH3:13].[O-]CC.[Na+].Cl>C(O)C.O>[CH2:12]([N:14]1[C:1]([NH2:2])=[C:3]([CH:9]([CH3:10])[CH3:11])[C:4](=[O:6])[NH:17][C:15]1=[O:16])[CH3:13]
Reactant: CCNC(N)=O
Reactant: CCOC(=O)C(C#N)C(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCn1c(N)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 12.25 h
Yield: 39.3 %

Procedure:
A flask was charged with ethyl 2-cyano-3-methylbutanoate (3b, 10.0 g, 64.4 mmol), ethyl urea (3a, 5.96 g, 67.6 mmol) and EtOH (129 mL). To the slurry at room temperature was added sodium ethoxide in ethanol (21% w/w soln, 28.8 mL), mild exotherm detected. The heterogeneous reaction mixture was then heated to reflux. The reaction was refluxed for 4 to 12 h. Upon reaction completion, as determined by TLC analysis, the reaction mixture was concentrated and solvent exchanged to acetonitrile (ACN) through 3×20 mL co-evaporations leaving a basic 1-2 vol. solution in ACN. To the reaction mixture was added 1-2 vol. of water followed by a pH adjustment with 2N HCl (aq.). As the pH approached 10 white to off-with solids began forming and as the pH was further reduced to 9 (by pH paper) white slurry resulted. This slurry was aged for 0.5-24 h and then filtered. The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE. The white to off-white solids were then dried in a vacuum oven at 40-50° C. giving 4.99 g (39%) of 1-ethyl-5-isopropyl-6-amino uracil 2:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[CH:8][C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:4][CH:3]=1.C([Li])CCC.[C:23](=[O:25])=[O:24].Cl>O.O1CCCC1>[S:13]1[C:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([C:23]([OH:25])=[O:24])=[CH:3][CH:4]=2)=[CH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]1=2
Reactant: O=C=O
Reactant: Brc1ccc(C=Cc2cc3ccccc3s2)s1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(C=Cc2cc3ccccc3s2)s1
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a stirred, chilled (-70° C.) suspension of 2-[2-(5-bromo-2-thienyl)ethenyl]benzo[b]thiophene (15.6 g) and tetrahydrofuran (400 ml) was added n-butyl lithium (21.4 ml of a 2.5M solution in hexanes), under nitrogen over 10 mins. The solution was stirred at -70° C. for 1.5 hr, and was transferred via canula to a flask containing a suspension of dry ice (excess) and tetrahydrofuran (1000 ml). The suspension was stirred for 2 hrs and allowed to warm to room temperature overnight. The mixture was poured into water (500 ml), acidified with hydrochloric acid, and the tetrahydrofuran was removed in vacuo. The resulting suspension was filtered, and the filter cake was washed with water and dried in vacuo overnight. The filter cake was recrystallized from dimethyl sulfoxide/10% hydrochloric acid to yield 10.5 g (75%) of product, mp 236°-237° C.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:45])[C:29]([CH3:44])([CH3:43])[NH:30][C:31]([C:33]1[N:37]2[N:38]=[C:39](Cl)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:25]([O:27][C:28](=[O:45])[C:29]([CH3:44])([CH3:43])[NH:30][C:31]([C:33]1[N:37]2[N:38]=[C:39]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)[CH:40]=[CH:41][C:36]2=[N:35][N:34]=1)=[O:32])[CH3:26]
Reactant: CCOC(=O)C(C)(C)NC(=O)c1nnc2ccc(Cl)nn12
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)NC(=O)c1nnc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 60 °C
Yield: 50.7 %

Procedure:
1.25 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.20 g of N-(6-chloro[1,2,4]triazolo[4,3-b]pyridazine-3-carbonyl)-2,2-dimethylglycine ethyl ester were dissolved in 20 ml of N,N-dimethylformamide; 1.33 ml of N-ethyldiisopropylamine was added, followed by stirring under heating at an external temperature of 60° C. for 7.5 hours. After cooling, cold aqueous sodium bicarbonate was added; the reaction mixture was extracted with ethyl acetate, washed with saturated saline, and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the precipitated crystal was recrystallized from ethanol-ethyl acetate fir (1:3), collected by filtration, and dried, to yield 1.17 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].[C:15](=[S:17])=S.O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:14][C:12]1[C:3]2[C:2](=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=2[O:10][CH3:11])[O:1][C:15](=[S:17])[CH:13]=1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Reactant: S=C=S
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(OC)c2c(O)cc(=S)oc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
336.0 g of potassium t-butoxy was suspended in 2 liters of toluene. Under cooling on ice, 2 liters of 196.0 g of 2'-hyroxy-4',6'-dimethoxyacetophenone and 72.0 ml carbon disulfide in toluene were added dropwise to said suspension. The mixture was stirred for 20 hours at room temperature, and 7 liters of water was added for extraction of a toluene layer. This toluene solution was adjusted to pH 4-5 by addition of 800 ml of 10% sulfuric acid (aq.) and was then stirred for 5 hours at room temperature. The solution was allowed to stand overnight. The resulting yellow crystals were collected by filtration under reduced pressure, sufficiently washed with water and dried at 50° C. for 3 days under reduced pressure, thus giving rise to 160.0 g crude 4-hydroxy-5,7-dimethoxychromene-2-thion.