Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reaction time: 4 h

Procedure:
3,5-Dichlorobenzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (step 1) (3.53 g, 8.75 mmol) was dissolved in DCM (20 ml). 4M HCl in dioxane (22 ml, 88 mmol) was added which resulted in the formation of a white solid. After gas evolution ceased, DCM (20 ml) was added and the reaction mixture was stirred vigorously for 4 hrs. The resulting mixture was filtered and the white solid was dried in a vacuum oven under reduced pressure to afford the title compound as a hydrochloride salt;
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][C:25](=[O:31])[NH:26]2>>[CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=[C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[CH:30][C:22]=2[CH3:21])[NH:26][C:25]1=[O:31]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Reactant: Cc1cccc2c1CC(=O)N2
Product: Cc1cccc2c1C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCC1)CC3)C(=O)N2
Yield: 62.8 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-methyl-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (32 mg, 62.8%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH:13]4[CH2:19][CH2:18][N:16]([CH2:17][C:7]=3[C:6]=2[CH:5]=1)[CH2:15][CH2:14]4.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[N:28][CH:29]=1)#[CH:23]>>[CH3:30][C:27]1[N:28]=[CH:29][C:24](/[CH:22]=[CH:23]\[N:9]2[C:10]3[CH:11]=[CH:12][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:5][C:6]=3[C:7]3[CH2:17][N:16]4[CH2:15][CH2:14][CH:13]([C:8]2=3)[CH2:19][CH2:18]4)=[CH:25][CH:26]=1
Reactant: C#Cc1ccc(C)nc1
Reactant: FC(F)(F)Oc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc(/C=C\n2c3c(c4cc(OC(F)(F)F)ccc42)CN2CCC3CC2)cn1

Procedure:
The coupling of 9-(trifluoromethoxy)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (140 mg, 0.473 mmol; Example 175) and 5-ethynyl-2-methylpyridine (111 mg, 0.945 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.66-1.80 (m, 2H), 1.84-1.98 (m, 2H), 2.40 (s, 3H), 2.95-3.23 (m, 5H), 4.24 (s, 2H), 6.83 (d, J=8 Hz, 1H), 6.92-6.99 (m, 2H), 7.06-7.16 (m, 3H), 7.28 (s, 1H), 7.85 (s, 1H); MS (DCI/NH3) m/z 414 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[C:26]([C:28]1[CH:29]=[CH:30][C:31](F)=[N:32][C:33]=1[CH3:34])#[N:27].N12CCN(CC1)CC2>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:31]1[CH:30]=[CH:29][C:28]([C:26]#[N:27])=[C:33]([CH3:34])[N:32]=1
Reactant: Cc1nc(F)ccc1C#N
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Product: Cc1nc(Oc2ccc(C(C)C(O)(c3cc(C)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1C#N

Procedure:
In analogy to Example 163, 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5) was reacted with 5-cyano-2-fluoro-6-picoline in the presence of triethylamine and 1,4-diazabicyclo[2.2.2]octane to give the title compound as a colorless solid. MS (m/e)=492.1 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH2:36][CH2:35]1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OCCN1CCNCC1
Product: CC1(C)c2cc(N3CCN(CCO)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
According to the same method as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and N-(2-hydroxyethyl)piperazine.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@H:11]4[C@:18]([CH3:27])([CH2:19][C:20](=[O:26])[C:21]=32)[C@@H:14]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:12]4)[CH2:6]1)(=O)C.Cl(O)(=O)(=O)=O.O>CO>[OH:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@H:11]4[C@:18]([CH3:27])([CH2:19][C:20](=[O:26])[C:21]=32)[C@@H:14]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:12]4)[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC[C@]2(C)C3=C(CC[C@H]2C1)[C@@H]1CC[C@H](C(C)=O)[C@@]1(C)CC3=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CO
Product: CC(=O)[C@H]1CC[C@H]2C3=C(C(=O)C[C@]12C)[C@@]1(C)CC[C@@H](O)C[C@@H]1CC3
Reaction time: 19 h
Yield: 38 %

Procedure:
3α-Acetoxy-5α-pregn-8-ene-11,20-dione (400 mg.) was dissolved in methanol (40 ml.) and perchloric acid (60% w/v; 2 ml.) was added and the solution was allowed to stand at room temperature for 19 hours. The reaction mixture was poured into water and the steroid extracted with chloroform. The solvent was removed from the extract and the residue twice crystallised from methyl acetate-petrol to give the title compound (135 mg.) m.p. 170°-172°, [α]D + 250°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB(/[CH:43]=[CH:44]/[CH2:45][CH2:46][OH:47])O1>CC(N(C)C)=O>[NH2:28][C:18]1[N:17]=[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2](/[CH:43]=[CH:44]/[CH2:45][CH2:46][OH:47])[CH:7]=3)=[CH:10][CH:11]=2)[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(Cl)c3)cc2)cc(-c2ccccc2)n1
Reactant: CC1(C)OB(/C=C/CCO)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1nc(Nc2ccc(Oc3ccnc(/C=C/CCO)c3)cc2)cc(-c2ccccc2)n1
Temperature: 150 °C
Yield: 14.5 %

Procedure:
N4-{4-[(2-chloropyridin-4-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine (0.10 g, 0.26 mmol, Example 48), K2CO3 (0.089 g, 0.64 mmol), and DMA (2.5 mL) were placed into a small microwave vial. The mixture was degassed for 10 min before (3E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-ol (0.10 g, 0.33 mmol) and Pd(dppf)Cl2 CH2Cl2 complex (0.012 g, 0.020 mmol) were added. The mixture was heated at 150° C. for 20 min in a microwave reactor. The mixture was cooled, filtered, and purified by prep-HPLC. Concentration of the desired fractions gave 0.016 g of the title compound (10%). MS ES: 426 (M+H)+, calcd 426, RT=1.90 min.
Reaction SMILES: C[O-].[Na+].[NH:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[C:9]1([S:15]([C:18]2[C:19]([S:29][CH3:30])=[N:20][N:21]3[C:26](Cl)=[CH:25][C:24]([CH3:28])=[N:23][C:22]=23)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[C:9]1([S:15]([C:18]2[C:19]([S:29][CH3:30])=[N:20][N:21]3[C:26]([N:4]4[CH:8]=[CH:7][N:6]=[CH:5]4)=[CH:25][C:24]([CH3:28])=[N:23][C:22]=23)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Reactant: c1c[nH]cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nn2c(-n3ccnc3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.9 %

Procedure:
0.08 g (1.5 mmol) of sodium methanolate was added to a suspension of 0.122 g (1.8 mmol) of imidazole in 30 ml of DMF and stirred at 60° for 15 min. Subsequently, a solution of 0.53 g (1.5 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]-pyrimidine in 10 ml of DMF was added to this suspension and stirred at 60° for 1 hr. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 15:1) and crystallization from EtOH yielded 0.30 g (51%) of 3-benzenesulphonyl-7-imidazol-1-yl-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystal, m.p. >230°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[S:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].[C:29]([C:33]1[CH:37]=[C:36]([NH:38][C:39](=O)[O:40]C2C=CC=CC=2)[O:35][N:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[S:21][C:22]1[CH:23]=[C:24]([NH:25][C:39]([NH:38][C:36]2[O:35][N:34]=[C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:37]=2)=[O:40])[CH:26]=[CH:27][CH:28]=1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OCCOC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)on1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)no4)c3)c2cc1OCCOC
Yield: 52 %

Procedure:
The title compound was prepared as described in Example 113C by using compound 3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio)aniline (138 mg, 0.34 mmol) and phenyl 3-tert-butylisoxazol-5-ylcarbamate described in Example 132A (116 mg, 0.45 mmol) to give 1-(3-(6,7-bis(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)-3-(3-tert-butylisoxazol-5-yl)urea (100 mg, 52%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.05 (s, 1H), 8.69 (s, 1H), 7.85 (s, 1H), 7.46 (d, 1H), 7.45-7.38 (m, 3H), 7.31 (d, 1H), 6.05 (s, 1H), 4.36-4.32 (m, 4H), 3.79-3.76 (m, 4H), 3.37 (s, 6H), 1.24 (s, 9H); LC-MS (ESI) m/z 568 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCC1
Yield: 26.5 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and pyrrolidine (0.32 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 1-[(4-bromophenyl)sulfonyl]pyrrolidine (0.12 g) was provided after purification. HRMS: calcd for C10H12BrNO2S+H+, 289.98449; found (ESI, [M+H]+), 289.9847. HPLC purity 99.1% at 210-370 nm, 8.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14](O)=[O:15])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([Cl:24])=[O:15])=[CH:12][C:11]([C:17]([F:20])([F:19])[F:18])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a 100 mL flask, 1-(3,5-dichloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (0.40 g, 1.22 mmol), dichloromethane (10 mL) and oxalyl dichloride (0.31 g, 2.44 mmol) were added sequentially. After five drops of N,N-dimethyl formamide were added, a large amount of gas was released. After being stirred for 8 hours at room temperature, the reaction mixture was concentrated under reduced pressure. Then toluene (30 mL) was added, and was concentrated again under vacuum to give the product (0.42 g) as yellow solid in 100% yield.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][C:7]1[N:12]=[C:11]([C:13]2[N:14]=[C:15]([N:18]=[C:19]([NH2:21])[NH2:20])[S:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=1.[O-:22][C:23]#[N:24].[K+].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:20][C:19](=[N:18][C:15]1[S:16][CH:17]=[C:13]([C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][CH2:5][NH:4][C:23]([NH2:24])=[O:22])[N:12]=2)[N:14]=1)[NH2:21]
Reactant: N#C[O-]
Reactant: NCCc1cccc(-c2csc(N=C(N)N)n2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)NCCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 44.6 %

Procedure:
A mixture of 4-[6-(2-aminoethyl)pyridin-2-yl]-2-(diaminomethyleneamino)thiazole trihydrochloride (1.5 g) and potassium cyanate (0.5 g) in water (30 ml) was stirred for 5 hours at ambient temperature. The reaction mixture was adjusted to pH 9.5 with potassium carbonate and the mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate. The extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 2-(diaminomethyleneamino)-4-[6-(2-ureidoethyl)pyridin-2-yl]thiazole (0.55 g).
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:20]([NH2:22])=[O:21])=[CH:8][C:9]([C:16]([F:19])([F:18])[F:17])=[C:10]([CH:15]=1)[C:11]([O:13]C)=[O:12])([CH2:3][CH3:4])[CH3:2].[OH-].[Na+].ClCCl.Cl>CO>[NH2:22][C:20]([C:7]1[C:6]([NH:5][C@H:1]([CH3:2])[CH2:3][CH3:4])=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:16]([F:17])([F:18])[F:19])[CH:8]=1)=[O:21]
Reactant: CC[C@@H](C)Nc1cc(C(=O)OC)c(C(F)(F)F)cc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC[C@@H](C)Nc1cc(C(=O)O)c(C(F)(F)F)cc1C(N)=O
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
(R)-Methyl 5-(sec-butylamino)-4-cyano-2-(trifluoromethyl)benzoate (45 mg, 0.150 mmol) was dissolved in DMSO (1 mL) and was treated with 30% aqueous hydrogen peroxide (0.05 mL) and potassium carbonate (6 mg, 0.043 mmol) at ambient temperature for 2 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, then filtered and concentrated to afford a yellow oil which was purified by column chromatography (silica gel, 10-40% ethyl acetate in hexanes) to afford (R)-methyl 5-(sec-butylamino)-4-aminocarbonyl-2-(trifluoromethyl)benzoate (27 mg, 0.085 mmol, 57% yield). (R)-M ethyl 5-(sec-butylamino)-4-aminocarbonyl-2-(trifluoromethyl)benzoate (27 mg, 0.085 mmol) was suspended in methanol (1 mL) and was treated with 1 M sodium hydroxide (0.2 mL, 0.2 mmol) at 45° C. for 1 h. Dichloromethane (0.5 mL) and 1M sodium hydroxide (0.2 mL, 0.2 mmol) was added and the mixture was stirred at 45° C. for a further 1.5 h. Dichloromethane (0.5 mL) and 1M sodium hydroxide (0.2 mL, 0.2 mmol) were added, and the mixture was stirred at 45° C. for a further 1 h and then at ambient temperature for 15 h. The reaction mixture was concentrated to afford an aqueous residue that was cooled in an ice bath, was acidified with 1N hydrochloric acid to pH ˜2, then extracted with ethyl acetate (2×). The organic portion was dried over sodium sulfate, then filtered and concentrated to provide 4-(aminocarbonyl)-5-{[(1R)-1-methylpropyl]amino}-2-(trifluoromethyl)benzoic acid (23 mg, 0.076 mmol, 89% yield). MS (EI) for C13H15F3N2O3: 305 (MH+).
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=O)[O:3]1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26]>>[F:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[CH3:20])[CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: CON(Cc1ccc(C)c(F)c1)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(C)c(F)c1)C(=O)C=C(O)C(=O)NS(C)(=O)=O
Yield: 67.7 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-fluoro-4-methyl-benzyl)-N-methoxy-acetamide (0.135 g, 0.418 mmol) with methanesulfonamide (0.042 g, 0.44 mmol) as described in the preparation of compound 22 gave 0.102 g (68% yield) of the title amide as a white solid. 1H NMR (400 MHz, DMSO) δ: mixture of rotamers: 2.2 (3H, s, CH3), 2.87 and 2.88 (3H, 2 S, SO2CH3), 3.63 and 3.67 (3H, 2 s, OCH3), 4.73 and 4.78 (2H, 2 s, NCH2), 6.14 and 6.16 (1H, 2 s, CH), 7.04-7.27 (3H, m, aromatics). HRMS (ESI/neg) calculated for C14H16FN2O6S: [M−H]−: 359.071312; found: 359.071347.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH2:7][C:8]([OH:10])=[O:9].C([Li])CCC.Br[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>C1COCC1.O>[CH3:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH:7]([CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:8]([OH:10])=[O:9]
Reactant: Cc1c(CC(=O)O)sc2ccccc12
Reactant: BrCCCc1ccccc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(CCCc2ccccc2)C(=O)O)sc2ccccc12
Temperature: 25 °C
Yield: 36.8 %

Procedure:
To a stirred solution of 3-methylbenzo[b]thiophene-2-acetic acid (1.00 g) in THF at −78° C. under nitrogen was added a solution of n-butyllithium in hexanes (2.5M; 3.98 ml). Stirring was continued for 15 mins at this temperature before 1-bromo-3-phenylpropane (965 mg) was added. The mixture was stirred for 30 mins before allowing to warm up to RT and then stirred at RT for a further 1 h. The reaction mixture was poured on to a mixture of water (50 ml) and 1 N sodium hydroxide solution (10 ml). The organic layer was separated and washed with water (2×10 ml), brine (10 ml) and dried (MgSO4). Filtration and evaporation of solvents under reduced pressure gaven the crude product, which was purificatied by silica gel column chromatography, eluting with 2:1 hexane/ethyl acetate, to give the title compound (579 mg, 37%) as a pale green oil. Rf 0.45 (2:1 hexane/ethyl acetate).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>C(Cl)Cl.Cl>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23]([O:1][CH2:2][C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])(=[O:24])=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: O=C(CO)OCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)OCC(=O)OCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Benzyl 2-hydroxyacetate (211 mg, 1.268 mmol) was dissolved in DCM (10 ml). TEA (0.265 ml, 1.901 mmol) and 3,4-dimethoxybenzene-1-sulfonyl chloride (300 mg, 1.268 mmol) were added, and the reaction was stirred at RT for 3 hours to achieve completion. The reaction mixture was diluted with HCl 1N and extracted with DCM. The organic phase was washed with HCl 1N and Na2CO3 sat. sol., dried over Na2SO4 and concentrated under vacuum to give benzyl 2-(3,4-dimethoxyphenylsulfonyloxy)acetate (400 mg, 86% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15]([NH2:16])=[CH:14][C:12](=[O:13])[N:11]([CH2:17][CH2:18][CH3:19])[C:9]2=[O:10])=[CH:4][CH:3]=1.C(O)=O.N([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:35]([NH2:37])=O>>[CH2:17]([N:11]1[C:12](=[O:13])[C:14]2[NH:37][CH:35]=[N:16][C:15]=2[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]1=[O:10])[CH2:18][CH3:19]
Reactant: NC=O
Reactant: CCCn1c(=O)cc(N)n(-c2ccc(Cl)cc2)c1=O
Agent: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCCn1c(=O)c2[nH]cnc2n(-c2ccc(Cl)cc2)c1=O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
A mixture of 1-(4-chlorophenyl)-3-n-propyl-6-aminouracil (28.0 g; 0.1 mole), formic acid (15.1 ml; 0.4 moles) and sodium nitrite (7 g; 0.1 mole) in formamide (600 ml) was heated to 60° C. for 10 minutes. The temperature was then increased to 100° C. and sodium dithionite (2.3 g; 0.013 moles) was added over a period of 10 minutes. After addition, the temperature was increased to 190° C., mantained for 30 minutes and the reaction mixture was cooled and extracted with chloroform. The organic solution was extracted with 2N sodium hydroxide aqueous solution, washed with diethyl ether, acidified with 2N hydrochloric acid aqueous solution and extracted with chloroform. The organic extracts were washed with water, dried (Na2SO4) and the solvent was removed in vacuo to give 1-n-propyl-3-(4-chlorophenyl)-xanthine (19.5 g; yield 64.3%). After recrystallization from 90% ethanol, the melting point is 233°-234° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C@@:15]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)([CH2:20][N+:21]([O-])=O)[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Ni].O>[C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][C@:15]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:16]([F:19])([F:18])[F:17])[CH2:20][N:21]=2)=[CH:9][C:8]=1[CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Cc1cc(C2=NC[C@@](c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
Alternatively, the title compound can be obtained by carrying out the following experiment: To a vigorously stirred solution of 4-[(R)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (100 mg) in ethanol (6 mL) was added Raney Nickel (1.44 g, 50% suspension in water, previously washed with dry ethanol) and the reaction was stirred at room temperature under hydrogen (1 atm) for one hour. Then the solution was filtered over celite, and the resulting filtrate was concentrated in vacuo to give the title compound (78 mg) as a pale yellow solid. Chiral HPLC analysis (Chiralpack IA, Heptane:2-propanol:diethylamine=90:10:0.1, 1 ml/min, retention time 5.77 minutes (91.43%), 8.71 minutes (3.79%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.N1C=CC=CC=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26]([NH:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1)(=[O:28])=[O:27]
Reactant: COC(=O)c1cc(N)c2nc[nH]c2c1
Reactant: O=S(=O)(Cl)CCCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)CCCCCl)c2nc[nH]c2c1
Reaction time: 1 h
Yield: 50.2 %

Procedure:
To a solution of methyl 4-amino-1H-benzimidazole-6-carboxylate (D251) (1.1 g, 5.76 mmol, 1 equiv) in CH2Cl2 (80 ml) at room temperature were added pyridine (1.02 ml, 12.67 mmol, 2.2 equiv), 4-chloro-1-butanesulfonyl chloride (D20) (2.31 g, 12.1 mmol, 2.1 equiv) and DMAP (704 mg, 5.76 mmol, 1 equiv) and the resulting mixture was stirred for 1 h then concentrated in vacuo. The residue was diluted with AcOEt and the organic phase was washed with a 2N aqueous HCl solution and brine, then dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (AcOEt/iso-hexane: 2/3) gave methyl 4-{[(4-chlorobutyl)sulfonyl]amino}-1H-benzimidazole-6-carboxylate (D252) (1 g, 50%) as a colorless oil. [M+H]+=346.1, RT=2.97 min.