Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH:12]=[N:11][C:10]([CH3:13])=[N:9]2)[CH:7]=1>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[N:11][C:10]([CH3:13])=[N:9]2)[C:5]([O:14][CH3:15])=[CH:4][C:3]=1[NH2:16]
Reactant: COc1cc([N+](=O)[O-])c(F)cc1-n1cnc(C)n1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(F)cc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
Step B (2): 10% Palladium on carbon (0.523 g, 4.92 mmol) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 1-(5-fluoro-2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.24 g, 4.92 mmol) dissolved in methanol (100 mL). The flask was repeatedly evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 18 h under the hydrogen atmosphere. The vessel was subsequently purged with nitrogen gas. The crude reaction mixture was filtered through a short diatomaceous earth (Celite®) plug. The reaction vessel and plug were rinsed with fresh methanol. The combined filtrates were concentrated in vacuo. The residue was dried on high vacuum overnight to afford 2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (1.05 g, 96% yield) as a gray solid. LC-MS (M+H)+ 223.1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.46 (s, 1 H) 7.39 (d, J=11.29 Hz, 1 H) 6.44 (d, J=7.63 Hz, 1 H) 3.89 (br. s., 2 H) 3.83 (s, 3 H) 2.47 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:16]1[C:20]2=[CH:21][CH:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:19]2[CH:18]=[CH:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[CH2:14][NH:15][C:25]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[O:16][CH:17]=[CH:18][C:19]=12)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc2occc12
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CN
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1CNC(=O)c1cccc2occc12

Procedure:
prepared by reaction of (1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester with benzofuran-4-carboxylic acid (M. A. Eissenstat et al. J. Med. Chem. 1995, 38, 3094-3105).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH2:5][CH2:6][CH2:7][SH:8].[F:9][C:10]([F:24])([F:23])[CH2:11][N:12]=[C:13]([NH2:22])[NH:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17](Cl)[N:16]=1>C(O)C>[F:24][C:10]([F:9])([F:23])[CH2:11][N:12]=[C:13]([NH2:22])[NH:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17]([S:8][CH2:7][CH2:6][CH2:5][NH2:4])[N:16]=1
Reactant: NCCCS
Reactant: NC(=NCC(F)(F)F)Nc1cncc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: NCCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C

Procedure:
Sodium hydride (50% w/w dispersion in oil; 0.57 g.) was added to ethanol (10 ml.) portionwise. To the resulting solution was added 3-aminopropanethiol hydrochloride (0.75 g.) and the mixture stirred at room temperature. 2-[2-(2,2,2-Trifluoroethyl)guanidino-6-chloropyrazine (0.5 g.) was added in one portion and the mixture heated under reflux on the steam bath overnight. The mixture was cooled, evaporated, water (10 ml.) added and the mixture extracted with ethyl acetate. The extracts were dried over magnesium sulphate, filtered and evaporated to yield an oil, which was chromatographed eluting with methanol/methylene chloride/ammonia 10:40:1 v/v/v to yield 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(3-aminopropylthio)pyrazine as a pale yellow solid (0.39 g.) which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([Cl:13])[C:9]=1[O:10][CH2:11][CH3:12])[NH2:6])[CH3:2].CCN(C1C=CC=CC=1)CC.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:6][C:26](=[O:27])[O:28][CH:29]([CH3:31])[CH3:30])[CH:7]=[C:8]([Cl:13])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1c(Cl)cc(N)cc1CC
Solvent: Cc1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CCOc1c(Cl)cc(NC(=O)OC(C)C)cc1CC
Temperature: 0 °C
Reaction time: 12 h
Yield: 88.3 %

Procedure:
3-Ethyl-4-ethoxy-5-chloroaniline (1.9 g) and diethylaniline (1.5 g) were dissolved in toluene (20 ml). To the resultant solution was dropwise added isopropyl chloroformate (1.2 g) in 5 minutes under ice-cooling. After being allowed to stand at room temperature for 12 hours, the reaction mixture was poured into ice-water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene as the eluent to give isopropyl N-(3-ethyl-4-ethoxy-5-chlorophenyl)carbamate (Compound No. 53) (2.4 g) in a yield of 89%. M.P., 79°-80.5° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)CCC.[CH2:19]([O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)[CH3:20]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:31])=[CH:25][CH:26]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1ccc(-c2cccs2)cc1
Yield: 68 %

Procedure:
Nitrogen was bubbled through a mixture of 2-tributylstannyl thiophene (15.68 ml, 49.4 mmol) and ethyl(4-bromophenyl)acetate (6 g, 24.7 mmol) in toluene (250 ml) before 0.5 g of tetrakis (triphenylphosphine) palladium (0) was added. The mixture was heated at reflux under nitrogen for 4 hours before it was filtered through magnesol and concentrated. The residue was purified using silica-gel column chromatography by eluting it with 20% ethyl acetate: hexane solution. Ethyl [4-(2-thienyl)phenyl]acetate was isolated as a yellow oil (4.15 g). Yield 68%; MS: 247.5 (M+H)+
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[O:14]=[C:4]1[C:5]2[N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[S:1][CH:2]=[CH:3]1
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1c2ccccc2c2sccc(=O)c21

Procedure:
By the same method as described in Example 7, 4.8 g of thiopyrano[3,2-b]indol-4(5H)-one is alkylated with ethyl bromoacetate to give 6.0 g of product, mp 163°-165° C, after recrystallization from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.B(F)(F)F.CCOCC.C(OCC)(=O)C>CCOCC.B(F)(F)F.CCOCC>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[CH:10][N:9]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(-c2nc[nH]c2-c2ccc(F)cc2)cc1
Reactant: C1=COCCC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ncn(C3CCCCO3)c2-c2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A mixture of 124 g (0.484 mole) of 4,5-bis(4-fluorophenyl)imidazole, 84 g (1.0 mole) dihydropyran, 20 g boron trifluoride etherate and 1 l ethyl acetate was heated at reflux over a weekend. Analysis by TLC (ethyl acetate) showed the presence of some unchanged starting material, so 20 g (~0.24 mole) of dihydropyran and 5 g boron trifluoride etherate was added and heating was continued overnight. The mixture was then diluted with 1 l ether and washed with 10% sodium bicarbonate solution (3×1 l). The organic layer was dried and concentrated on a rotary evaporator. The residual solid was recrystallized from methylcyclohexane (removing some insoluble starting material by filtration) to give 140.2 g (85%) of 4,5-bis(4-fluorophenyl)-1-(2-tetrahydropyranyl)imidazole as a white solid, mp 149°-152°. F-NMR indicated purity ~95%. A smaller run was chromatographed to give pure material mp 158°-9°. IR: 3.25μ (=CH); 3.38, 3.49μ (sat. CH); 6.22, 6.28, 6.41, 6.60, 6.69μ (C=C and/or C=N); 8.20μ (CF); 9μ region (C--O--C). H-NMR: m(1.4-2.1 δ, 6H); m (3.4 δ, 1H); m (4.0 δ, 1H); m (4.7 δ, 1H); m (6.6-7.5 δ, 8H); s (7.8 δ, 1H). F-NMR: two multiplets (112.4 25 δ and 116.5 δ, each decouples to a singlet).
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:16])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:17][CH2:18][C:19]([OH:21])=[O:20].C[O-].[Na+]>CN(C=O)C>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:7][C:6](=[O:16])[C:5]=1[C:3]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:4]
Reactant: COC(=O)c1c(O)c2ccccc2oc1=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1c(O)c2ccccc2oc1=O
Yield: 42.5 %

Procedure:
To a mixture of 4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (150 mg, 0.68 mmol) in DMF (12 mL) was added glycine (1.03 g, 13.6 mmol) and NaOMe (0.5 M in MeOH, 20.4 mL, 10.2 mmol) at rt. It was concentrated in an evaporator to remove most MeOH solvent. The resulting mixture was refluxed for 2 h. After cooled, it was diluted with water (100 mL) and acidified by 1 N HCl to pH=3-4. Precipitate was collected, rinsed with water and dried in vacuo. Crude solid was triturated in hexanes, and solid product was collected and dried to give the title compound (76 mg). MS ESI(+) m/e: 264 (M+1).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=1.[CH:26]([C:29]1[N:30]=[C:31]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[O:32][C:33]=1[CH:34]([CH3:37])[CH2:35]O)([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.CCOCC>[CH3:14][O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:37][CH:34]([C:33]2[O:32][C:31]([C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=3)=[N:30][C:29]=2[CH:26]([CH3:28])[CH3:27])[CH3:35])[CH:19]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)CO
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)Cc1cccc(OCC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)c1

Procedure:
Azodicarboxylic dipiperidide (0.31 g, 1.23 mmol) is stirred in 5 mL toluene at −30 to −20 deg C. Tri-n-butyl phosphine (0.31 mL, 1.23 mmol) is added dropwise and the mixture is stirred at −30 to −20 deg C. 10–15 min. An intimate mixture of (3-hydroxy-phenyl)-acetic acid methyl ester (0.13 g, 0.77 mmol) and 2-[4-isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol (0.20 g, 0.701 mmol) in toluene (5 mL) is added dropwise and the resulting mixture is stirred 18 hr at room temperature. The thick suspension is diluted with 25 mL ether and cooled on ice/water for 30 min. The mixture is filtered, concentrated, and purified via silica gel chromatography eluting with 98:2 hexanes:acetone to afford the title compound as a colorless thick oil, 0.10 g, 31%. MS M++1 462. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: Br[CH2:2][CH:3]([C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1)[CH2:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:7]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:6]=1.[C-]#N.[Na+].[CH3:34][N:35](C)C=O>O>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([N:7]2[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[CH:9][C:5]([CH2:4][CH:3]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH2:2][C:34]#[N:35])=[N:6]2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(-c2cc(CC(CBr)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2cc(CC(CC#N)c3cccc(C)c3)nn2-c2ccc(C)cc2)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
To a screw-cap vial were added 3-(3-bromo-2-m-tolyl-propyl)-1,5-di-p-tolyl-1H-pyrazole (prepared by the method of Example 67; 300 mg, 0.65 mmol, 1.0 equiv), sodium cyanide (160 mg, 3.3 mmol, 5.0 equiv) and N,N-dimethylformamide (3.0 mL). The sealed mixture was then heated at 100° C. for 48 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with diethyl ether (3×10 mL). The combined extracts were washed with water (4×10 mL) then brine (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by flash chromatography (25% ethyl acetate/hexanes) giving the desired nitrile (171 mg, 65%). MS (ESI): mass calculated for C28H27N3, 405.22; m/z found, 406.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][CH2:6][CH2:5]2.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[N:7]([S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])c1cc(Br)cc2c1NCC2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)N2CCc3cc(Br)cc([N+](=O)[O-])c32)cc1
Yield: 85 %

Procedure:
A solution of 5-bromo-7-nitroindoline (5 g, 0.021 mol), 4-methoxyphenylsulfonyl chloride (6.36 g, 0.030 mol) in pyridine (10 ml) was stirred at 120° C. for 16 h. The reaction was quenched with water and extracted with CH2Cl2. The combined organic layer was dried over anhydrous MgSO4 and evaporated to give a residue that was chromatographed over silica gel (EtOAc:n-hexane=1:2) to afford compound 17, yield 85%.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[O:12]1[C@@H:14]([CH2:15][CH3:16])[CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:12][C@@H:14]([CH2:15][CH3:16])[CH2:13][N:9]1[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]1=[O:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](O)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
To 1,2-Benzenedicarboximide (4.29 g) in DMF (10 ml), (S)-(−)-1,2-epoxybutane (2.1 g) was added followed by K2CO3 (4.03 g) and heated at 60° C. for 48 h. The reaction was diluted with water, extracted with EtOAc, dried and solvent removed to give the subtitle compound as a white solid, 1.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:11]([C:26]([NH:28][CH2:29][CH:30]=[CH2:31])=O)[CH2:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:11]([CH2:26][NH:28][CH2:29][CH:30]=[CH2:31])[CH2:10]1
Reactant: C=CCNC(=O)C1CN(c2c(Cl)cccc2Cl)CCN1Cc1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=CCNCC1CN(c2c(Cl)cccc2Cl)CCN1Cc1ccc(OC)c(OC)c1

Procedure:
In a manner similar to Preparation 2, react 4-(2,6-dichlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-N-(2-propenyl)-2-piperazinecarboxamide with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:12][C:9]2[S:10][CH:11]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[N:8]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1nc(-c2sccc2Cl)cs1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2sccc2Cl)cs1

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (7.6 mg) with purity >90%. MS (pos) m/z 405.2, 407.2.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C@H:11]([CH2:29][C:30]1[N:31]=[CH:32][NH:33][CH:34]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[C:17]([CH3:28])[CH:16]=1)=[O:13].CN1CCOCC1>C1COCC1>[NH:33]1[CH:34]=[C:30]([CH2:29][C@@H:11]([NH:10][C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[C:12](=[O:13])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[O:22])=[C:17]([CH3:28])[CH:16]=2)[N:31]=[CH:32]1
Reactant: Cc1cc(NC(=O)[C@H](N)Cc2c[nH]cn2)ccc1C(=O)N1CCCC1
Reactant: O=C(O)c1ccc(Br)s1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)[C@@H](Cc2c[nH]cn2)NC(=O)c2ccc(Br)s2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 10c from 5-bromo-thiophene-2-carboxylic acid and (R)-2-amino-3-(1H-imidazol-4-yl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propionamide with PPA and NMM in THF.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:16]=[CH:17][CH2:18][CH2:19][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].C[N+]1([O-])CC[O:25]CC1.S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([NH:4][C:1](=[O:3])[CH3:2])([CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:25])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CCCC=CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(CCCCC=O)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl 2-acetamido-2-pentenylmalonate (4.0 g) was dissolved in 210 ml of acetone and 3.3 g of N-methylmorpholine-N-oxide and 36 ml of a 1% aqueous osmium tetraoxide solution were added thereto. The mixture was stirred at room temperature for 2 hours. A solution of 700 mg of sodium sulfite in 20 ml of water was added thereto and the mixture was stirred for 15 minutes. The reaction mixture was concentrated and subjected to silica gel column chromatography using chloroform/methanol (10:1) as an eluent and a fraction having an Rf value: 0.3 (chloroform:methanol=10:1) was concentrated. The residue was dissolved in 630 ml of 1,4-dioxane and 70 ml of a 0.2 M aqueous meta-sodium periodate solution was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtrated, concentrated, extracted with ethyl acetate and washed with water. The hexane layer was dried and concentrated to give 4.17 g of colorless, oily diethyl-2-acetamido-2-(4-formylbutyl)malonate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8](O)=[O:9])([OH:3])=[O:2].[CH:14]([NH2:16])=O>>[C:1]([C:4]1[CH:5]=[C:6]2[C:7]([C:8](=[O:9])[NH:16][CH:14]=[N:13]2)=[CH:11][CH:12]=1)([OH:3])=[O:2]
Reactant: NC=O
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Product: O=C(O)c1ccc2c(=O)[nH]cnc2c1

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 1 which is concerned with the preparation of starting materials, 4-carboxyanthranilic acid (14.2 g) was reacted with formamide to give 7-carboxyquinazolin-4-one (8.5 g). A mixture of a portion (4 g) of the material so obtained, methanol (40 ml) and concentrated sulphuric acid (2 ml) was stirred and heated to reflux for 6 hours. The mixture was cooled to ambient temperature and the precipitate was isolated. There was thus obtained 7-methoxycarbonylquinazolin-4-one (5.7 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([NH2:7])=[O:6].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>[Cl-].[Zn+2].[Cl-].C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:16])([F:17])[CH2:3][N:4]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:7][C:5]1=[O:6]
Reactant: COc1ccc(N(CC(F)(F)F)C(N)=O)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1C
Product: COc1ccc2c(c1)C(c1ccccc1)NC(=O)N2CC(F)(F)F
Yield: 62 %

Procedure:
A mixture of 3.23 g (0.013 mole) of N-(2,2,2-trifluoroethyl)-N-(p-methoxyphenyl)urea, 1.6 g (0.015 mole) of benzaldehyde, 5.3 g (0.039 mole) of anhydrous zinc chloride, and 65 ml of xylene was stirred for a while and then heated under reflux for 15 hours, removing the water formed azeotropically. Thereafter, 20 ml of 1N-hydrochloric acid was added to the reaction mixture and the mixture was stirred for a while. The organic layer was separated from the reaction mixture, washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The resulting residue was treated with isopropyl alcohol to give 2.71 g (62%) of 1-(2,2,2-trifluoroethyl)-4-phenyl-6-methoxy-3,4-dihydro-2(1H)-quinazolinone, m.p. 168°-169° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH:13]=[CH:12]2)=[O:10])=[C:4]([Cl:20])[CH:3]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:4]1[CH:3]=[C:2](/[CH:23]=[CH:22]/[C:21]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]=[C:6]([Cl:8])[C:5]=1[C:9]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1)=[O:10]
Reactant: O=C(c1c(Cl)cc(Br)cc1Cl)n1ccc2cnccc21
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A solution of (4-bromo-2,6-dichlorophenyl)(1H-pyrrolo[3,2-c]pyridin-1-yl)methanone (100 mg, 0.27 mmol) and ethyl acrylate (3.06 mL, 30.58 mmol) in dimethylformamide (3 mL) was stirred at room temperature. Triethylamine (0.15 mL, 1.08 mmol) was added followed by triphenylphosphine (42.6 mg, 0.16 mmol) and palladium acetate (18.16 mg, 0.008 mmol). The reaction mixture was purged with argon and heated under reflux for about 20 hours. The reaction mixture was cooled to room temperature and the residue was poured into water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under rotary evaporator. Ethyl (2E)-3-[3,5-dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)phenyl]prop-2-enoate (64.8 mg, 61.59%) was isolated by silica gel column chromatography using ethyl acetate in hexane (15-17%) as eluant.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:26])=[CH:3]\[C:4]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][N:13]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)=[CH:9][CH:8]=1)=[O:5].[C:27](OCC)(OCC)(OCC)[CH3:28]>>[CH3:27][C:28]1[N:6]([C:7]2[CH:15]=[C:14]3[C:10]([CH:11]=[CH:12][N:13]3[CH2:16][O:17][C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:24]#[N:25])=[CH:9][CH:8]=2)[C:4](=[O:5])[CH:3]=[C:2]([CH3:26])[N:1]=1
Reactant: C/C(N)=C/C(=O)Nc1ccc2ccn(COc3cccc(C#N)c3)c2c1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1cc(=O)n(-c2ccc3ccn(COc4cccc(C#N)c4)c3c2)c(C)n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of (Z)-3-amino-N-(1-((3-cyanophenoxy)methyl)-1H-indol-6-yl)but-2-enamide (1.04 g, 3.00 mmol) and triethyl orthoacetate (20 mL) was stirred at 130° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (272 mg, 25%). The compound was characterized by the following spectroscopic data: