Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[CH3:18].O1CCCC1.[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31]>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:32]([C:27]3[CH:28]=[CH:29][C:30]([Cl:31])=[C:25]([Cl:24])[CH:26]=3)(=[O:34])=[O:33])=[CH:10][CH:9]=2)[C:5]([CH3:18])=[N:6]1)=[O:12])([CH3:15])([CH3:17])[CH3:16]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(N)cc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)cc12
Yield: 43.4 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide can be obtained as described in Example 1 from 1 g of 5-amino-N-tert-butoxycarbonyl-3-methyl-1H-indazole, 50 ml of tetrahydrofuran, 1.15 ml of triethylamine and 1.1 g of 3,4-dichlorobenzenesulfonyl chloride. 0.8 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3,4-dichlorobenzenesulfonamide is thus obtained in the form of a white solid melting at 171° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1.[Cl:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>>[ClH:21].[Cl:22][CH2:23][CH2:24][CH2:25][C:26]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=1)=[O:27]
Reactant: O=C(Cl)CCCCl
Reactant: Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Product: Cl
Product: O=C(CCCCl)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Yield: 91 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-amino-4-(3'-chloro-4'-fluoroanilino)-7-fluoroquinazoline was reacted with 4-chlorobutyryl chloride to give 6-(4-chlorobutyramido)-4-(3'-chloro-4'-fluoroanilino)-7-fluoroquinazoline hydrochloride as a solid in 91% yield;
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:27])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24](O)=[O:25])[N:22]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH:1]1([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[NH:15][C:16](=[O:27])[NH:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[O:25])[N:22]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CC(=O)O)cs2)c(C(=O)C2CCCC2)c1
Reactant: CN1CCNCC1
Product: Cc1ccc(NC(=O)Nc2nc(CC(=O)N3CCN(C)CC3)cs2)c(C(=O)C2CCCC2)c1

Procedure:
4-(2-{2-[3-(2-Cyclopentanecarbonyl-4-methylphenyl)-ureido]-thiazol-4-yl}-acetyl)-1-methyl-piperazine (337 mg) is prepared from 2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylacetic acid (386 mg, 1.0 mmol) and N-methylpiperazine following the general procedure K.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([NH2:8])[N:7]=1.[F:13]F.[He]>F>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([F:13])=[C:6]([NH2:8])[N:7]=1
Reactant: COC(=O)c1ncc(N)nc1N
Reactant: FF
Agent: F
Agent: [He]
Product: COC(=O)c1nc(F)c(N)nc1N
Temperature: -78 °C

Procedure:
In a Kel-FR reactor cooled to -78° C in an acetone-dry ice bath is placed methyl 3,5-diaminopyrazinoate (6g.) and liquid hydrogen fluoride (70 ml.). A stream of fluorine-helium mixture (1:4 v/v) is passed through the solution for 51/2 hours at -78° C. followed by a vigorous stream of nitrogen to remove the solvent. The reaction residue is treated with conc. hydrochloric acid (60 ml.), evaporated to dryness, dissolved in water (75 ml.) and neutralized with aqueous sodium hydroxide to give methyl 3,5-diamino-6-fluoropyrazinoate (5 g.) which is purified by sublimation (140°-50° C., 0.05 mm Hg.) and recrystallization from 2-propanol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15]C(C)(C)C)=[O:14])[C:8](=[O:23])[C:7]3=[CH:24][N:25](S(C4C=CC(C)=CC=4)(=O)=O)[C:5]([C:6]=23)=[N:4][CH:3]=1.CCO.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:20]([CH3:21])[CH3:22])[C:13]([OH:15])=[O:14])[C:8](=[O:23])[C:7]3=[CH:24][NH:25][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@@H](C(=O)OC(C)(C)C)C(C)C)C3=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 110.5 %

Procedure:
A mixture of (R)-tert-butyl 2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate (650 mg, 1.25 mmol), EtOH (4 mL), and aqueous NaOH (1N, 2 mL) was stirred at room temperature for 40 min. The mixture was subsequently diluted with DCM and washed with brine. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/DCM) gave a yellow oil (425 mg), which was dissolved in 50% TFA/DCM. The solution was stirred at room temperature for 1 h, concentrated, and dried under vacuum to give the title compound as a yellow solid (360 mg, 93%). 1H NMR (500 MHz, CD3OD) δ 0.91 (d, J=7.0 Hz, 3H), 1.11 (d, J=7.0 Hz, 3H), 2.36-2.47 (m, 1H), 4.80-5.08 (m, 3H), 7.76 (s, 1H), 8.19 (s, 1H). [M+H] calc'd for C14H14ClN3O3, 308, 310; found, 308, 310.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH2:41]([N:43]1[CH:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[N:44]1)[CH3:42]>O1CCCC1.O>[CH2:41]([N:43]1[CH:47]=[C:46]([S:48]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:50])=[O:49])[CH:45]=[N:44]1)[CH3:42]
Reactant: CCn1cc(S(=O)(=O)Cl)cn1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1cc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)cn1
Reaction time: 0.08 h
Yield: 97.4 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 50 mg) at room temperature, and the mixture was stirred for 5 min. 15-Crown-5 (273 mg) was added. Then 1-ethyl-1H-pyrazole-4-sulfonyl chloride (181 mg) was added and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 290 mg, 97%).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15]>ClCCl>[OH:13][CH:10]1[CH2:11][CH2:12][N:8]([C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)=[O:21])[CH2:9]1
Reactant: OC1CCNC1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2.22 g of triethylamine (20 mmol), followed by 1.74 g of pyrrolidin-3-ol (20 mmol), were added to a solution of 3.71 g of 3-nitrobenzoyl chloride (20 mmol) in 40 ml of dichloromethane cooled to 0° C. The reaction medium was stirred at ambient temperature for 2 hours and was then diluted with 50 ml of dichloromethane. The organic phase was washed with 50 ml of a 1 N hydrochloric acid solution and then with 50 ml of a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated. 3.78 g of (3-hydroxypyrrolidin-1-yl)-(3-nitrophenyl)methanone were obtained and used without purification in the next step. Yield=80%.
Reaction SMILES: [NH3:1].[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]>C(Cl)Cl>[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:1])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: O=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ammonia (0.5 M in 1,4-dioxane, 5 mL) was added to 4-formylbenzenesulfonyl chloride (0.5 g), followed by DCM (10 mL). The reaction mixture was stirred vigorously for 3 h at RT, then concentrated under reduced pressure. The crude residue was purified by flash chromatography to afford 4-formyl-benzenesulfonamide. MS=183.9 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].[NH2:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(Cl)CCl>C(Cl)Cl>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)c(CC(=O)NCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Indomethacin (500 mg, 1.40 mmol) was taken up in 10 mL of CH2Cl2 along with tert-butyl 2-aminoethylcarbamate (223 mg, 1.40 mmol) and EDC (295 mg, 1.54 mmol). The resulting reaction mixture was stirred at room temperature for 18 and diluted with CH2Cl2 (10 mL). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 550 mg of tert-butyl 2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethylcarbamate (79% yield).
Reaction SMILES: CI.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:32])[NH:12][C:13]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1.[C:33](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:32])[N:12]([CH3:33])[C:13]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:14][C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:6][CH:5]=1
Reactant: O=c1[nH]c(CCCCc2ccccc2)nc(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(CCCCc2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 1.25 h

Procedure:
Methyl iodide (22 μl, 0.351 mmol) was added to a stirring mixture of 5-(4-fluorophenyl)-2-(4-phenylbutyl)-6-(4-pyridyl)-4(3H)-pyrimidinone (140 mg, 0.351 mmol) and potassium carbonate (49 mg, 0.351 mmol) in N,N-dimethylformamide (5 ml). After 75 min, it was evaporated and the resultant product purified on a silica gel column (hexane-acetone=3:1; 2:1) to provide the title compound. MS (m/z): 414.3 (M+H)+; C26H24FN3O requir. 413.5.
Reaction SMILES: C([Li])CCC.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O[C:16](=[O:33])[CH2:17][CH:18]1[CH2:23][CH2:22][C:21]([N:30]([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)C.[Cl-].[NH4+]>C1COCC1>[CH3:32][N:30]([CH3:31])[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:22][CH2:23][CH:18]([CH2:17][C:16]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:33])[CH2:19][CH2:20]1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)Nc2ccccc2)CC1
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6 M solution in hexane; 7.1 ml; 11.4 mmol) was added dropwise at 0° C. to a solution of aniline (0.53 g; 5.7 mmol) in 10 ml THF. The mixture was allowed to come to RT and was subsequently stirred for 1 h. A solution of (4-dimethylamino-4-phenyl-cyclohexyl)-acetic acid ethyl ester (1.5 g; 5.2 mmol) in 15 ml THF was added dropwise at −78° C. The mixture was subsequently stirred for 1 h and then allowed to come to RT. It was hydrolysed with ammonium chloride solution and extracted with MC. After concentration, the crude product was chromatographed on silica gel (eluent:ether). 308 mg (18%) of the less polar and 620 mg (36%) of the more polar diastereoisomer were obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8](/[CH:9]=[N:10]/[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][O:14][C:15]3=[O:20])=[CH:7][CH:6]=1)[CH3:3].[CH3:23][N:24]1[C:28]([CH:29]=O)=[N:27][CH:26]=[N:25]1.[CH3:31][CH2:32][O-:33].[Na+]>C(OCC)(=O)CC>[CH3:1][N:2]([CH2:4][C:5]1[CH:22]=[CH:21][C:8]([CH:9]2[CH:29]([C:28]3[N:24]([CH3:23])[N:25]=[CH:26][N:27]=3)[C:32](=[O:33])[C:31]3[C:16]([C:15]([O:14][CH2:13][CH3:12])=[O:20])=[CH:17][CH:18]=[CH:19][C:11]=3[NH:10]2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccc(/C=N/c2cccc3c2COC3=O)cc1
Reactant: Cn1ncnc1C=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Product: CCOC(=O)c1cccc2c1C(=O)C(c1ncnn1C)C(c1ccc(CN(C)C)cc1)N2
Temperature: 45 °C
Reaction time: 3 h
Yield: 15.7 %

Procedure:
To a solution of (E)-4-(4-((dimethylamino)methyl)benzylideneamino)isobenzofuran-1(3H)-one (2.21 g, 7.5 mmol) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (1.01 g, 9.16 mmol) in ethyl propionate (110 ml) was added rapidly EtONa (sodium (490 mg, 21 mmol) in 35 mL ethanol) at 40° C., then the mixture was stirred at 45° C. for 3 hr. The resulting mixture was evaporated under reduced pressure, extracted with ethyl acetate (200 mL×3), and then concentrated the extract. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol=100:1 to 10:1) to obtain a green solid (510 mg, yield 16%). LC-MS (ESI) m/z: 434 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:17])[C:10]=1[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:17][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([Cl:1])[C:10]=1[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=1)=[O:7]
Reactant: O=C(O)c1cc(Cl)c(OC2CCCC2)c(Cl)c1
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC3CCCC3)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.2 %

Procedure:
A solution of 3,5-dichloro-4-(cyclopentyloxy)benzoic acid (3) (100 mg, 363 μmol) in DCM (5 mL), cooled to 0° C., was treated with oxalyl chloride (63.6 μL, 727 μmol), followed by a drop of DMF. The resultant mixture was stirred for 1 h at RT. The solvent was evaporated in vacuo and the residue dissolved in DCM (5 mL), and then treated with a solution of methyl 4-aminobenzoate (54.9 mg, 363 μmol) and DIPEA (190 μL, 1.09 mmol) in DCM (5 mL). The reaction mixture was stirred for 12 h at RT and then partitioned between DCM (20 mL) and aqueous HCl (20 mL, 1 M). The phases were separated and the organic phase was washed successively with water (2×20 mL), and brine (20 mL), dried over MgSO4, filtered and then the solvent was removed in vacuo. The residue was purified by silica gel chromatography (12 g, 0-100% EtOAc in isohexane) to afford methyl 4-(3,5-dichloro-4-(cyclopentyloxy)benzamido)benzoate (AAA-002) (30 mg, 20%): m/z 406 (M−H)− (ES−). NMR (400 MHz, CDCl3) δ: 8.06 (2H, d), 7.85 (1H, br s), 7.82 (2H, s), 7.71 (2H, d), 5.05 (1H, m), 3.92 (3H, s), 2.10-1.90 (4H, m), 1.85-1.70 (2H, m), 1.70-1.60 (2H, m).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:53][C:54]1[C:59]([CH3:60])=[CH:58][CH:57]=[CH:56][C:55]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:65]2[CH2:66][CH2:67][CH:62]([NH:61][C:55]3[CH:56]=[CH:57][CH:58]=[C:59]([CH3:60])[C:54]=3[CH3:53])[CH2:63][CH2:64]2)=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: Cc1cccc(NC2CCNCC2)c1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(NC2CCN(C(=O)CC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.101 g, 0.00039 mole) in DMF (3 mL) was added DIPEA (0.233 g, 0.0018 mole), HOBt (0.053 g, 0.00039 mole) and EDCI.HCl (0.138 g, 0.00072 mole). After 2 minutes (2,3-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00036 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (1% methanol in chloroform) afforded 0.07 g (44%) of N-biphenyl-4-yl-3-[4-(2,3-dimethyl-phenylamino)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 442.24 (M+1)+, 95.5%, 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 7.7 (m, 6H), 7.6 (t, 2H), 7.4 (d, 1H), 6.8 (t, 1H), 6.5 (d, 1H), 6.4 (d, 1H), 4.4 (t, 2H), 4.0 (d, 1H), 3.6 (bs, 3H), 3.2 (t, 1H), 2.8 (t, 1H), 2.2 (s, 3H), 2.0 (bs, 5H), 1.5 (d, 1H), 1.4 (d, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH2:13][C@H:12]1[C:15]([OH:17])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.FC(F)(F)C(O)=O.[NH2:50][C:51]1[S:52][CH:53]=[C:54]([C:56]2[CH:67]=[CH:66][C:59]([C:60]([NH:62][CH:63]3[CH2:65][CH2:64]3)=[O:61])=[CH:58][CH:57]=2)[N:55]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH2:13][C@H:12]1[C:15](=[O:17])[NH:50][C:51]1[S:52][CH:53]=[C:54]([C:56]2[CH:57]=[CH:58][C:59]([C:60](=[O:61])[NH:62][CH:63]3[CH2:65][CH2:64]3)=[CH:66][CH:67]=2)[N:55]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Reactant: O=C(O)[C@@H]1CCN1C(=O)OCc1ccccc1
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3CCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-Azetidine-1,2-dicarboxylic acid 1-benzyl ester (45.7 mg, 0.19 mmol) was dissolved in DMF (1.5 mL). Triethylamine (53 μL, 0.38 mmol) and pentafluorophenyl trifluoroacetate (33 μL, 0.19 mmol) were added, and the reaction was stirred at ambient temperature for 30 minutes. Then 4-(2-Amino-thiazol-4-yl)-N-cyclopropyl-benzamide trifluoroacetic acid salt (62.9 mg, 0. 17 mmol) was added. The reaction was stirred at ambient temperature overnight and then heated to 70° C. for 4 hours. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 7.2 mg. MS: 477.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.50-0.85 (m, 4H), 2.10-2.30 (m, 1H), 2.48-2.62 (m, 1H), 2.78-2.90 (m, 1H), 3.80-4.07 (m, 2H), 4.80-5.13 (m, 3H), 7.07-7.42 (m, 4H), 7.78-7.99 (m, 5H), 8.40-8.47 (m, 1H), 12.40-12.58 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]2[CH:26]=[N:27][CH:28]=[N:29][CH:30]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3N=N[N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2].C(OC1N(CCOCC2C=CN=CC=2)C2C(C)=C(C)N3N=NN=C3C=2N=1)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[N:29][CH:28]=[N:27][CH:26]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)[CH3:2]
Reactant: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCC#Cc1cncnc1
Agent: CCOc1nc2c(c(C)c(C)n3nnnc23)n1CCOCc1ccncc1
Solvent: Cc1ccccc1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCOCC#Cc1cncnc1
Yield: 14.6 %

Procedure:
The method described in Part D of Example 109 was used with the following modification. The reaction was carried out in refluxing toluene, and 8-ethoxymethyl-5,6-dimethyl-7-[2-(3-pyrimidin-5-ylprop-2-ynyloxy)ethyl]-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine (6.20 g, 15.3 mmol) was used in lieu of 8-ethoxy-5,6-dimethyl-7-[2-(pyridin-4-ylmethoxy)ethyl]-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine. The crude product was purified by column chromatography on silica gel (200 g, eluting with 95:5 dichloromethane:methanol) to provide 0.852 g of 2-(ethoxymethyl)-6,7-dimethyl-1-{2-[(3-pyrimidin-5-ylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]pyridin-4-amine as a white powder, mp 122-124° C.
Reaction SMILES: [NH3:1].CS(O[CH2:7][C@H:8]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:9][CH2:10][CH2:11]OS(C)(=O)=O)(=O)=O>C1COCC1>[NH:1]1[CH2:11][CH2:10][CH2:9][C@@H:8]([NH:17][C:18](=[O:19])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7]1
Reactant: N
Reactant: CS(=O)(=O)OCCC[C@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCCNC1)OCc1ccccc1
Reaction time: 46 h

Procedure:
Liquid ammonia (ca. 30 ml) was added to a solution of (2R)-2-{[(benzyloxy)carbonyl]amino}-5-[(methylsulfonyl)oxy]pentyl methanesulfonate (1 g) in THF (15 ml) at −78° C. in a bomb reaction vessel and then the resultant mixture was allowed to reach room temperature. After 46 h, the solution was concentrated under reduced pressure to give an off-white solid which was purified using SPE (silica, eluting with methanol, methanol:aqueous ammonia 95:5, 9:1) to give the title compound (0.587 g) as an off white solid.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[NH:21])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=1)C=C>C(#N)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:17]([O:16][C:14]([NH:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][NH2:4])=[CH:11][CH:10]=1)=[NH:21])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: C=CCNCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Temperature: 25 °C

Procedure:
The N-allyl-4-(t-butoxycarbonylamidino)benzylamine (3.97 mmoles, 1.15 g) and chlorotris(triphenylphosphine)-rhodium(I) (0.21 mmoles, 195 mg) was stirred in acetonitrile/water (84:16, 92 mL) under nitrogen. The mixture was refluxed for 3 hr and allowed to cool to room temperature. Then the mixture was filtered through a pad of celite and the solvent removed in vacuo. The residue was dried on a high vacuum pump to yield an orange glassy product 4-(t-Butoxycarbonylamidino)benzylamine product was verified by HPLC/MS and used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([S:12][CH3:13])[C:3]=1[CH:14]([F:16])[F:15].[OH-].[Li+].O>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:12][CH3:13])[C:3]=1[CH:14]([F:16])[F:15]
Reactant: COC(=O)c1ccc(Cl)c(C(F)F)c1SC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1c(C(=O)O)ccc(Cl)c1C(F)F
Yield: 93 %

Procedure:
Methyl 4-chloro-3-difluoromethyl-2-methylsulphenylbenzoate (9.1 g) and lithium hydroxide (2.2 g) were dissolved in methanol and water and the mixture stirred overnight at room temperature. The mixture was then evaporated and the residue dissolved in water and washed with ethyl acetate. The aqueous layer was acidified to pH 1 with 2M HCl and extracted with ethyl acetate. The organic extract was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 4-chloro-3-difluoromethyl-2-methylsulphenylbenzoic acid (8.02 g) as a beige solid NMR (CDCl3) 2.5(s,3H), 7.5(d,1H), 7.65(t,1H), 7.8(d,1H).