Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N+:14]=[N-:15]>>[ClH:1].[C:19]1([CH:18]=[CH:17][CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#CCCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCC=Cc1ccccc1
Agent: Cl
Product: Nc1nc(CCCc2cn(CC=Cc3ccccc3)nn2)c[nH]1
Yield: 38.4 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.115 g, 0.620 mmol) was reacted with (3-azido-propenyl)-benzene (0.119 g, 0.748 mmol) following the general procedure for click reactions outlined above to produce 4-{3-[1-(3-Phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-propyl}-1Himidazol-2-ylamine hydrochloride (0.082 g, 43%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.34-7.24 (m, 6H), δ 6.67 (d, 1H), δ 6.34 (q, 1H), δ 6.25 (s, 1H), δ 5.08 (d, 2H), δ 2.72 (t, 2H), δ 2.47 (t, 2H), δ 1.91 (m, 2H) ppm; 13C (75 MHz, CD3OD) 149.1, 137.9, 133.5, 129.5, 128.9, 128.7, 128.3, 128.2, 127.7, 126.8, 54.8, 48.9, 31.3, 29.6, 27.5 ppm; HRMS (ESI) calcd for C17H21N6 (M+) 308.1822. found 308.1821.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.[CH3:16][S:17][CH2:18][CH2:19][C:20](O)=[O:21].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:2]1([NH:1][C:20](=[O:21])[CH2:19][CH2:18][S:17][CH3:16])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: NC1(c2ccccc2Cl)CCC=CC1=O
Reactant: CSCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: CSCCC(=O)NC1(c2ccccc2Cl)CCC=CC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A solution of 6-amino-6-(2-chlorophenyl)-2-cyclohexen-1-one (50 mg, 0.23 mmol), 3(methylthio)propanoic acid (prepared by the known base hydrolysis from the commercial methyl ester)(33 mg, 0.28 mmol), hydroxybenzotriazole (31 mg, 0.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.35 mmol) in dimethylformamide (1 ml) was stirred at room temperature for 18 h. The reaction was partitioned between saturated bicarbonate and ethyl acetate, the organic phase was washed with brine, dried (Na2SO4), and the solvent removed by evaporation. Purification was achieved by preparative thin layer chromatography on silica gel eluting with 1:1 ethyl acetate/hexane. Isolation of the UV active band at Rf 0.4 gave 6-(2-chlorophenyl)-6-(3-(methylthio)propanoyl)amino-2-cyclohexen- 1-one (60.6 mg, 65%). The title compound was found to be active at 6μm in the CMK assay.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]([C:20]([F:23])([F:22])[F:21])=[N:12]2)=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+]>CO.[Pd].O>[F:23][C:20]([F:21])([F:22])[C:13]1[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[N:12]=1
Reactant: O=[N+]([O-])c1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A solution of 1-[(4-nitrophenyl)methyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (410 mg, 1.26 mmol) in methanol (3 ml) was added dropwise to a stirred suspension of 10% palladium on charcoal in water (1.3 ml) containing sodium borohydride (95 mg, 2.50 mmol), under argon with cooling. The resulting mix was stirred at room temperature for 1 hour. The reaction mix was filtered and then acidified using 2M HCl to destroy any excess sodium borohydride, and then basified again using 2M aqueous sodium hydroxide. The mix was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give a yellow oil, which was chromatographed on a 5 g pre-packed silica column eluting from 0-20% ethyl acetate in petroleum ether to give the title compound as a yellow oil (166 mg, 43%).
Reaction SMILES: F[C:2](F)(F)[C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[CH:6][NH:5][CH:4]=1.[NH3:18]>O1CCOCC1>[Cl:15][C:9]1[C:10]([Cl:14])=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]1[C:3]([C:2]#[N:18])=[CH:4][NH:5][CH:6]=1
Reactant: N
Reactant: FC(F)(F)c1c[nH]cc1-c1cccc(Cl)c1Cl
Solvent: C1COCCO1
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
4.0 g of 3-trifluoromethyl-4-(2,3-dichlorophenyl)-pyrrole, 21 ml of 25% aqueous ammonia and 40 ml of dioxane are stirred for 26 hours at 180° C. in an autoclave. After cooling to room temperature, the reaction mixture is filtered, and the clear filtrate is concentrated by evaporation. The residue is taken up in ethyl acetate, washed with water and subsequently with diluted sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated by evaporation. The residue is caused to crystallise by the addition of hexane; it is then filtered off and dried to thus obtain 3.4 g (100% of theory) of 4-(2,3-dichlorophenyl)-3-cyanopyrrole having a melting point of 150° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[O:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][C:13](=[O:21])[CH2:12]1.C(OC(=O)C)(=O)C>C(N(CC)CC)C>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:12]2[C:13](=[O:21])[NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:11]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1COc2ccccc2N1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(C=C2Oc3ccccc3NC2=O)cc1
Reaction time: 8 h

Procedure:
4-Cyanobenzaldehyde (1.98 g, 0.015 mol) was added to a mixture of 2H-1,4-benzoxazin-3(4H)-one (1.49 g, 0.01 mol), acetic anhydride (4 ml) and triethylamine (2 ml). The reaction mixture was refluxed for 7 h, left overnight at room temperature and poured into crushed ice. The precipitated solid was collected by filtration and washed with acetonitrile. The crude product was purified by recrystalization from DMF:ethanol.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Li].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C1COCC1>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](=[O:39])[CH2:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH:10]3[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]3)=[CH:8][CH:9]=2)=[O:3])=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(C2CN(C(=O)OC(C)(C)C)CCO2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(C(=O)CC(=O)c3ccc(Cl)cc3)cc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
tert-Butyl 2-(4-acetylphenyl)morpholine-4-carboxylate (210 mg, 0.69 mmol) was dissolved in THF (3.5 ml). Lithium-bis-(trimethylsilyl)-amide solution (2.05 ml, 2.05 mmol, 1.0 M solution in THF) was added dropwise and the yellow reaction mixture was stirred at −78° C. for 1 hour. 4-Chlorobenzoyl chloride (120 mg, 0.69 mmol) was added and the reaction mixture was stirred for 90 min and was quenched by addition of 1M aqueous hydrochloric acid. Ethyl acetate was added and the organic layer was dried over MgSO4 and evaporated. The crude material was purified by flash chromatography (10 g silica gel, 10 to 50% ethyl acetate in heptane) to yield an off-white solid (215 mg, 70%). MS (ISP): 388.2 ([{35Cl}M-tBu+H]+), 390.3 ([{37Cl}M-tBu+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:2]=1.Cl.[CH3:18][C:19]([CH3:21])=O>>[CH2:21]([N:10]([CH2:9][CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH:19]=[CH2:18]
Reactant: CC(C)=O
Reactant: O=C(NCC=Cc1cccnc1)C(F)(F)F
Agent: Cl
Product: C=CCN(CC=Cc1cccnc1)C(=O)C(F)(F)F
Yield: 42 %

Procedure:
14.0 g (51.8 mmol) of N-allyl-N-[3-(3-pyridyl)[-allyl]-2,2,2-trifluoroacetamide were dissolved in 1.40 ml of acetone, and 30 ml of 10% strength aqueous hydrochloric acid were added and the mixture was irradiated under nitrogen in a boro-silicate glass apparatus at room temperature with a 150 watt high-pressure mercury lamp for 48 h. The reaction solution was then concentrated, taken up in 150 ml of water and adjusted to pH 8-9 with aqueous ammonia solution. The aqueous phase was extracted twice with tert-butyl methyl ether, and the combined organic phases were dried over sodium sulfate and concentrated. The residue was fractionated by column chromatography (silica gel, methylene chloride+2% methanol) to yield 6.2 g (42%) of unchanged N-allyl-N-[3- (3-pyridyl)allyl]-2,2,2-trifluoroacetamide and 3.7 g (26%) of 2,2,2-trifluoro-1-[exo-6-(3-pyridyl) -3-azabicyclo[3.2.0]hept-3-yl]ethanone as a dark oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:24](O)[CH3:25]>>[CH2:24]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([C:11]([OH:13])=[O:12])[CH:4]=1)[CH3:25]
Reactant: CCO
Reactant: O=C(O)c1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxyisophthalic acid (10.0 g) in ethanol (100 mL) was added conc. sulfuric acid (3.0 mL), and the mixture was heated for 4 hours under reflux. The reaction solution was allowed to stand for cooling to room temperature, and poured into ice-water. Sodium bicarbonate was added thereto while stirring until the pH reached 10 to 11. The resulting precipitated solid was filtered off. To the filtrate was added conc. hydrochloric acid until the pH reached 2 to 3, and the precipitated solid was filtered off. The filtered solid was recrystallized from methanol and water (2:1, v/v) to give the title compound (4.53 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22]O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][O:12][C:10]2[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: OCCCCc1ccccc1
Product: COC(=O)c1ccc(OCCCCc2ccccc2)cc1F
Yield: 97 %

Procedure:
Following the process described in example 18 (point A), starting from methyl 2-fluoro-4-hydroxybenzoate and 4-phenyl-1-butanol, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with hexane:ethyl acetate, 95:5 (97% yield).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15]([C:23](O)=[O:24])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH3:40][N:41]1[CH2:46][CH2:45][N:44]([C:23]([C:15]2[S:14][C:6]3[N:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:2](=[O:1])[CH:3]=[CH:4][C:5]=3[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:24])[CH2:43][CH2:42]1
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCN(C(=O)c2sc3c(ccc(=O)n3-c3ccccc3)c2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
To a suspension of the compound of Example 59 (100 mg, 0.29 mmol) in DCM (2 mL) was added EDC (67 mg, 0.348 mmol) and HOBT (43 mg, 0.32 mmol) and the mixture stirred at r.t. for 15 minutes. A solution N-methyl piperazine (28 mg, 0.32 mmol) in DCM (0.5 mL) was added and the reaction stirred at r.t. for 18 h. The reaction mixture was diluted with DCM (10 mL), washed with water (2×5 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by chromatography on silica (0–20% THF in DCM) to give the title compound as an off-white solid (82 mg). δH (DMSO-d6) 7.67 (1H, dd, J 10, 1 Hz), 7.62–7.52 (3H, m), 7.51–7.40 (5H, m), 7.35–7.31 (2H, m), 6.51 (1H, dd, J 10, 1 Hz), 2.44 (8H, m), 1.88 (3H, s). LCMS (ES+) RT 2.18 minutes, 430 (M+H)+.
Reaction SMILES: C([O:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[CH3:16][C:12]1[C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([OH:23])=[O:8]
Reactant: Cc1cccc(C(=O)OCc2ccccc2)c1-c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: Cc1cccc(C(=O)O)c1-c1ccccc1
Yield: 99.8 %

Procedure:
A mixture of 0.35 g (1.18 mmol) of benzyl-3-methyl-2-phenylbenzoate and 0.25 g of 10% Pd/C in 8 mL of a 4.4% solution of HCO2H in methanol was heated at reflux for 2 h. The reaction mixture was filtered through a thin layer of celite and concentrated to give 0.25 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2].C(O)C>CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[C:46]([C:50]([O:52][CH:53]([O:55][C:56]([O:58][CH:59]3[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]3)=[O:57])[CH3:54])=[O:51])=[CH:47][CH:48]=[CH:49][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CCO
Product: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 95.4 %

Procedure:
Using 10.0 g of (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[2'-(N-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate, the reaction and after-treatment of Example 1 was repeated except that ethanol was used in lieu of methanol. The procedure provided 6.83 g of (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methylbenzimidazole-7-carboxylate (yield 91%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][CH:9]=[CH:10][C:3]=12.CCN(C(C)C)C(C)C.[NH2:20][C@@H:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1>C(O)CCC>[C@@H:21]1([NH:20][C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22]1
Reactant: N[C@H]1CCc2ccccc21
Reactant: Clc1nc[nH]c2nccc1-2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc2c(c1)CC[C@@H]2Nc1ncnc2[nH]ccc12
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (2.10 g, 13.6 mmol), DIPEA (3.57 mL, 20.5 mmol) and (S)-(+)-1-aminoindan (1.93 mL, 15.0 mmol) in 1-butanol (60.0 mL) and was heated to reflux for 60 hours, cooled down to room temperature and concentrated. The residue was purified by flash chromatography (0 to 100% EtOAc/DCM) to afford the title compound (2.72 g, 80%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[N:21]=[CH:20][C:19]4[C:14](=[CH:15][C:16]([O:22][CH:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[CH:17][CH:18]=4)[N:13]=3)=[CH:10][C:4]=2[NH:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:26]1[CH2:27][CH2:28][CH:23]([O:22][C:16]2[CH:15]=[C:14]3[C:19]([CH:20]=[N:21][C:12]([NH:11][C:9]4[CH:8]=[CH:7][C:5]5[NH:6][C:2](=[O:1])[NH:3][C:4]=5[CH:10]=4)=[N:13]3)=[CH:18][CH:17]=2)[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnc(Nc4ccc5[nH]c(=O)[nH]c5c4)nc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]c2ccc(Nc3ncc4ccc(OC5CCNCC5)cc4n3)cc2[nH]1
Yield: 30 %

Procedure:
A solution of crude tert-butyl 4-(2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-ylamino) quinazolin-7-yloxy)piperidine-1-carboxylate in 30% TFA/DCM was stirred at room temperature for 30 min. The solvent was evaporated and crude was purified by semi-prep HPLC to provide pure product in 30% yield ES/MS m/z 377.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[C:21]([O:23][CH3:24])=[O:22]>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1cccc(F)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccc(F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(3-fluorophenyl)acetate hydrochloride (from Example D12 above), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.2 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 95:5 CHCl3/MeOH as the eluent.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[Cl:12][CH2:13][CH2:14]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:12][CH2:13][CH2:14][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: ClCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Yield: 83.9 %

Procedure:
A slurry containing 2-amino-3-nitrophenol (32.0 g, 0.208 mol), 1,2-dichloroethane (260.0 g, 2.65 mol), potassium carbonate (35.0 g, 0.252 mol) and 2-butanone (750 ml) was refluxed for 24 hours. The mixture was cooled, filtered and the solids were washed with ethyl acetate. The filtrate was concentrated to an oily residue that was dissolved in ethyl acetate (500 ml). The organic layer was washed sequentially with 1N sodium hydroxide (250 ml), water (500 ml) and brine (2×500 ml) and then dried over anhydrous magnesium sulfate. Concentration of the filtered solution and trituration of the residue with hexanes afforded 37.8 g (84.6%) of product as an orange solid: mp 71-73° C.; MS EI m/e 216 (M+).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)=[C:6]1[CH:20]([CH3:22])[CH3:21])#[N:2].[OH-].[Na+].C([OH:27])C>Cl>[C:1]([CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH2:14][C:15]2[NH:19][CH:18]=[CH:17][N:16]=2)=[C:6]1[CH:20]([CH3:22])[CH3:21])(=[O:27])[NH2:2]
Reactant: CC(C)c1c(Cc2ncc[nH]2)c2ccccc2n1CCC#N
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1c(Cc2ncc[nH]2)c2ccccc2n1CCC(N)=O
Reaction time: 18 h

Procedure:
1-(2-Cyanoethyl)-2-isopropyl-3-(1-imidazolylmethyl)indole (2.0 g) was dissolved in concentrated hydrochloric acid (10 ml) and the solution was allowed to stand for 18 hours at room temperature. It was cautiously basified with dilute sodium hydroxide solution and the mixture was extracted with ethyl acetate (3×25 ml). The combined ethyl acetate extracts were washed with water and dried (Na2SO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with a mixture of chloroform and methanol (95:5) gave initially a small amount of impurity followed by pure product. Evaporation of the product containing fraction gave a gum which solidified on trituration with ethanol. The solid was crystallised from ethanol/petrol (b.p. 60°-80° C.) to give 1-(2-carbamoylethyl)-2-isopropyl-3-(1-imidazolylmethyl)indole (1.03 g), m.p. 169°-171° C. Found: C, 69.54; H, 7.25; N, 18.12. C18H22N4O4 requires: C, 69.64; H, 7.14; N, 18.05.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:23])[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21]>>[CH3:21][N:20]([CH3:22])[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:14]([CH3:23])[CH3:13])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CN(C)CCNCCN(C)C
Product: CCCCCCC/C=C/C(=O)N(CCN(C)C)CCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N-(2-(dimethylamino)ethyl)-N′,N′ dimethylethane-1,2-diamine as starting materials to give the aimed compound.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)N)=[CH:6][CH:5]=1.C[O:22][C:23](=[O:32])[CH2:24][CH:25]([CH3:31])[CH2:26][C:27](=O)[CH2:28][CH3:29]>C(O)(C)(C)C>[CH3:2][S:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:11]3[C:16](=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:28]([CH3:29])=[C:27]2[CH2:26][CH:25]([CH3:31])[CH2:24][C:23]([OH:32])=[O:22])=[CH:6][CH:5]=1
Reactant: COc1ccc(N(N)Cc2ccc(SC)cc2)cc1
Reactant: CCC(=O)CC(C)CC(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)CC(=O)O)n2Cc1ccc(SC)cc1

Procedure:
Following the method of Example 2, but using 1-[4-methylthiobenzyl]-1-[4-methoxyphenyl]hydrazine hydrochloride and methyl-3-methyl-5-oxoheptanoate as starting materials, in t-butanol as solvent, the title compound was prepared
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.N([O-])=O.[Na+].[ClH:35]>>[Cl:35][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1
Reactant: Cl
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Agent: O=N[O-]
Agent: [Na+]
Product: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 50 mg (0.107 mmol) of 2-amino-6-([2-(4-chlorophenyl)-1,3-thiazol-4-yl]methylsulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile were dissolved in 1.5 ml of concentrated hydrochloric acid, and 22 mg (0.321 mmol) of sodium nitrite were added. The mixture was stirred initially at 0° C. for one hour and then at room temperature overnight. Purification of the reaction mixture was by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 9 mg (17% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]([C:8](=O)[CH2:9][CH3:10])[C:6]#[N:7])C.Cl.C(N)=[NH:14].C(N(CC)CC)C>C(O)C>[CH2:9]([C:8]1[C:5]([C:6]#[N:7])=[CH:4][N:2]=[CH:1][N:14]=1)[CH3:10]
Reactant: N=CN
Reactant: CCC(=O)C(C#N)=CN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1ncncc1C#N
Yield: 35 %

Procedure:
A mixture of crude 2-((dimethylamino)methylene)-3-oxopentanenitrile (0.98 equiv.), formamidine hydrochloride (2.0 equiv.) and triethyl amine (2.0 equiv.) in ethanol (1.0 M) was refluxed for 36 h. The solvent was removed and the residue was purified by silica column chromatography (20% ethyl acetate in petroleum ether) to afford the title product (35% yield). 1H-NMR (400 MHz, CDCl3) δ (ppm) 9.20 (s, 1H), 8.83 (s 1H), 2.98 (d, J=7.6 Hz, 2H), 1.32 (t, J=7.6 Hz, 3H); MS (ESI) m/z 134.1 [M+H]+.