Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I)([F:4])[F:3].[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C.[Cu](I)I>[F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:20]#[C:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([F:4])[F:3]
Reactant: FC(F)(F)Sc1ccccc1I
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: FC(F)(F)Sc1ccccc1C#Cc1ccccc1
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A suspension of PdCl2PPH3 (0.027 g, 0.063 mmol) and copper iodide (0.0035 g, 0.018 mmol) in 3 ml of triethylamine was charged into a 50-ml eggplant flask equipped with a stirrer. To this suspension, a solution of (trifluoromethyl)(2-iodophenyl)sulfide (0.57 g, 1.9 mmol) prepared in Example 1 and phenylacetylene (0.23 g, 2.2 mmol) in 2 ml of triethylamine was added dropwise at room temperature, and the mixture was stirred overnight. After completion of the reaction, a solvent was removed, water was added to the obtained residue, and the mixture was extracted three times with ether. The obtained organic layers was collected and washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (Benzen/Hexane=20/80) to give target (trifluoromethyl)-(2-(2-phenylethynyl)phenyl)sulfide (0.5 g, 96%).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])[C:10]1=[O:34])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[F:33][C:27]1[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=1[N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:34]
Reactant: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(-c2ccc(F)cc2F)c(=O)n1O
Yield: 100.7 %

Procedure:
Twenty percent Pd/C (50 mg) was added to a solution of 3-benzyloxy-1-(2,4-difluorophenyl)-6-fluoro-7-pyrrolidin-1-yl-1H-quinazoline-2,4-dione (Example K-4, 0.22 g, 0.5 mmol) in 40 mL of THF, and this was shaken under 50 PSI of hydrogen for 16 hours. The mixture was filtered and concentrated to afford 0.19 g of a solid. This solid was triturated with ether and filtered to give 0.08 g of the title compound as a solid, mp 232-234° C.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].Br[CH:18]([CH3:20])[CH3:19].[OH-].[Na+]>C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3.C1C=CC=CC=1>[CH:18]([CH:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:2]([F:16])([F:1])[CH:3]([F:4])[F:5])=[CH:8][CH:9]=1)[C:14]#[N:15])([CH3:20])[CH3:19]
Reactant: CC(C)Br
Reactant: N#CCc1ccc(OC(F)(F)C(F)F)cc1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)C(C#N)c1ccc(OC(F)(F)C(F)F)cc1
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 100.1 %

Procedure:
A mixture of 39.85 g (0.171 mol) of p-(1,1,2,2-tetrafluoroethoxy)phenylacetonitrile, 3.71 g (9.96 mmol, 5.8 mol %) of dicyclohexyl-18-crown-6, 22.0 ml (28.8 g, 0.234 mol) of 2-bromopropane, 55 ml of benzene, and 55 ml of 50% sodium hydroxide is stirred for 45 minutes during which there is an exotherm from 25° C. to 43° C. The reaction mixture is then heated at 45° C. for 16.5 hours. After dilution with 200 ml of water, the reaction mixture is extracted with 200 ml of ether. The ether solution is washed with 400 ml of 12% hydrochloric acid, 200 ml of 5% hydrochloric acid, and 300 ml of water. The ether solution is dried with sodium sulfate, filtered, and then evaporated to give 47.13 g of an oil. This oil is vacuum distilled to give 34.83 g (74%), boiling point 83° C. to 85° C. at 0.055 to 0.090 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]=[N+]=[N-])[CH2:10][CH:9]1[CH2:16][O:17][CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH2:13])[CH2:10][CH:9]1[CH2:16][O:17][CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: COCC1CC(N)CN1C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
The 4-azido-2-methoxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester (122.00 mg, 0.48 mmol) was taken up in ethyl acetate in a Paar vessel. The solution was flushed with argon and Pd/C (100.00 mg) was added to the vessel. The argon atmosphere was replaced by hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen atmosphere was replaced by argon and the solution was filtered through a celite pad. The pad was washed twice with ethyl acetate. The solvent was removed under reduced pressure. The product was used without further purification. Yield 99.76 mg. C11H22N2O3 MS me/230.2 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.Cl>>[CH2:7]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1cccc(-c2[nH]c(-c3ccc(N)cc3)nc2C(=O)Nc2nccs2)c1
Agent: Cl
Product: CCCCNc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3cccc(OC)c3)[nH]2)cc1
Yield: 83.1 %

Procedure:
2-(4-Aminophenyl)-5-(3-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.8 g) obtained in Example 155 was treated in the same manner as in Example 74 to give the objective 2-(4-butylaminophenyl)-5-(3-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide (0.38 g), melting point 228-231° C. (hydrochloride).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1.[NH2:17][NH2:18].O>CO>[NH:17]([C:3](=[O:2])[CH2:4][CH:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1)[NH2:18]
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(CC(=O)NN)C1
Temperature: 65 °C
Yield: 96 %

Procedure:
To a solution of tert-butyl 3-(2-methoxy-2-oxoethyl)azetidine-1-carboxylate (25.0 g, 109 mmol) in MeOH (150 mL) was added NH2NH2.H2O (27.3 g, 546 mmol) at rt. The mixture was heated at 65° C. for 12 hrs and then concentrated. The residue was diluted with DCM (400 mL), washed with water (2×) and saturated sodium chloride (2×), dried over Na2SO4, and concentrated to give tert-butyl 3-(2-hydrazinyl-2-oxoethyl)azetidine-1-carboxylate (24.0 g, 96%) as a yellow gum. ESI-MS (EI+, m/z): 252 [M+Na]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH3:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:24])[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4ccccc4C)c(C(=O)O)s3)c2cc1OC
Yield: 56.9 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 2-methylphenylboronic acid (20.4 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-o-tolyl-thiazole-5-carboxylic acid (22.5 mg, 57%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.43 (br.s., 1 H); 8.82 (s, 1 H); 7.68 (s, 1 H); 7.41 (d, 1 H); 7.40 (s, 1 H); 7.31-7.39 (m, 2 H); 7.27 (td, 1 H); 3.85 (s, 3 H); 3.81 (s, 3 H); 2.29 (s, 3 H). MS m/z 396 (M+1).
Reaction SMILES: [CH2:1]([SH:5])[CH:2]([SH:4])[CH3:3].Cl[CH:7]([CH3:11])[C:8](=O)[CH3:9]>>[CH3:3][CH:2]1[CH2:1][S:5][C:8]([CH3:9])=[C:7]([CH3:11])[S:4]1
Reactant: CC(=O)C(C)Cl
Reactant: CC(S)CS
Product: CC1=C(C)SC(C)CS1
Yield: 36.5 %

Procedure:
The procedure of Example 1(a) is repeated, using 1,2-propanedithiol and 3-chloro-2-butanone to give 2,3-dihydro-2,5,6-trimethyl-1,4-dithiin as a clear green liquid, bp 49.5°-51°/0.7 mm, yield 36.5%, NMR 1.36 (3d), 1.88 (6s), 2.4-3.6 (3m) (CDCl3). IR, 2905 (sh); 1605, 1410 (broad); 1250, 1155 (sh); 1065 (br); 730, 705.
Reaction SMILES: [N:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:6]([CH3:23])[CH:5]=1)=[C:2]=[O:3].[CH3:24][N:25]([CH3:42])[CH2:26][CH2:27][CH2:28][N:29]([CH3:41])[C:30]1[C:31]([NH2:40])=[CH:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>C1(C)C=CC=CC=1>[CH3:42][N:25]([CH3:24])[CH2:26][CH2:27][CH2:28][N:29]([CH3:41])[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][C:31]=1[NH:40][C:2]([NH:1][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:6]([CH3:23])[CH:5]=1)=[O:3]
Reactant: Cc1cc(N=C=O)ccc1Oc1ncccc1-c1ccncn1
Reactant: CN(C)CCCN(C)c1ccc(C(F)(F)F)cc1N
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)Nc2cc(C(F)(F)F)ccc2N(C)CCCN(C)C)ccc1Oc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To 4-(2-(4-isocyanato-2-methylphenoxy)pyridin-3-yl)pyrimidine (93 mg, 0.33 mmol) in toluene (3 mL) was added N1-(3-(dimethylamino)propyl)-N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine (82 mg, 0.30 mmol). The mixture was stirred for 2.5 days at RT, then concentrated and purified by semi-preparative HPLC (Gilson, acidic mobile phase) to yield the title compound as an off-white solid. MS m/z=580 [M+H]+. Calc'd for C30H32F3N7O2: 579.63.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[O:40][CH:41]=1)(=[O:36])[CH3:35]>O1CCCC1>[Br:1][CH2:35][C:34]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[O:40][CH:41]=1)=[O:36]
Reactant: CC(=O)c1coc2ccccc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1coc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.4 %

Procedure:
A solution of phenyltrimethylammonium tribromide (2.47 g) in tetrahydrofuran (20 ml) was added dropwise at ambient temperature under nitrogen over 5 minutes to a stirred solution of 3-acetylbenzo[b]furan (1 g) in tetrahydrofuran (20 ml), then the mixture was stirred at ambient temperature for a further 1.5 hours, filtered, and the solvent removed in vacuo. The residue was triturated with ether, and the resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 3-(2-bromoacetyl)benzo[b]furan as an off-white solid (0.25 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][N:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1.[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH3:25])=[CH:32][CH:33]=1)[CH2:40][C:36]1[N:35]([CH3:34])[CH:39]=[CH:38][N:37]=1
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CNCc2ncc[nH]2)cc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.4 %

Procedure:
The compound (45.5 mg) obtained in Example 24-3 was dissolved in anhydrous methanol (1.8 ml) and added with 1-methyl-2-imidazole carboxaldehyde (16.5 mg) and sodium cyanoborohydride (18.9 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off and the resultant was added with a 1 mol/l sodium hydroxide aqueous solution and subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (32.7 mg) of the subject compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:15](C)C=O.S(Cl)(Cl)=O>O1CCCC1>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CN(C)C=O
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of 100 g (0.55 mol) of acid 5 in 600 ml of tetrahydrofuran (THF) and 1 ml of N,N-dimethylformamide (DMF) 131 g (1.1 mol) of thionyl chloride were added. The mixture was stirred under reflux for 4 h and at room temperature for 12 h. The mixture was concentrated to 300 ml and added to a mixture of 1500 g of ice and 1500 ml of ammonia. The mixture was stirred for 3 h at 5° C. The resulting crystals were isolated at 10° C., washed with water, 100 ml of iso-propanol, and 100 ml of MTBE and dried in a vacuum oven at 50° C. Recrystallisation from toluene/MTBE (3/1). Yield: 68%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:30][CH:31](OC)OC)[C:12]([C:14]1[NH:15][CH:16]=[C:17]([C:19](=[O:29])[C:20]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=2[F:28])[CH:18]=1)=[O:13]>CC#N.O>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][N:11]1[CH:30]=[CH:31][C:18]2[C:17]([C:19](=[O:29])[C:20]3[C:21]([F:28])=[CH:22][C:23]([F:27])=[CH:24][C:25]=3[F:26])=[CH:16][NH:15][C:14]=2[C:12]1=[O:13]
Reactant: COC(CN(Cc1nc2ccccc2[nH]1)C(=O)c1cc(C(=O)c2c(F)cc(F)cc2F)c[nH]1)OC
Solvent: O
Solvent: CC#N
Product: O=C(c1c(F)cc(F)cc1F)c1c[nH]c2c(=O)n(Cc3nc4ccccc4[nH]3)ccc12
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A methanesulofonic acid 1.5 mL solution of the product from Step B (910 mg, 1.87 mmol) was stirred at 95° C. in an oil bath for 25 min. The reaction mixture was cooled to room temperature, diluted with MeCN—H2O (2:3) mixture (3 mL). The resulting solution was purified by reverse phase HPLC (C-18 column) (eluent: gradient mixture of acetonitrile-water with 0.5% TFA) to give the title compound (414 mg). LC/MS: m/z 423(M+H). 1H-NMR (d6-DMSO, 500 MHz): δ 5.59 (s, 2H), 7.06 (d, 1H), 7.35-7.39 (m, 4H), 7.61-7.68 (m, 3H), 7.93 (d, 1H), 13.14 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[N:19]=[C:14]2[CH:13]=[CH:12]1)[CH3:2].N#N.O=P(Cl)(Cl)Cl.CN([CH:45]=[O:46])C>>[CH:45]([C:13]1[C:14]2[C:15](=[N:16][C:17]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:19]=2)[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:34])[CH:12]=1)=[O:46]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCCCCCn1ccc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: N#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCCCCCn1cc(C=O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture comprising 7-(2,3-di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester (Intermediate B) (479 mg, 1.051 mmol) in anhydrous DMF (1 ml) was degassed with N2 and treated dropwise with POCl3 (0.147 ml, 1.577 mmol). The mixture was stirred at room temperature for 3 hours and treated with a further portion of POCl3 (0.147 ml, 1.577 mmol). After stirring at RT for 16 hours, the mixture was partitioned between water (100 ml) and EtOAc (20 ml) and the pH of the bi-phasic solution was adjusted to pH 8-9 using sat. NaHCO3 solution. The aqueous portion was extracted with EtOAc (×3) and the combined organic extract were washed with water (×1), brine (×1), dried over MgSO4 and filtered and concentrated under reduced pressure to afford the titled compound as a brown oil;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH2:21]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH:21][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=2)[CH:8]=1)=[O:14]
Reactant: COc1cccc(CN)c1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Product: COc1cccc(CNC(=O)c2ccc3cc(O)ccc3c2)c1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and 3-methoxy-benzylamine (commercially available) according to the procedure described for Example A. MS (m/e): 306.2 (MH−, 100%)
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)([O:3]C(C)(C)C)=O.[CH2:15]([N:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)CC(O)=O)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:13]([C@H:9]1[NH:8][C:1](=[O:3])[CH2:15][N:17]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:12])[CH3:14]
Reactant: CCN(CC(=O)O)Cc1ccccc1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC[C@H]1NC(=O)CN(Cc2ccccc2)C1=O
Temperature: 12.5 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (R)—N-BOC-2-aminobutyric acid (3.36 g) and ethyl N-benzylglycine (4.52 g) in dichloromethane (50 ml) at 15° C. was added dicyclohexylcarbodiimide (3.59 g). The temperature was maintained at 10-15° C. for a further 2 h and then allowed to stir at ambient temperature for a further 16 h. The mixture was filtered and the mother liquor collected and solvent evaporated under reduced pressure. The residue was re-dissolved in dichloromethane (20 ml) and hydrogen chloride gas passed through the mixture for 20 minutes. The mixture was quenched with aq. saturated sodium bicarbonate solution and extracted with ethyl acetate, collected, dried (MgSO4) and solvent evaporated under reduced pressure to leave a colourless oil. This was purified by crystallisation from ether/iso-hexane mixtures to give the subtitle compound as a white solid. Yield: 1.35 g
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:10]1=[O:20].[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([CH:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[C:10]3=[O:20])=[C:6]([Cl:21])[CH:5]=2)=[CH:36][CH:35]=1)=[O:33]
Reactant: O=C1[C@H](Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCOCC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCOCC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
Treat a solution of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (3.0 g, 6.3 mmol), 4-methoxycarbonylphenylboronic acid (2.3 g, 13 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.73 g, 0.63 mmol) in dimethoxyethane (40 mL) with 2M aqueous potassium carbonate (9.5 mL). Heat the mixture to 80° C. overnight. Cool to room temperature, quench with 1N hydrochloric acid and extract with ethyl acetate. Wash the organic layer with brine, dry over magnesium sulfate, and filter. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to afford 2.56 g (88%) of desired product: MS (m/z): 462 (M+).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:14]=[C:15]([CH2:16][C:17]([OH:19])=[O:18])[C:5]=3[C:4]=2[CH:3]=1.C([O-])=O.[NH4+].ClCCl>C(O)C.[Pd]>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][CH:2]=[CH:3][C:4]=2[C:5]2[C:15]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:12](=[O:26])[C:6]1=2
Reactant: Cn1c2ccc(Cl)cc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Product: Cn1c2ccccc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Yield: 100 %

Procedure:
A solution of 3.3 g (9 mmol) of 8-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid, of 2.8 g (44 mmol) of ammonium formate and of 1.8 g of 10% palladium-on-charcoal in 500 ml of ethanol is heated at reflux for 5 h. The reaction mixture is cooled, dichloromethane is added, the catalyst is removed by filtration through diatomaceous earth and the solvent is evaporated under reduced pressure. 3 g (9 mmol) of compound are obtained, which compound is used as is in the following stage.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12]S(C)(=O)=O)=[CH:9][CH:10]=2)[C:5]([C:17]([O:19]C)=[O:18])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5]([C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)c2ccc(OS(C)(=O)=O)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Br)c2ccc(O)cc12

Procedure:
To a solution of the the product from Step F (802 mg, 2.23 mmol) in 50 mL of THF was added 10 mL of 2N NaOH solution, and the reaction was heated at reflux overnight. The solution was acidified with 1N HCl and extracted with 3× EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give a solid, which was triturated with dichloromethane to give the titled product.
Reaction SMILES: C(OC([N:8]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1)[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:30]2[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=2)[CH2:33][S:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:29])[CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C([O-])(O)=O.[Na+]>[N:21]1([C:19]2[CH:18]=[CH:17][C:16]([NH:27][C:28]([C:30]3[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=3)[CH2:33][S:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:29])=[C:15]([C:11]3[CH:10]=[C:9]([NH:8][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:53])([F:54])[F:52])[CH:46]=4)[CH:14]=[CH:13][N:12]=3)[CH:20]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(N(Cc3cccc(C(F)(F)F)c3)C(=O)OC(C)(C)C)ccn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of methyl 3-(3-(2-(4-(tert-butoxycarbonyl(3-(trifluoromethyl)benzyl)amino)pyridin-2-yl)-4-(piperidin-1-yl)phenylcarbamoyl)-benzylthio)propanoate (800 mg, 1.05 mmol, 1.00 equiv) in dichloromethane (2 mL), and 2,2,2-trifluoroacetic acid (5 mL). The resulting solution was stirred for 3 h at room temperature. The reaction progress was monitored by LCMS. The resulting solution was diluted with 20 mL of NaHCO3 (aq), extracted with 3×50 mL of dichloromethane, and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether:ethyl acetate (5:1). The product was obtained as 200 mg (29%) of a yellow solid.