Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)=[C:9]([NH2:22])[N:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl>[Br:30][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)[N:15]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(OCCC2CC2)nc2c1ncn2C1CCCCO1
Solvent: ClC(Cl)Cl
Product: Nc1nc(OCCC2CC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 1 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
2-[(2-Cyclopropylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.579 g) was dissolved in chloroform (15 mL) and was cooled in an ice bath to 1° C. NBS (1.02 g) was added gradually, keeping the reaction temperature below 2° C. The reaction was stirred for 30 mins (with cooling in an ice bath) before being allowed to warm to room temperature. The reaction was then stirred for 6 h. Chloroform (50 mL) was added and the mixture was partitioned with water (50 mL) and was separated using a hydrophobic frit. The organics were evaporated under reduced pressure to give the title compound as a brown foam (1.867 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16](Br)=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21]SC>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:21][CH3:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSSC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)s2)CC1
Product: CSc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Yield: 78 %

Procedure:
Prepared in analogy to example 4 (b) from 4-(5-bromo-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 4(a)) and dimethyl disulphide. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a yellow crystalline solid (yield 78%). MS (m/e): 316.3 (M+H+, 100%).
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][CH:17]=[N:18][C:12]=3[CH:11]2[C:19]([O:21][CH3:22])=[O:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:31]([N:50]1[C:54]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]2[CH:66]=[CH:65][C:64]([CH2:67]Br)=[CH:63][CH:62]=2)=[N:53][N:52]=[N:51]1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:23]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([N:10]2[CH2:15][CH2:14][C:13]3[N:16]=[CH:17][N:18]([CH2:67][C:64]4[CH:63]=[CH:62][C:61]([C:56]5[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=5[C:54]5[N:50]([C:31]([C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=6)([C:38]6[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=6)[C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:51]=[N:52][N:53]=5)=[CH:66][CH:65]=4)[C:12]=3[CH:11]2[C:19]([O:21][CH3:22])=[O:20])=[O:9])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)C1c2nc[nH]c2CCN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1c2c(ncn2Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)CCN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 11.8 %

Procedure:
Methyl 5-diphenylacetyl-4,5,6,7-tetrahydroimidazo-[4,5-c]pyridine-4-carboxylate (1.60 g) is dissolved in dimethylformamide (20 ml), and thereto is added sodium hydride (60% oil-dispersion, 176 mg) under ice-cooling. The mixture is stirred at 0° C. for 20 minutes, and thereto is added [2'-(1-trityl-1H-tetrazol-5-yl)bipheyl-4-yl]methyl bromide (2.40 g), and the mixture is stirred under ice-cooling for one hour, and further at room temperature for one hour. The reaction solution is concentrated under reduced pressure, and to the residue are added chloroform and water. The organic layer is dried, and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/methanol=100:1) to give methyl 5-diphenylacetyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (430 mg) as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>C1COCC1.CCOC(C)=O>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:10]3[N:9]=[C:8]([C:6]4[CH:5]=[C:4]([C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=2)(=[O:22])=[O:21])=[CH:37][CH:36]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: NCc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NCc4ccc(F)cc4)c3)n2)n1
Yield: 46.6 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-fluorobenzylamine (0.23 ml, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.110 g, 46%) as a white solid. MS (ISP) 578.2 [(M+H)+]; mp 175° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12](OC)=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[CH3:1][S:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COC(=O)c1ccc2nc(SC)oc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CSc1nc2ccc(CO)cc2o1
Temperature: -30 °C
Reaction time: 15 h
Yield: 53.9 %

Procedure:
To a stirred solution of methyl 2-(methylthio)benzo[d]oxazole-6-carboxylate (4.24 g, 19 mmol) from Step 1 of this Example in anhydrous DCM (100 mL) under an argon atmosphere at −78° C. was added dropwise diisobutylaluminum hydride (1.0 M solution in DCM, 40 mL, 40 mmol). The mixture was allowed to warm to −30° C. over 2 h. The reaction was quenched by addition of saturated aq sodium potassium tartrate and the resulting mixture stirred at rt for an additional 15 h. The organic layer was separated and the aqueous layer extracted with additional DCM (×2). The combined organic layers were washed with water dried over MgSO4, filtered, and concentrated under reduced pressure to afford (2-(methylthio)benzo[d]oxazol-6-yl)methanol (2 g, 54%) as a tan solid that did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 7.51-7.61 (m, 2H), 7.28 (d, J=8.3 Hz, 1H), 5.34 (t, J=5.7 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H), 2.76 (s, 3H). LCMS (ESI) m/z 196 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH3:17])[C:7]=1[CH2:18][CH2:19][CH2:20][CH3:21])=[O:5])C.[OH-].[Na+]>CO>[CH2:18]([C:7]1[C:8]2[C:13](=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[C:4]([OH:5])=[O:3])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1c(C(=O)OCC)ccc2c(OC)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1c(C(=O)O)ccc2c(OC)cccc12

Procedure:
As in Example 112, 1-butyl-5-methoxy-2-naphthalenecarboxylic acid ethyl ester (3.45 g) in methanol (40 mL) was saponified with 2N sodium hydroxide solution (10 mL) at reflux for 1.75 hours. 3.1 g of crude acid, mp 151°-153° C., was obtained from the usual work up and crystallization of a sample from diethyl ether-hexane gave 1-butyl-5-methoxy-2-naphthalenecarboxylic acid, mp 154°-155° C. Anal. Calcd for C16H18O3 : C, 74.39; H, 7.02 Found: C, 74.05; H, 7.05
Reaction SMILES: [CH:1]([O:3][C@@H:4]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:6]([CH2:7][C:8](=[O:33])[C@@H:9]3[C@@H:24]2[CH2:23][C@H:22]([O:29][CH:30]=[O:31])[C@@:21]2([CH3:32])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:20])[CH2:15][CH2:16][C:17](O)=[O:18])[CH2:5]1)=[O:2].C(N(CC)CC)C.[NH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44].C(OC(N1C2C(=CC=CC=2)C=CC1OCC)=O)C>C(OCC)(=O)C>[CH:1]([O:3][C@@H:4]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:6]([CH2:7][C:8](=[O:33])[C@@H:9]3[C@@H:24]2[CH2:23][C@H:22]([O:29][CH:30]=[O:31])[C@@:21]2([CH3:32])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:20])[CH2:15][CH2:16][C:17]([NH:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44])=[O:18])[CH2:5]1)=[O:2]
Reactant: CC(C)(N)CO
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3C[C@H](OC=O)[C@]12C
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@H](CCC(=O)NC(C)(C)CO)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](OC=O)CC[C@]4(C)[C@H]3C[C@H](OC=O)[C@]12C
Temperature: 25 °C

Procedure:
To a stirred solution of 3α,12α-diformyloxy-7-oxo-5β-cholan-24-oic acid (19 g) in 400 ml of ethyl acetate were added 8.0 ml of triethylamine, a solution of 6.0 ml of 2-amino-2-methyl-1-propanol in 50 ml of ethyl acetate, and 15 g of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline and the mixture was refluxed for 5 hrs. After cooling to room temperature, the reaction mixture was washed successively with water (50 ml×1), 1N HCl solution (50 ml×4), water (50 ml×1), 5% NaHCO3 solution (50 ml×2), and then water to neutrality (50 ml×3). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to give an oily residue (21.5 g) which could not be crystallized. PMR (δ ppm): 0.66 (3H, s, 18--CH3), 0.85 (3H, d, J=6 Hz, 21--CH3), 1.08 (3H, s, 19--CH3), 1.53 (6H, s, --C(CH3)2 --), 3.88 (2H, s, --CH2OH), 4.71 (1H, m, 3β--H), 5.22 (1H, m, 12β--H), 7.58 (1H, s, --NH--), 8.03 and 8.18 (2H, s, 2×--COH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:20]([O-:22])=[O:21])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=O)[CH2:13]2.P(Br)(Br)([Br:30])=O.N1C=CN=C1>ClCCCl>[Br:30][C:14]1[NH:15][C:16]2[C:12]([CH:13]=1)=[C:11]([N+:20]([O-:22])=[O:21])[C:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:4][C:3]=1[O:2][CH3:1])=[CH:18][CH:17]=2
Reactant: O=P(Br)(Br)Br
Reactant: COC(=O)Cc1ccc(Oc2ccc3c(c2[N+](=O)[O-])CC(=O)N3)c(OC)c1
Agent: c1c[nH]cn1
Solvent: ClCCCl
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(Br)cc3c2[N+](=O)[O-])c(OC)c1
Temperature: 90 °C

Procedure:
To a solution of methyl 2-(3-methoxy-4-(4-nitro-2-oxoindolin-5-yloxy)phenyl)acetate (0.177 g, 0.476 mmol) in DCE (10 mL), phosphoryl tribromide (0.273 g, 0.952 mmol) was added dropwise at room temperature. The mixture was heated at 90° C. for 1 h, and then imidazole (0.049 g, 0.714 mmol) was added and heated for another 2 h. The reaction was quenched with ice, adjusted PH to 8 and diluted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. MS ESI (pos.) m/z: 435.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[O:13]([CH2:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([N:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[CH2:20][O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:28][CH2:27]2)[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=C(COc1ccccc1)N1CCNCC1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(C(=O)COc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 5-bromo-4-chloro-3-nitro-pyridin-2-ylamine (0.126 g, 0.50 mmol) and isopropanol (9 ml) was added 2-phenoxy-1-(piperazin-1-yl)ethanone×HCl (0.141 g, 0.55 mmol) followed by diisopropylethylamine (0.20 ml, 1.10 mmol). The reaction mixture was heated at 45° C. for 22 h, then allowed to cool to room temperature and diluted with isopropanol (4 ml). The precipitate was collected by filtration and washed with isopropanol and diethyl ether. The title compound was thus obtained as a yellow solid (0.163 g, 75%). 1H-NMR (500 MHz, DMSO-d6) 3.08 (br s) and 3.59 (br s) (8H, 2× piperazine N(CH2)2), 4.87 (s, 2H, COCH2O), 6.93 (m, 3H) and 7.28 (m, 2H) (ArH), 7.08 (s, 2H, NH2), 8.21 (s, 1H, 6-H);
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[C:23](Cl)(Cl)=[S:24].C(=O)([O-])O.[Na+]>O1CCCC1>[N:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]2)=[CH:17][CH:18]=1)=[C:23]=[S:24]
Reactant: S=C(Cl)Cl
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(N=C=S)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
Triethylamine (5.1 mL, 36.6 mmol) was added to a solution of 4-(4-methylpiperazin-1-ylmethyl)phenylamine (F652-02, 3.14 g, 15.3 mmol) in tetrahydrofuran (250 mL), and after cooling by ice, thiophosgene (1.11 mL, 14.6 mmol) was added. After stirring at room temperature overnight, aqueous sodium hydrogencarbonate was added to the mixture. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove sodium sulfate, and the solvent was distilled off under reduced pressure to obtain brown oil. The brown oil was purified by silica gel column chromatography (chloroform, methanol) to obtain 1-(4-isothiocyanatobenzyl)-4-methylpiperazine (F652-03, brownish oil, 2.64 g, 70%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:47][CH2:46][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26]([CH3:44])[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[N:39][C:38]2=[CH:42][C:35]3=[N:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:48])([O:17][CH2:18][CH:19]=[CH:20][CH2:21][C@H:22]([CH3:45])[O:23][C:24]2[CH:25]=[C:26]([CH3:44])[CH:27]=[CH:28][C:29]=2[C:30]2[CH:43]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:46][CH2:47]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(C)ccc1-c1cccc-3c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2c(c1)O[C@@H](C)CC=CCOC1(C)CCN(CC1)c1c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(nn13)-c1cccc-2c1
Yield: 18.3 %

Procedure:
A mixture of methyl (2S)-2-(tert-butoxy)-2-[(22S)-4,18,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate (8 mg, 0.012 mmol), NaOH (0.061 mL, 0.061 mmol) in MeOH (1.5 mL) was refluxed for 3 h. It was then filtered and prep-HPLC to isolate 1.4 mg (18%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.09 (s, 1H), 6.99 (s, 1H), 6.82 (d, J=7.3 Hz, 1H), 6.30 (br. s., 1H), 5.75-5.59 (m, 2H), 4.77 (t, J=11.6 Hz, 1H), 4.58 (br. s., 1H), 4.01-3.92 (m, 1H), 3.91-3.83 (m, 1H), 3.60-3.20 (m, 2H), 2.75 (d, J=7.3 Hz, 1H), 2.51 (s, 3H), 2.40-2.26 (m, 4H), 2.17 (br. s., 1H), 2.03 (d, J=13.7 Hz, 1H), 1.86 (d, J=12.5 Hz, 1H), 1.68-1.53 (m, 2H), 1.22 (s, 3H), 1.16 (s, 9H), 1.05 (d, J=6.1 Hz, 3H). LCMS (M+1)=639.3.
Reaction SMILES: [Cl:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([Cl:13])=[CH:5][C:3]=1[NH2:4].[F:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[C:17]([N:19]=[C:20]=[S:21])=[O:18]>C1C=CC=CC=1>[Cl:1][C:2]1[C:8]([C:9]([F:11])([F:10])[F:12])=[CH:7][C:6]([Cl:13])=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:17](=[O:18])[C:16]1[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:15]=1[F:14])=[S:21]
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1Cl
Reactant: O=C(N=C=S)c1c(F)cccc1F
Solvent: c1ccccc1
Product: O=C(NC(=S)Nc1cc(Cl)cc(C(F)(F)F)c1Cl)c1c(F)cccc1F
Reaction time: 10 h
Yield: 64.3 %

Procedure:
To a solution of 2,5-dichloro-3-trifluoromethylaniline (0.5 g) in 10 ml of dry benzene was added a solution of 2,6-difluorobenzoylisothiocyanate (0.45 g) in 5 ml of dry benzene under water-cooling and the solution was stirred for 10 hours. The benzene was then distilled off under reduced pressure and the residue was washed with n-hexane to obtain the desired product 0.6 g. (m.p. 136°-141° C.)
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[CH3:14][O:15][C:16]1[CH:40]=[CH:39][C:19]([CH2:20][N:21]2[C:25]([NH:26][CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29](OCC)=[O:30])=[CH:24][CH:23]=[N:22]2)=[CH:18][CH:17]=1>C(O)C>[OH:30][C:29]1[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:27][N:26]=[C:25]2[N:21]([CH2:20][C:19]3[CH:39]=[CH:40][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[N:22]=[CH:23][C:24]=12
Reactant: CCOC(=O)C(=CNc1ccnn1Cc1ccc(OC)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1O
Temperature: 45 °C

Procedure:
Diphenyl ether (180 ml) was heated to about 230° C. (Internal temperature 200-210° C.) under inert atmosphere in a round bottom flask fitted with distillation set and a solution of diethyl ({[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]amino}methylidene)propanedioate (85 gm, 0.227 mol) (example 2) in absolute ethanol (130 ml) was added dropwise. The reaction mixture was heated for about 2 hours. Volatile solubles were distilled out. The mixture was cooled to 45° C. and methanol (150 ml) was added dropwise. Solid, which precipitated out was filtered and washed with methanol and hexane and dried under vacuum.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:8]([O:20][CH3:21])=[CH:9][CH:10]=[C:11]([C:16](OC)=[O:17])[C:12]=2[C:13](=O)[CH:14]=1)=[O:4].[NH2:22][NH2:23]>CCO>[CH3:21][O:20][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[O:17])[NH:23][N:22]=[C:13]3[CH:14]=[C:5]([C:3]([OH:2])=[O:4])[NH:6][C:7]=1[C:12]=23
Reactant: COC(=O)c1cc(=O)c2c(C(=O)OC)ccc(OC)c2[nH]1
Reactant: NN
Solvent: CCO
Product: COc1ccc2c(=O)[nH]nc3c2c1NC(C(=O)O)=C3
Temperature: 68 °C

Procedure:
6-Methoxy-3-oxo-2,7-dihydro-3H-pyrido[4,3,2-de]phthalazine-8-carboxylic acid hydrozide (39) To a suspension of 38 (0.45 g, 1.54 mmol) in EtOH (20 mL) was added hydrazine (1 mL) at room temperature. The reaction mixture was heated at 68° C. for 1.5 h and then cooled to room temperature. The resulting precipitate was filtered and washed with Et2O to afford a white solid (39, 0.31 g, 74%). 1H NMR (DMSO-d6, 300 MHz) δ 10.5 (br s, 1H), 9.0 (br s, 1H), 7.15-7.25 (m, 2H), 7.1 (br s, 1H), 6.8 (br s, 1H), 4.90 (br s, 2H), 4.03 (s, 3H). Mp: 305-307° C.; Anal. Calcd for C12H11N5O3.(0.75H2O): C, 50.26; H, 4.39; N, 24.42. Found: C, 50.33; H, 4.46; N, 22.04.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.N1([CH:25]=[O:26])CCCCC1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[N:7]1[C:2]([CH:25]=[O:26])=[CH:3][CH:4]=[CH:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: O=CN1CCCCC1
Reactant: Brc1cccc(-c2ccccn2)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(-c2ccccn2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A cooled (−78° C.) solution of commercially available 6-bromo-2,2′-bipyridine (600 mg; 2.55 mmol) in anh. THF (10 ml) was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (1.60 ml; 2.56 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 30 min. Piperidine-1-carbaldehyde (577 mg; 5.10 mmol) was added dropwise to the cooled (−78° C.) reaction mixture, and stirring was continued at −78° C. for 30 min. Aq. sat. NH4Cl (25 ml) and AcOEt (50 ml) were added, and the separated organic layer was further washed with brine (20 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (toluene/AcOEt=8/2) afforded [2,2′-bipyridine]-6-carbaldehyde as a dark-purple solid. LC-MS (conditions C): tR=0.75 min.; [M+H]+: 185.24 g/mol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([NH2:15])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22].C(N(CC)C(C)C)(C)C>C(Cl)Cl.Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([NH:15][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=2)=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)Nc1ncc(N)cc1Br
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ncc(NC(=O)c2cccc(F)c2)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
(5-Amino-3-bromo-pyridin-2-yl)-carbamic acid tert-butyl ester (50 mg, 0.17 mmol), 3-fluoro-benzoyl chloride (28 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.03 mL, 0.19 mmol) were dissolved in CH2Cl2 (2 mL), and stirred or 1 h at 0° C. The reaction solution was diluted with 1 M HCl/CH2Cl2, and filtered through an Extrelut column. The column was washed with CH2Cl2, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 20 to 70% EtOAc/hexanes to provide of [3-bromo-5-(3-fluoro-benzoylamino)-pyridin-2-yl]-carbamic acid tert-butyl ester (47 mg, 66% yield) as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21](=[O:30])[NH:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[N:27]1[CH:28]=[CH:29][C:24]([CH2:23][NH:22][C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]4)[CH:20]=[CH:19][N:18]=2)=[O:30])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccnc(C(=O)NCc4ccncc4)c3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NCc1ccncc1)c1cc(-c2ccc3[nH]c(C(=O)O)cc3c2)ccn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To 5-{2-[(Pyridin-4-ylmethyl)-carbamoyl]-pyridin-4-yl}-1H-indole-2-carboxylic acid ethyl ester (160 mg, 0.4 mmol) in ethanol (4 ml) is added aqueous sodium hydroxide (2N) and the mixture is stirred at 70° C. for 2 hours. The reaction is cooled, diluted with water (30 ml), acidified with aqueous HCl (3N) to pH 4-5, extracted with dichloromethane (50 ml). The combined organic layer is dried (sodium sulfate), filtered and evaporated in vacuo to give the title compound, 95 mg, 64%, LC/MS ESI m/z (M+H)+=273.8.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40](OC)=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)(C1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C(C)C.Cl.[CH3:87][O:88][C:89](=[O:93])[C@H:90]([CH3:92])[NH2:91]>>[OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:91][C@@H:90]([CH3:92])[C:89]([O:88][CH3:87])=[O:93])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)[C@H](C)N
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Agent: CC(C)C(O)(c1ccc2cc(C(=O)O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Yield: 162.4 %

Procedure:
In a manner to that described in Example 9-(i), methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (533 mg) was converted to 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid, which was reacted with L-alanine methyl ester hydrochloride (283 mg) in a similar manner as described in Example 24-(i) to give the titled compound (604 mg) as a colorless powder.