Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:35]=[C:36]([CH:38]4[CH2:41][N:40]([C:42]5[CH:51]=[CH:50][C:49]6[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=6)[N:43]=5)[CH2:39]4)[N:37]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OCC5C=CC=CC=5)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1>CO.C(Cl)Cl.[Pd]>[N:19]1([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:35]=[C:36]([CH:38]5[CH2:39][N:40]([C:42]6[CH:51]=[CH:50][C:49]7[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=7)[N:43]=6)[CH2:41]5)[N:37]=[C:8]4[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(C5CN(c6ccc7ccccc7n6)C5)cn34)cn2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: c1ccc2nc(N3CC(c4cn5c(-c6ccc(N7CCNCC7)nc6)cnc(N6CCOCC6)c5n4)C3)ccc2c1

Procedure:
Compound 29d (100 mg, 0.147 mmol) in MeOH (15 mL) and DCM (5 mL) was hydrogenated over 10% Pd/C (20 mg) overnight under balloon pressure. The reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated and dried under reduced pressure to obtain the title compound 99. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.36 (d, J=2.3 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.84-7.92 (m, 2H), 7.71 (d, J=7.8 Hz, 1H), 7.49-7.60 (m, 2H), 7.33-7.37 (m, 1H), 7.19-7.25 (m, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 5.77 (s, 1H), 4.44-4.52 (m, 2H), 4.24 (t, J=6.8 Hz, 2H), 4.10-4.20 (m, 4H), 3.68-3.78 (m, 8H), 3.36 (br. s., 2H), 2.97-3.10 (m, 2H), 2.56 (br. s., 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C31H33N9O: 548.3 (M+H). Found 548.3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:16]=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].[O-:18][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]([OH:18])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCn1cc(C=O)c2ccc(C(=O)OC)cc21
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCn1cc(C(=O)O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (800 mg, 3.5 mmol), prepared as shown in example 1P, step A, is dissolved in acetone (98 mL). A solution of KMnO4(655 mg, 4.15 mmol) in H2O (31 mL) is added. The reaction mixture is stirred at room temperature for 90 minutes. Another addition of KMnO4 (108 mg) in H2O (6 mL), followed by stirring for another 45 minutes is required to drive the reaction to completion. The reaction mixture is then quenched with 10% H2O2 (1.5 mL). The mixture is filtered through celite. The filtrate is stripped down under vacuum to roughly ⅓ of the volume. The residue is acidified with 6N HCl, and is extracted into ethyl acetate. The solids isolated from the ethyl acetate layer are triturated with acetone to yield 1-ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (696 mg, 79%) as a light orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]#[C:9][CH2:10][CH3:11]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)#[C:9][CH2:10][CH3:11]
Reactant: C#CCC
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CCC#Cc1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.3 %

Procedure:
To a solution of 2-bromopyridine (50 g) dissolved in diethylamine (500 mL) was added dichlorobis(triphenylphosphine)palladium(II) (2.2 g) and copper iodide (0.3 g), and the reaction mixture was stirred for 4 hours at room temperature while introducing 1-butyne (100 g) as a gas. The resulting reaction mixture was bubbled with nitrogen, and then ethyl acetate was added. After the reaction mixture was filtered through celite to remove insoluble residue, the filtrate was washed with water and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (35 g) was obtained as a brown oil from the n-hexane:ethyl acetate (5:1) fraction.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:10](=[CH:11][S:12][C:13]=2[N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.O.NN>C(O)C>[NH2:15][C:13]1[S:12][CH:11]=[C:10]2[CH2:9][C:8]3[C:3]([C:2](=[O:1])[C:14]=12)=[CH:4][CH:5]=[CH:6][CH:7]=3
Reactant: O=C1c2ccccc2Cc2csc(N3C(=O)c4ccccc4C3=O)c21
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1scc2c1C(=O)c1ccccc1C2
Temperature: 25 °C

Procedure:
To a suspension of 2-[4-oxo-9H-naphtho[2,3-c]thiophene-3-yl]-isoindole-1,3-dione (0.45 mmol, Example 32, Part G) in absolute ethanol (5 mL) is added hydrazine hydrate (0.5 mmol). The mixture is heated to reflux for one hour, cooled to room temperature, concentrated in vacuo, and the residue dissolved in methylene chloride. The solution is chilled to 5° C. for one hour, during which time the phthaloyl hydrazide precipitates. The precipitate is removed by filtration, the filtrate concentrated in vacuo, and the residue purified by column chromatography on silica gel, eluting with a 4:1 mixture of petroleum ether and ethyl acetate. Fractions containing the product are collected, evaporated, and the product recrystallized.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:39]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)=[O:46])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1cccnc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(=O)c3cccnc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and N-methoxy-N-methylnicotinamide.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([O:10][CH2:11][C@H:12]([CH3:34])[O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:22]=1)[C:17]([OH:19])=[O:18])([CH3:9])([CH3:8])[CH3:7]>CC(OC)(C)C>[C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([O:10][CH2:11][C@H:12]([CH3:34])[O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:22]=1)[C:17]([O:19][NH2+:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])([CH3:9])([CH3:8])[CH3:7]
Reactant: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Solvent: CC(C)(C)N
Solvent: COC(C)(C)C
Product: C[C@@H](COC(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O[NH2+]C(C)(C)C)c1
Temperature: 25 °C
Yield: 181.5 %

Procedure:
A solution of tert-butylamine was prepared by charging tert-butylamine (0.31 L, 2.94 mol) to a reaction vessel containing MTBE (2.27 L). The solution was stirred at ambient temperature and then charged into a second reaction vessel containing 3-[(1S)-2-tert-butoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]benzoic acid (1.13 Kg, 267 mol) and MTBE (2.54 L). The temperature was maintained between 20-30° C. during the addition, the residual tert-butylamine was washed in with MTBE (0.57 L). The reaction mixture was heated to 38-40° C. for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to 18-25° C. over 1-2 hours and then held until crystallisation occurred. The product was isolated by filtration washed twice with MTBE (2.28 L), and dried in a vacuum oven at 38-40° C. This resulted in (1.32 Kg, 100% yield) of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][C@H:17]([CH:20]([O:25][C:26]2[C:27]([CH3:33])=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:16]1)=O)(C)(C)C>COC1C=CC=CC=1.ClCCl>[Cl:32][C:29]1[N:28]=[C:27]([CH3:33])[C:26]([O:25][CH:20]([C@H:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)[CH2:21][CH:22]2[CH2:23][CH2:24]2)=[CH:31][CH:30]=1
Reactant: Cc1nc(Cl)ccc1OC(CC1CC1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(Cl)ccc1OC(CC1CC1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
Add trifluoroacetic acid (1.51 g, 1.0 mL, 13.2 mmol) to a solution of (3S)-3-[1-(6-chloro-2-methyl-3-pyridyloxy)-2-cyclopropyl-ethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (S-1) (99.0 mg, 0.260 mmol) in methoxybenzene (1.0 mL) and dichloromethane (2.0 mL). Stir under nitrogen at room temperature for 1 h. Load the mixture directly onto a pre-packed SCX column and rinse with CH2Cl2 followed by CH3OH. Elute with 2M NH3 in methanol and concentrate under reduced pressure to give 58 mg (79%) of (3S)-3-[1-(6-chloro-2-methyl-3-pyridyloxy)-2-cyclopropyl-ethyl]-pyrrolidine (S-1). MS (m/z)=281.2 [M+1]
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[N:5]=[C:4]([OH:13])[CH:3]=1.[C:14]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[N:5]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH:7]=1
Reactant: Oc1cc(F)cc(-c2nccs2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc(F)cc(-c2nccs2)n1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 4-fluoro-6-(thiazol-2-yl)pyridin-2-ol (35 mg, 0.18 mmol) as a solution in DMF (1 mL). To the vial was added K2CO3 (49 mg, 0.36 mmol), then iodomethane (25 μL, 0.40 mmol). The vial was capped with a PTFE-lined cap and then placed in a 40° C. heating block with stirring for 2 h. The reaction mixture was transfered to a 125 mL separatory funnel and was diluted with water (25 mL). The mixture was extracted with CH2Cl2 (2×25 mL). The combined organics were dried over MgSO4; filtered; the concentrated in vacuo. The resulting residue was subjected to SiO2 column chromatography (hexanes:EtOAc, 100:0 to 50:50) to afford 2-(4-fluoro-6-methoxypyridin-2-yl)thiazole as a white solid (31 mg, 82%). 1H-NMR (500 MHz, CDCl3) δ 7.92 (d, J=3.2 Hz, 1H), 7.66 (dd, J=1.9, 1.1 Hz, 1H), 7.48 (d, J=3.3 Hz, 1H), 6.44 (d, J=2.0 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH:36]1([C:39]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[O:40])[CH2:38][CH2:37]1>ClCCl.O.C(N(CC)CC)C>[CH:36]1([C:39]([N:41]2[CH2:46][CH2:45][N:44]([C:8]([C:7]3[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=3)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[CH2:43][CH2:42]2)=[O:40])[CH2:37][CH2:38]1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: O=C(C1CC1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cccc(C(=O)N2CCN(C(=O)C3CC3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a solution of 3-(methoxycarbonyl)benzoic acid (0.9 g, 5 mmol) in dichloromethane (20 mL), 1-hydroxybenzotriazole (0.75 g, 5.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.06 g, 5.5 mmol) and triethyl amine (2 mL) were added. The mixture was stirred at room temperature for 30 min, and then cyclopropyl(piperazin-1-yl)methanone (1.0 g, 5 mmol) was added and the mixture was stirred at room temperature for 16 h. The resulting mixture was added water (50 mL) and extracted with dichloromethane (100 mL×3), the organic phase was washed with sodium bicarbonate, brine and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate 20:1 to 2:1), 0.95 g of methyl 3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)benzoate as an oil was obtained, Yield 60%. 1H-NMR (400 MHz, CDCl3) 0.80-0.82 (m, 2H), 1.00-1.04 (m, 2H), 1.24-1.27 (m, 1H), 3.25-3.78 (m, 8H), 3.94 (s, 3H), 7.52-7.55 (t, J=7.6 Hz, 1H), 7.63-7.65 (d, J=7.6 Hz, 1H), 8.09-8.14 (m, 2H); LC-MS (ESI) m/z: 317 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11].[C:18]12([C:28](O)=[O:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2>>[CH3:1][C:2]1[N:3]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])/[C:4](=[N:8]/[C:28]([C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)=[O:29])/[S:5][C:6]=1[CH3:7]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CC(Br)c1ccccc1
Reactant: Cc1nc(N)sc1C
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(C(C)c2ccccc2)c1C

Procedure:
4,5-dimethylthiazol-2-ylamine, (1-bromo-ethyl)benzene and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.51-1.75 (m, 12H) 1.91 (d, J=6.86 Hz, 6H) 2.03-2.11 (m, 3H) 2.14 (s, 3H) 5.98-6.31 (m, 1H) 7.21 (d, J=8.11 Hz, 2H) 7.25 (t, J=7.33 Hz, 1H) 7.34 (t, J=7.49 Hz, 2H); MS (ESI) m/z 394 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:11][CH2:12][C:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14].CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:17]([NH:16][C:13]([CH3:15])([CH3:14])[CH2:12][Cl:11])=[O:18])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2ncsc2c1
Reactant: CC(C)(CCl)N=C=O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(CCl)NC(=O)Nc1ccc2ncsc2c1
Temperature: 25 °C
Yield: 18.5 %

Procedure:
Benzothiazol-6-ylamine (1.8 g, 12.00 mmol) was added portion wise to solution of 1-chloro-2-isocyanato-2-methyl-propane (2 g, 13.60 mmol) in toluene (20 mL) over a period of 5 minutes. The resulting mixture was stirred at room temperature for 2½ days. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was concentrated and extracted with ethylacetate. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 630 mg of the product (16.57% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].Cl[CH2:39][C:40](=[O:42])[CH3:41].C(N(CC)CC)C.O>CC(=O)CC>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:40]([CH3:41])([OH:42])[CH2:39][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)CCl
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC1(C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
To a solution of (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (134 mg, 0.26 mmol) in butanone (1.9 mL) was added chloroacetone (0.03 mL, 0.33 mmol) and triethylamine (0.04 mL, 0.28 mmol), and the reaction was stirred at room temperature for 16 hours. The mixture was transferred to a separatory funnel containing water (5 mL) and extracted twice with dichloromethane. The organic extracts were filtered through a phase separator, adsorbed onto silica gel, and purified by flash chromatography (0-25% ethyl acetate/B, where B=1:1 dichloromethane/hexanes) to provide the title compound as a yellow solid (117 mg, 79%): mp 114-116° C.; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.19 (dd, J=10.1, 6.2 Hz, 3H), 7.79 (dd, J=11.5, 4.7 Hz, 4H), 7.50-7.44 (m, 1H), 7.44-7.36 (m, 4H), 7.29-7.25 (m, 1H), 3.55 (d, J=11.5 Hz, 1H), 3.45 (s, 1H), 3.34 (d, J=11.5 Hz, 1H), 2.98 (dt, J=13.8, 6.9 Hz, 1H), 1.43 (s, 3H), 1.27-1.16 (m, 6H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 582 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](Cl)[N:18]=3)[C:13](=[O:21])[C:12]([C:22]([OH:24])=[O:23])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8].Cl.Cl.[NH2:27][CH:28]1[CH2:31][NH:30][CH2:29]1.CN1CCCC1.C(OCC)C>C(#N)C.C(O)C>[NH2:27][CH:28]1[CH2:31][N:30]([C:17]2[N:18]=[C:19]3[C:14]([C:13](=[O:21])[C:12]([C:22]([OH:24])=[O:23])=[CH:11][N:10]3[C:4]3[C:5]([F:9])=[CH:6][C:7]([F:8])=[C:2]([NH2:1])[CH:3]=3)=[CH:15][CH:16]=2)[CH2:29]1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3ccc(Cl)nc32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CC#N
Solvent: CCO
Solvent: CCOCC
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3ccc(N4CC(N)C4)nc32)c(F)cc1F
Temperature: 80 °C
Yield: 57.2 %

Procedure:
With stirring at 80° C., 100 mg of 1-(3-amino-4,6-difluorophenyl)-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid was added to a solution of 61 mg of 3-aminoazetidine dihydrochloride and 119 mg of N-methylpyrrolidine in 3 ml of acetonitrile. The solution was stirred at 80° C. for 2 hours and 50 minutes. After the reaction solution was allowed to cool down, decantation with diethyl ether was carried out. The solid was dispersed by adding a small amount of ethanol and collected by filtration. The solid was washed with ethanol and then diethyl ether to give 63 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[Cl:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]23)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: Clc1cccc(Br)c1Cl
Product: Clc1cccc(Nc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)c1Cl

Procedure:
Using 1-bromo-2,3-dichlorobenzene and following the procedures described in EXAMPLE 33, Parts C and D, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)Carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 37 as a powder. 1H NMR (CDCl3,300 MHz) δ 1.79-1.89 (m, 2H), 2.58-2.69 (m, 1H), 2.79-3.25 (m, 7H), 3.41-3.50 (m, 1H), 3.60-3.68 (m, 2H), 3.74 (s, 2H), 6.01 (s, 1H), 6.73 (d, 1H, J=2 Hz), 6.81-6.85 (m, 3H), 6.95-6.98 (m 1H). LRMS (ES)+: 406 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]([O:17][CH2:18][CH3:19])=[CH2:16])CCC>[Cu]I.CN(C=O)C>[CH2:18]([O:17][C:15]([C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1)=[CH2:16])[CH3:19]
Reactant: COc1cccnc1Br
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Solvent: CN(C)C=O
Product: C=C(OCC)c1ncccc1OC
Temperature: 80 °C
Yield: 84.3 %

Procedure:
Add copper (I) iodide (38 mg, 0.2 mmol) to a mixture of 2-bromo-3-methoxy-pyridine (188 mg, 1.0 mmol), tributyl(1-ethoxyvinyl)tin (0.68 mL, 2.0 mmol), and DMF (anhydrous, 4 mL) in a sealed tube. Flush with N2, seal, heat at 80° C. for 3 h. Purify the mixture by flash chromatography on silica gel eluting with 0-30% EtOAc/hexanes to afford 2-(1-ethoxy-vinyl)-3-methoxy-pyridine (151 mg, 84%).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:8]=1)(=[O:3])N.Cl.C[O:28]CCO>>[CH2:10]([NH:9][C:7]1[CH:8]=[C:4]([C:1]([OH:28])=[O:3])[S:5][CH:6]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCNc1csc(C(N)=O)c1
Reactant: COCCO
Agent: Cl
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)O)c1

Procedure:
A mixture of 4.4 g. of 2-carbamyl-4-hexadecylaminothiophene, 50 ml. of methyl cellosolve, and 50 ml. of 6 N hydrochloric acid is refluxed for 40 hours and then allowed to cool. The solid is filtered and recrystallized from methanol. The solid is then dissolved in hot sodium bicarbonate solution, filtered, and the filtrate is acidified with concentrated hydrochloric acid. The resulting precipitate is collected and recrystallized from isopropanol to yield the product.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.Cl.[CH2:9]([C:11]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:10].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[N:6]=[C:5]([N:14]2[CH2:15][CH2:16][C:11]([CH2:9][CH3:10])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:13]2)[S:4][N:3]=1
Reactant: Clc1nsc(Cl)n1
Reactant: CCOC(=O)C1(CC)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC)CCN(c2nc(Cl)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
3,5-dichloro-1,2,4-thiadiazole (135 mg, 0.87 mmol) was added to a solution of ethyl 4-ethylpiperidine-4-carboxylate hydrochloride (190 mg, 0.87 mmol) and Triethylamine (264 mg, 2.61 mmol) in THF (9 mL) and stirred at rt for 1 h, giving a suspension, which was filtered, and the filtrate concentrated in vacuo to give ethyl 1-(3-chloro-1,2,4-thiadiazol-5-yl)-4-ethylpiperidine-4-carboxylate as a yellow oil (260 mg, 98%). ESI-MI m/z 304.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:5]([C:7]1[CH:8]=[C:9]([NH:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([CH3:25])[CH:16]=3)[C:11]=2[CH:26]=1)=[O:6].CO.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:5]([C:7]1[CH:8]=[C:9]([NH:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:10]2[N:14]=[CH:13][N:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([CH3:25])[CH:16]=3)[C:11]=2[CH:26]=1)=[O:6]
Reactant: COC(=O)c1ccc(-n2cnc3c(NCCC(F)(F)F)cc(C(=O)c4ccc(OC)c(F)c4)cc32)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)c2cc(NCCC(F)(F)F)c3ncn(-c4ccc(C(=O)O)c(C)c4)c3c2)cc1F
Temperature: 23 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
To a solution of 660 mg (1.25 mmol) methyl 4-{6-(3-fluoro-4-methoxybenzoyl)-4-[(3,3,3-trifluoropropyl)amino]-1H-benzimidazol-1-yl}-2-methylbenzoate which was prepared according to intermediate example 101b in 25 mL tetrahydrofurane and 8 mL methanol were added 6.2 mL of a 1M aqueous lithium hydroxide solution and the mixture was stirred at 23° C. overnight. Water was added, the mixture was acidified by the addition of a 1M hydrochloric acid and extracted with dichloromethane and methanol. The organic layer was washed with brine and dried over sodium sulfate. After filtration and removal of solvent the residue was purified by chromatography to give 632 mg (98%) of the title compound.