Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][S:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[C:15](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:15][N:8]1[C:7]2[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[S:11][CH2:10][C:9]1=[O:12]
Reactant: O=C([O-])[O-]
Reactant: O=C1CSc2cc([N+](=O)[O-])ccc2N1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1C(=O)CSc2cc([N+](=O)[O-])ccc21
Temperature: 50 °C
Yield: 90 %

Procedure:
To a stirred suspension of 3,4-dihydro-7-nitro-2H-1,4-benzothiazin-3-one (Step 2, 4.7 g, 22.3 mmol) and potassium carbonate (3.70 g, 26.8 mmol) in dry DMF (40 mL) in an ice bath is added iodomethane (4.16 mL, 66.8 mmol). The reaction mixture is taken out of the ice bath and heated at 50° C. for 1-2h. The resulting mixture is allowed to cool down. Water (35 mL) and ice are added and the precipitate is filtered off and washed with water (10 mL). The resulting solid is dried under high vacuum to give the title compound as a yellow solid (4.5 g, 90%), MS m/z 225.5 (M+H)+.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[CH3:19][N:20]1[CH2:24][CH2:23][C@@:22]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH2:25][C:26]#[CH:27])[C:21]1=[O:36].N(CC)CC>C1COCC1.[Cu](I)I>[CH3:19][N:20]1[CH2:24][CH2:23][C@@:22]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])([CH2:25][C:26]#[C:27][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[C:21]1=[O:36]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(I)n1
Reactant: C#CC[C@]1(NC(=O)OC(C)(C)C)CCN(C)C1=O
Agent: I[Cu]I
Solvent: CCNCC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Temperature: 20 °C
Reaction time: 18 h
Yield: 106.7 %

Procedure:
Copper Iodide (149.46 mg, 0.7800 mmol), followed by PdCl2(Ph3P)2 (275.41 mg, 0.3900 mmol) was added portionwise to a solution of 2-iodo-4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (4 g, 10.99 mmol) (which may be prepared as described in Description 6), tert-butyl N-[(3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]carbamate (1.98 g, 7.85 mmol) (which may be prepared as described in Description 4) and Et2NH (4.06 mL, 39.24 mmol) in THF (50 mL) under N2 and the reaction was stirred at 20° C. for 18 hrs. The solvent was evaporated and the residue was suspended in EtOAc and washed with water/sat. aq. NaHCO3. The organics were collected, dried (Na2SO4) and the solvent evaporated to afford a brown oil. This was purified using a Biotage SP4, with a 100 g SNAP cartridge, eluting with 50 to 100% EtOAc/i-hexane to afford tert-butyl N-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (D7) (4.09 g, 8.3726 mmol) as a pale yellow foam;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])[OH:6])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:7]1[C:8]([CH3:22])=[N:9][C:10]2[N:11]([N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=2)[C:12]=1[I:13])=[O:6])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c(C(O)C(=O)OCC)c(I)n2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)c1c(C)nc2cc(C(=O)OCC)nn2c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a mixture of ethyl 6-(2-ethoxy-1-hydroxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (3.7 g, 6.41 mmol) in CH2Cl2 (80 mL) was added Dess-Martin Periodinane (2.72 g, 6.41 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with ethyl acetate (500 mL) and washed with sat. aq. NaHCO3 solution (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (5-70% EtOAc/hexane) to afford the desired ethyl 6-(2-ethoxy-2-oxoacetyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (2.5 g, 5.8 mmol, 91% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 4.50 (dq, J=14.5, 7.1 Hz, 4H), 2.56 (s, 3H), 1.46 (t, J=7.2 Hz, 3H), 1.48 (t, J=7.2 Hz, 3H). LCMS (M+H)=431.87.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:4][CH2:3]1.N1C=CN=C1.[C:41]([Si:45](Cl)([CH3:47])[CH3:46])([CH3:44])([CH3:43])[CH3:42].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[Si:45]([O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)[CH2:6][CH2:7]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:47])[CH3:46]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O[Si](C)(C)C(C)(C)C)CC2)c2ccnn12
Reaction time: 2 h

Procedure:
To a solution of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.68 g) and imidazole (0.74 g) in N,N-dimethylformamide (20 mL) was added tert-butyl(chloro)dimethylsilane (1.1 g), and the mixture was stirred for 2 hr. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (1.89 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[CH:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[NH:33][CH2:32][C:31]=12>C(Cl)Cl>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:33]2[C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH2:36][N:30]3[CH:29]=[CH:28][CH:27]=[C:31]3[CH2:32]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 131.1 %

Procedure:
To a mixture of 1.93 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.13 ml of triethylamine. After stirring for 3 minutes, a mixture of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minutes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 48 hours and the volatiles are concentrated in vacuo to a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO3 and brine. The solution is dried with Na2SO4 and the volatiles concentrated in vacuo to give 3.0 g of a residue. A 300 mg sample of the residue is purified by thick layer chromatography using 10% ethyl acetate-methylene chloride to give 160 mg of the desired product. The remainder of the crude material is purified by flash chromatography using 10% ethyl acetate in methylene chloride to give the desired product as a residue which is crystallized from ethyl acetate to give 800 mg of the desired product as white crystals, m.p. 212°-215° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:21])[NH:8][C:9]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.Br[C:23]1[C:24]([C:30]([F:33])([F:32])[F:31])=[N:25][CH:26]=[C:27]([Cl:29])[CH:28]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1.C(O)(C)(C)C>[Cl:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:3]=[CH:4][C:5]3[CH2:6][C:7](=[O:21])[NH:8][C:9]4[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=4[C:11]=3[N:12]=2)[C:24]([C:30]([F:33])([F:31])[F:32])=[N:25][CH:26]=1
Reactant: FC(F)(F)c1ncc(Cl)cc1Br
Reactant: Nc1ncc2c(n1)-c1ccc(C(F)(F)F)cc1NC(=O)C2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C1Cc2cnc(Nc3cc(Cl)cnc3C(F)(F)F)nc2-c2ccc(C(F)(F)F)cc2N1
Temperature: 25 °C
Yield: 11.9 %

Procedure:
A mixture of 2-amino-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.42 g, 1.44 mmol), 3-bromo-5-chloro-2-(trifluoromethyl)pyridine (0.37 g, 1.44 mmol), Xphos (0.054 g, 0.115 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.052 g, 0.057 mmol) in a sealed microwave tube was evacuated and purged with argon 3 times. To the vial were added tert-butyl alcohol (5.3 mL) and 1.00 M of t-BuOK in tert-butyl alcohol (2.0 mL, 2.0 mol) via syringe. The mixture was allowed to stir to mix well, then was subjected to microwave irradiation at 150° C. for 1200 sec. The mixture was allowed to cool to rt and THF (6 mL) was added. The mixture was filtered and the solid was washed with THF. The organic solutions were combined and concentrated. The residue was purified by column chromatography to give 2-{[5-chloro-2-(trifluoromethyl)pyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.081 g, 12%) as a solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[CH3:28][C:29]1[C:30]2[CH:44]=[CH:43][CH:42]=[CH:41][C:31]=2[S:32][C:33]=1[CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]1[N:20]=[C:12]2[N:13]([C:14]([NH2:17])=[N:15][C:16]3[N:8]([CH2:7][CH2:6][N:38]4[CH2:39][CH2:40][N:35]([CH2:34][C:33]5[S:32][C:31]6[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=6[C:29]=5[CH3:28])[CH2:36][CH2:37]4)[CH:9]=[CH:10][C:11]=32)[N:18]=1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Cc1c(CN2CCNCC2)sc2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN2CCN(CCn3ccc4c3nc(N)n3nc(-c5ccco5)nc43)CC2)sc2ccccc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title B compound, 1-[(3-methylbenzo[b]thiophen-2-yl)methyl]piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 2-(furan-2-yl)-7-(2-(4-((3-methylbenzo[b]thiophen-2-yl)methyl)piperazin-1-yl)ethyl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=513.2). 1H NMR (DMSO -d6, 400 MHz) δ 2.32 (s, 3H), 2.50 (m, 8H), 2.69 (t, 2H, J=6.4 Hz), 3.72 (s, 2H), 4.23 (t, 2H, J=6.4 Hz), 6.58 (d, 1H, J=3.2 Hz), 6.71 (m, 1H), 7.15 (d, 1H, J=3.6 Hz), 7.18 (d, 1H, J=3.2 Hz), 7.28-7.38 (m, 2H), 7.50 (br s, 2H), 7.68 (d, 1H, J=7.6 Hz), 7.85 (d, 1H, J=7.6 Hz), 7.92 (d, 1H, J=0.8 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7](=O)[NH:8][N:9]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:7]1[N:8]=[N:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(=O)[nH]n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)c1ccc(Cl)nn1

Procedure:
6-Isopropyl-3 (2H)-pyridazinone (3.30 g) and phosphorus oxychloride (15.0 ml) were heated for 1 hour under reflux. After an excess of phosphorus oxychloride was distilled away, ice-water (200 ml) was added to the residues which were then adjusted to pH 6 with 20% aqueous sodium hydroxide solution. The reaction solution was extracted 3 times with ethyl acetate, and the extracts were combined, dried over anhydrous magnesium sulfate and concentrated. The residues were purified by silica gel column chromatography (ethyl acetate:chloroform=1:2) to give the title compound as pale red crystals. The yield was 1.60 g (40.8% based on 5-methyl-4-oxohexanoic acid). mp 32-33° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>S(Cl)(Cl)=O.CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:22][CH:21]=1
Reactant: COc1cccnc1C(O)c1cc(F)ccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cccnc1C(Sc1ccc(Cl)cc1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
After the 2-[(2,5-difluorophenyl)-hydroxymethyl]-3-methoxypyridine (251 mg, 1.0 mmol) obtained in Referential Example 9 was dissolved in thionyl chloride (2.0 ml), a catalytic amount of dimethylformamide was added to the resulting solution. The resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added dioxane, followed by further concentration. The residue thus obtained was dissolved in dimethylformamide (10 ml). To the resulting solution were added 4-chlorobenzenethiol (289 mg, 2.0 mmol) and potassium carbonate (1.10 g, 8.0 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, diethyl ether (50 ml) was added thereto. The resulting mixture was washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (hexane:ethyl acetate=10:1) to give the title compound (256 mg, 58%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]=[O:12])=[C:4]([O:13][CH3:14])[C:3]=1[O:15][CH3:16].[OH-:17].[K+]>O.C(O)C.[Ag]=O.[N+]([O-])([O-])=O.[Ag+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:17])=[O:12])=[C:4]([O:13][CH3:14])[C:3]=1[O:15][CH3:16]
Reactant: [OH-]
Reactant: COc1c(F)ccc(CCCC=O)c1OC
Agent: O=[Ag]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CCO
Product: COc1c(F)ccc(CCCC(=O)O)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
The product from Example 55 (12.6 g) was oxidized with silver oxide prepared in situ from a solution of silver nitrate (15.6 g) in H2O (22 ml) and potassium hydroxide (12.7 g) in H2O (22 ml). The reaction was done in ethanol (170 ml) with stirring at room temperature. After 1 hour, the precipitated silver salts were filtered, washed with water and concentrated to 1/2 volume. The aqueous basic layer was diluted with water extracted with hexane several times, acidified and extracted with ethyl acetate. The organic layer was separated, dried and evaporated to afford the desired acid in 30% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][CH3:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].C([O-])=O.[NH4+]>CCO.C(O)CC.[OH-].[Pd+2].[OH-]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][CH3:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1CC
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCCO
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2n1CC
Temperature: 25 °C
Yield: 90.2 %

Procedure:
The 1-ethyl-5-nitro-1H-indole-2-carboxylic acid ethyl ester (5 g, 19.1 mmol) of step (a) was dissolved in EtOH/n-PrOH (100 mL, 1/1). Palladium hydroxide (1.14 g) and ammonium formate (3.92 g, 62.2 mmol) were added to the above solution. The mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and the catalyst was filtered off through Celite. The solvent was removed under reduced pressure. The crude product was dissolved in dichloromethane (300 mL) and washed with NaHCO3 (150 ml×2). The organic layer was collected, dried (Na2SO4) and evaporated. The crude product was purified by chromatography to furnish the desired product (4 g, 90%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1.C(OC(=O)[NH:27][CH2:28][C@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)(C)(C)C.C(O)(=O)C(O)=O.C(N(CC)CC)C>C(Cl)Cl>[NH2:27][CH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[OH:20])[N:3]=2)[CH2:30]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCCNC1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (1.0 g, 3.46 mmol) was dissolved in 15 mL anhydrous CH2Cl2 under an N2 atmosphere and cooled using an ice bath and (S)-piperidin-3-ylmethyl-carbamic acid tert-butyl ester/oxalic acid (1.16 g, 3.81 mmol) was added in portions, followed by triethylamine (1.05 g, 1.45 mL, 10.4 mmol). The reaction was allowed to warm to room temperature and was complete after 1.5 hour. The mixture was partitioned between CH2Cl2 and H2O and separated, and the aqueous layer was extracted once more with CH2Cl2. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to a yellow solid. This solid was suspended in 40 mL CH2Cl2 and 20 mL of TFA were added. The reaction was complete after 1 hour. The solvent and the excess TFA were removed in vacuo, the residue was re-dissolved in CH2Cl2, and the pH was adjusted to 7 using an aqueous 1 M solution of NaOH. The reaction was partitioned between CH2Cl2 and H2O and separated, and the aqueous layer was extracted once more with CH2Cl2. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to yield of 2-(4-((S)-3-(aminomethyl) piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (900 mg, 71% overall yield) as a yellow solid. LC/MS: m/z 367.3 (M+H)+ at 1.35 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:25]I>CN(C)C=O.Cl>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]=[C:10]2[N:14]([CH3:25])[C:13]([CH3:15])=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[S:11]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1sc(NC(=O)c2ccc(C#N)cc2)nc1C
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(=NC(=O)c2ccc(C#N)cc2)n(C)c1C
Temperature: 25 °C

Procedure:
Ethyl 2-(4-cyanobenzoylamino)-4-methylthiazole-5-carboxylate (22.07 g) was added to a suspension of 60% oily sodium hydride (3.08 g) in N,N-dimethylformamide (hereinafter referred to as DMF) (300 ml) under ice-cooling, followed by stirring at room temperature for an hour. A solution of methyl iodide (4.8 ml) in DMF (50 ml) was added dropwise to the reaction mixture, followed by further stirring at room temperature for an hour. The reaction mixture was taken up in 3% hydrochloric acid, and the precipitated crystals were collected by filtration, and the resulting crude crystals were recrystallized from a mixture of methylene chloride and methanol to give ethyl 2-(4-cyanobenzoylimino)-3,4-dimethylthiazoline-5-carboxylate (15.97 g).
Reaction SMILES: [F:1][C:2]1[C:3](Br)=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].[O:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Li]CCCC>CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[CH:15]1[O:11][CH:12]2[CH:13]=[CH:14]1
Reactant: c1ccoc1
Reactant: Fc1ccc(Br)c(Br)c1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: Fc1cc2c(cc1F)C1C=CC2O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To 3,4-difluoro-1,2-dibromo-benzene (0.75 g, 2.78 mmol) and furan (1 mL, 14.7 mmol) in Et2O (15 mL) at −78° C. was added BuLi (1.1 mL, 2.5M in hexanes, 2.75 mmol) dropwise. The reaction was stirred for two hours at −78° C. and then was allowed to warm to room temperature. After 2 hours, the reaction mixture was quenched with water dropwise and then was poured into water. The organic layer was separated and the aqueous layer was extracted three times with Et2O. The combined organic layers were washed with brine, dried over MgSO4, concentrated and chromatographed (25% ethyl acetate:hexanes) on silica gel to give 24 (350 mg, 70%) as a colourless oil. Rf=0.21 on silica gel (20% ethyl acetate:hexanes); bp 40° C. @ 0.5 mmHg]; IR (neat, cm−1), 3017 (M), 1624 (s), 1465 (s), 1365 (s), 1253 (s), 1190 (m), 1040 (s), 857 (s). 1H NMR (400Mz, CDCl3) δ 7.06 (2H, dd, JH-F=7.7, 7.7 Hz), 7.01 (2H, s), 5.67 (2H, s); 13C NMR (400 MHz, CDCl3) δ 147.2 (dd, JC-F=247.9, 14.5 Hz), 145.1 (dd, JC-F=4.3, 4.3 Hz), 143.1, 110.8 (m), 82.1.HRMS calcd for C10H6O (M+): 180.0387. Found: 180.0394.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([OH:20])=O)[C:11]=2[N:10]=1.[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH2:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[NH:28][C:18]([C:17]1[C:11]2[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:22])[F:21])[NH:13][C:12]=2[CH:14]=[CH:15][CH:16]=1)=[O:20]
Reactant: O=C(O)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (3; 75 mg, 0.24 mmol) was taken up in DMF (2 mL) along with thiazol-2-amine (4; 24 mg, 0.24 mmol) and HATU (186 mg, 0.49 mmol). DIEA (81 μL, 0.49 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water and filtered. The collected solids were further purified by silica gel chromatography to afford the desired product, namely N-(thiazol-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound 208), as a white solid (35 mg, yield: 38%). MS (ESI) calcd for C18H11F3N4OS: 388.06; found: 389 [M+H].