Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[Br:14])([CH3:4])([CH3:3])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[Br:14][C:6]1[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][C:9]([N:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=1
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc(C(C)(C)C)c(Br)cc2[N+](=O)[O-])CC1
Temperature: 130 °C

Procedure:
A mixture of 1-(tert-butyl)-2-bromo-4-nitrobenzene (3 g) and N-methylpiperazine (8 g) was heated neat at 130° C. for 4 h. The residue was purified by column chromatography to give 1-[4-bromo-5-(tert-butyl)-2-nitrophenyl]-4-methylpiperazine, which was hydrogenated to furnish 4-(tert-butyl)-2-(4-methylpiperazinyl)-phenylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=O)[CH2:8][CH:7]1[CH3:21])=[O:5])[CH3:2].Cl.[NH2:23][OH:24].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=[N:23][OH:24])[CH2:8][CH:7]1[CH3:21])=[O:5])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)CC1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=NO)CC1C
Reaction time: 0.17 h
Yield: 116.8 %

Procedure:
A stirred solution of 6,7-dimethoxy-2-methyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (10.0 g, 34.1 mmol), hydroxylamine hydrochloride (7.1 g, 102 mmol), and sodium acetate (7.0 g, 85 mmol) in ethanol (50 mL) was heated at reflux for 2 h. Water (50 mL) was added, and the volatiles were removed in vacuo. Ethyl acetate (175 mL) was added, and the mixture was stirred vigorously for 10 min. The aqueous phase was separated and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a white foam (12.28 g, ca. 100%). 1H NMR (CDCl3) δ1.1 (d, 3H), 1.32 (t, 3H), 2.77 (dd, 1H), 3.07 (dd, 1H), 3.89 (s, 6H), 4.2-4.4 (m, 2H), 5.0 (m, 1H), 7.18 (s, 1H), 7.26 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:9][N:10]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[CH3:27][N:28]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35](OC)=[O:36])=[CH:33][CH:32]=1)[CH3:29].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC>[CH3:29][N:28]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:35]([N:13]2[CH2:14][CH2:15][CH2:16][N:10]([CH2:9][CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:12]2)=[O:36])=[CH:39][CH:40]=1)[CH3:27]
Reactant: COC(=O)c1ccc(CN(C)C)cc1
Reactant: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Agent: C[Al](C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CN(C)Cc1ccc(C(=O)N2CCCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The resulting 1-(3,3-diphenylpropyl)homopiperazine was dissolved in 3 mL of toluene under argon, followed by adding 0.65 mL of a 15% trimethylaluminum solution in hexane. The mixture was stirred at room temperature for 15 minutes, mixed with 187 mg of methyl 4-(dimethylaminomethyl)benzoate, stirred at 60° C. for 22 hours. The mixture was cooled to room temperature, mixed with 2N hydrochloric acid, and stirred. 20 mL of aqueous 2N sodium hydroxide was added and the mixture was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate/methanol 6:4) to obtain 234 mg of the titled compound. This was treated with a hydrogen chloride solution in ether, the solvent was removed under reduced pressure and the residue was dried to give the hydrochloride salt of the titled compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:18]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)=[O:19])[CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:4].O.[Li+].[OH-]>O1CCOCC1>[CH3:26][CH:23]1[CH2:22][CH2:21][CH:20]([C:18]([N:10]([CH:11]2[CH2:12][CH2:13][C:14](=[O:17])[CH2:15][CH2:16]2)[C:9]2[CH:8]=[C:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])=[O:19])[CH2:25][CH2:24]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C2CCC(=O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.6 %

Procedure:
3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (34 mg, 0.075 mmol) was dissolved in a 4:1 mixture of dioxane:H2O (1 ml) and then LiOH 1N (375 ul, 0.375 mmol) was added. After 3 hours of stirring at room temperature, solvents were removed and then partitioned between 5 ml of H2O acidified to pH 4 and 5 ml of EtOAc. The organic layer was separated and the aqueous phase was washed twice with ethyl acetate (2×5 mL). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 17 mg (52%) of 3-[(4-Methyl-cyclohexanecarbonyl)-(4-oxo-cyclohexyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (Compound 13).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:8])([OH:7])[CH3:6].N1C(C)=CC=CC=1C.[Si:17](OS(C(F)(F)F)(=O)=O)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:8])([O:7][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(O)CCCBr
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: CC(C)(CCCBr)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
To a −50° C. cooled solution of alcohol 8 (3 g, 16.6 mmol) in anhydrous CH2Cl2 (50 mL) was added 2,6-lutidine (2.32 mL, 2.13 g, 19.89 mmol) followed by TBSOTf (4.57 mL, 5.26 g, 19.9 mmol). The solution was stirred at 0° C. for 15 min and water (10 mL) was added. The mixture was extracted with CH2Cl2 (3×40 mL), and combined organic phases were washed with 1N aqueous solution of NaOH (40 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (1% ethyl acetate/hexane) to give 3.9 g (13.2 mmol, 80%) of 9. 1H NMR (400 MHz, CDCl3) δ: 0.07 (6H, s), 0.85 (9H, s), 1.21 (6H, s), 1.55 (2H, m), 1.95 (2H, m), 3.41 (2H, t, J=6.8 Hz)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8]([N:10]([CH2:14][CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]([CH3:13])[CH3:12])=[O:9])=[N:4][C:3]=1[C:29]1[CH:38]=[CH:37][C:32]([C:33](OC)=[O:34])=[CH:31][CH:30]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:9])[N:10]([CH2:14][CH2:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]([CH3:13])[CH3:12])=[N:4][C:3]=1[C:29]1[CH:38]=[CH:37][C:32]([CH2:33][OH:34])=[CH:31][CH:30]=1
Reactant: COC(=O)c1ccc(-c2nc(NC(=O)N(CCC(c3ccccc3)c3ccccc3)C(C)C)sc2Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(CCC(c1ccccc1)c1ccccc1)C(=O)Nc1nc(-c2ccc(CO)cc2)c(Cl)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl 4-(5-chloro-2-(3-(3,3-diphenylpropyl)-3-isopropylureido)thiazol-4-yl)benzoate 175 (0.424 g, 0.774 mmol) was dissolved in THF (5 mL) and cooled to 0° C. To this solution, lithium aluminium hydride (2M solution in THF, 0.77 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h, quenched with Rochelle's salt solution and then extracted with ethyl acetate. Organics were concentrated and purified by column chromatography on silica using 1:1 EtOAc:Hexane. Product 176 was obtained as a solid (0.38 g, 95%). Mass spectrum: calculated for C29H30ClN3O2S 519.2; found 520.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:13]CCCO2)[CH:5]=[CH:6][CH:7]=1.[CH:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:16])[CH3:15].C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=2)[CH:8]=[O:13])[CH2:19][CH2:18]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCNCC1
Reactant: Brc1cccc(C2OCCCO2)c1
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(c2cccc(C=O)c2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
A mixture of 2-(3-bromophenyl)-1,3-dioxane (2, 1.58 g, 6.5 mmol), 1-isopropylpiperazine (1.0 g, 7.8 mmol), rac-BINAP (60 mg, 0.096 mmol), and tert-BuONa (1.06 g, 11.1 mmol) in toluene (15 mL) was degassed under vacuum and flushed with nitrogen. Pd2(dba)3 (30 mg, 0.033. mmol) was added. The reaction mixture was degassed again and flushed with nitrogen and was heated at 100° C. under nitrogen for 16 h. The reaction mixture was poured into cold 1N HCl (30 mL) and stirred for 2 h. It was adjusted to pH 8 with 6N NaOH and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4), filtered, concentrated, and purified by silica gel chromatography eluting with 0-100% EtOAc (containing 5% v/v Et3N) in hexanes to afford the title compound as a viscous yellow oil (1.32 g, 87%): 1H NMR (500 MHz, CDCl3) δ 9.96 (s, 1H), 7.44-7.37 (m, 2H), 7.34-7.30 (m, 1H), 7.21-7.16 (m, 1H), 3.28 (t, J=5.0 Hz, 4H), 2.73 (sept, J=6.5 Hz, 1H), 2.69 (t, J=5.0 Hz, 4H), 1.10 (d, J=6.5 Hz, 6H); ESI MS m/z 233 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:15][CH2:16][Cl:17])=[CH:7][CH:6]=1)[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(OCCCCl)cc1

Procedure:
A suspension of 4-hydroxybenzoic acid ethyl ester (5.0 g, 30 mmol), 1-bromo-3-chloropropane (7.1 g, 45 mmol) and potassium carbonate (14 g, 100 mmol) in 50 mL of acetone using the procedure described in Example 88 Step 1 gave the product as a clear oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22](O)=[O:23])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:25])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][C:22]([NH:26][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:23])[N:20]=2)=[CH:12]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Product: O=C(C[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1)NCCN1CCOCC1
Yield: 60 %

Procedure:
The compound (100 mg, 0.28 mmol) prepared in Example 37 and 4-(2-aminoethyl)morpholine instead of 1-methylpiperazine were reacted according to the same procedure as Example 84 to give the title compound (80 mg, Yield 60%).
Reaction SMILES: [C:1]([C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)[N:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:21]([O:25][C:26](=[O:44])[C@@H:27]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:28][NH:29][C:30](=[O:33])[CH2:31][NH2:32])([CH3:24])([CH3:23])[CH3:22].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:21]([O:25][C:26](=[O:44])[C@@H:27]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:28][NH:29][C:30](=[O:33])[CH2:31][NH:32][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][C:10]1[N:9]=[C:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C:13]([NH2:14])=[CH:12][CH:11]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)c1nc(CCCC(=O)O)ccc1N
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)CN)NS(=O)(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1nc(CCCC(=O)NCC(=O)NC[C@H](NS(=O)(=O)c2ccccc2)C(=O)OC(C)(C)C)ccc1N
Reaction time: 8 h

Procedure:
Acid 5-5 (144 mg, 0.51 mmol), amine 5-7 (202 mg, 0.56 mmol), NMM (226 μL, 2.1 mmol) and BOP (241 mg, 0.77 mmol) were combined in 2.6 mL DMF. Mter stirring overnight the solvent was evaporated, the residue was dissolved in EtOAc, washed with water, sat. NaHCO3, 5% KHSO4, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 10% CHCl3/EtOAc) provided 5-8 as an off-white glass.
Reaction SMILES: [Na].[OH:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]2[N:11]=[C:12]([CH2:17][C:18]([OH:20])=O)[NH:13][C:14](=[O:16])[CH:15]=2)[CH2:5]1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.N1C=CC=CC=1>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:18](=[O:20])[CH2:17][C:12]1[NH:13][C:14](=[O:16])[CH:15]=[C:10]([N:6]2[CH2:7][CH2:8][O:9][CH:4]([CH2:3][OH:2])[CH2:5]2)[N:11]=1
Reactant: Clc1cccc2c1CCN2
Reactant: O=C(O)Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1)N1CCc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
In a 25 ml round-bottomed flask, 71 mg of the sodium salt of [4-(2-hydroxymethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid (example 25b, step 9b) and 38 mg of 4-chloro-2,3-dihydro-1H-indole are placed in 1 ml of dimethylformamide and 0.24 ml of pyridine, and then 57 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added. The reaction medium is stirred at ambient temperature for 20 h, then evaporated, water is added, and the resulting mixture is triturated. The solid formed is filtered off, and rinsed successively with water then with diisopropyl ether, with methylene chloride and then with pentane. The resulting solid is dried under vacuum for 2 h. (−)-2-[2-(4-Chloro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-hydroxymethylmorpholin-4-yl)-3H-pyrimidin-4-one (62 mg) is isolated in the form of a pulverulent solid (yield=63%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:21])([F:20])[C:9]1[NH:19][C:12]2=[N:13][CH:14]=[C:15]([CH2:17][NH2:18])[CH:16]=[C:11]2[CH:10]=1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1>CS(C)=O>[Cl:22][C:23]1[N:24]=[CH:25][N:26]=[C:27]([NH:18][CH2:17][C:15]2[CH:16]=[C:11]3[CH:10]=[C:9]([C:8]([F:7])([F:20])[F:21])[NH:19][C:12]3=[N:13][CH:14]=2)[CH:28]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: FC(F)(F)c1cc2cc(CNc3cc(Cl)ncn3)cnc2[nH]1
Temperature: 120 °C

Procedure:
Potassium carbonate (106 mg, 0.767 mmol) was added to 1-[2-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 75 mg, 0.349 mmol) and 4,6-dichloropyrimidine (104 mg, 0.697 mmol) in DMSO (2 mL). The mixture was heated at 120° C. for 1 hour in the microwave. Crude LCMS showed desired product and no starting material left so the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (10 mL), brine (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. This solid was dissolved in a mixture of acetonitrile and DMSO (1:1, 1.8 mL) and purified by MDAP. Fractions containing pure product were combined and concentrated under reduced pressure to give the title compound as a brown solid (24 mg);
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH2:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH2:26]>N1C=CC=CC=1>[NH2:19][C@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[NH:26][C:10]1[CH:11]=[C:12]2[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: N[C@@H]1CCCC[C@@H]1N
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N[C@@H]3CCCC[C@@H]3N)cc21
Yield: 69.1 %

Procedure:
A mixture of 2.53 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 4.6 g of cis-1,2-diaminocyclohexane in 10 ml of pyridine was heated as described in Example 1 giving 2.4 g of the desired product, m.p. 225°-227°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34].[Na+].[Cl-]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:11]([C:13]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=3[CH3:20])=[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(N)n2)[nH]c1-c1cc(Cl)ccc1C
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccnc(N)n2)n(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a solution of ethyl 5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxylate (1.0 g, 2.8 mmol) in dry THF (40 mL) cooled to 0° C. NaH 60% (1.342 g, 3.36 mmol) was added portion wise and the reaction mixture stirred for 30 min. (2-Chloromethoxy-ethyl)-trimethyl-silane (0.417 mL, 3.36 mmol) was added drop wise. The reaction mixture was allowed to warm up slowly to room temperature and stirred for 2 h. Saturated aqueous NaCl (30 mL) was added at 0° C. and the mixture was extracted with EtOAc (2×35 mL). The separated organic phase was dried over sodium sulfate and the solvent evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 98/2) to afford the title compound as an orange oil (0.80 g, 57%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH3:12]>>[NH2:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: N
Product: Nc1ccc2ccccc2c1
Temperature: 150 °C

Procedure:
To a 300 mL autoclave was added 36.5 g of 2-naphthol (2, 0.253 mol), 34.0 g of (NH4)2SO3.H2O (0.254 mol) and 85 mL of concentrated aqueous ammonia, the mixture was heated to 150° C. with an oil-bath for 10 h. The pressure was built to about 10 atm at 150° C. and then cooled to room temperature while stirring. The solid was filtered, washed with water, and dissolved in a mixture of 70 mL of concentrated hydrochloric acid, 300 mL of ethanol and 200 mL of water at 70° C. The solution was treated with 5 g of activated charcoal for 0.5 h at 70° C. and filtered. The impurity in the filtrate was extracted with 200 mL of toluene and discarded. The aqueous phase was cooled to room temperature and neutralized with 90 mL of concentrated aqueous ammonia. The mixture was extracted with toluene (2×400 mL) at 70° C. The toluene layer was washed with water (2×100 mL), and degassed under N2 for 5 min. The small amount of water in toluene was removed by refluxing with a Dean-Stark trap, and concentrated to obtain the crude product. The crude product was recrystallized from 200 mL of degassed toluene to afford 26.9 g of 3, the second crop from the mother liquid was 2.4 g. Yield: 29.3 g (80% ): mp 106-108° C., 1H NMR (CDCl3) —4.07 (s, 2H ), 7.19-7.24 (m, 2H), 7.47-7.52 (m, 1H), 7.61-7.66 (m, 1H), 7.85-7.97 (m, 3H), 13C NMR (CDCl3) —108.5, 118.2, 122.4, 125.8, 126.3, 127.7, 127.9, 129.2, 134.9, 144.0.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1.[Br:14]Br>CC(O)=O>[CH:1]1([C:4]2[NH:5][C:6]3[C:12]([Br:14])=[C:11]([NH2:13])[CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(C3CC3)[nH]c2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ccc2nc(C3CC3)[nH]c2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of 0.87 g (4.9 mmol) of 2-cyclopropyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.10 ml (1.9 mmol) of Br2 dropwise and resulting reaction mixture was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo and purified on silica gel column chromatography (5% MeOH/EtOAC) to yield 0.42 g (1.8 mmol, >95%) of the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: COc1ccc(OC)c(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5-dimethoxyaniline (32 mg, 0.193 mmol) similar to Example 13 and isolated as a light tan solid (15 mg, 21%). 1H NMR (CDCl3): 8.79 (dd, J=1.8, 4.8 Hz, 2H), 8.31 (dd, J=1.8, 4.8 Hz, 2H), 8.02 (bs, 1H), 7.59 (s, 1H), 6.98 (s, 1H), 6.90 (d, J=9.0 Hz, 1H), 6.69 (dd, J=2.9, 9.2 Hz, 1H), 3.90 (s, 3H), 3.87 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]2[CH2:15][C@@H:14]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[O:22]1[CH2:25][CH:24]([OH:26])[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cl-].[Na+].O>[O:22]1[CH2:25][CH:24]([O:26][C:2]2[N:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]([C@H:13]3[CH2:15][C@@H:14]3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:12])[CH3:9])=[CH:4][CH:3]=2)[CH2:23]1
Reactant: C[C@H](NC(=O)[C@H]1C[C@@H]1c1ccccc1)c1ccc(Cl)nc1
Reactant: OC1COC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NC(=O)[C@H]1C[C@@H]1c1ccccc1)c1ccc(OC2COC2)nc1
Temperature: 100 °C

Procedure:
(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(S)-1-(6-chloro-pyridin-3-yl)-ethyl]-amide (Compound 18) (2.00 g, 6.65 mmol) was dissolved in DMF (50 ml). Oxetan-3-ol (4.00 g, 54 mmol) and dicesium carbonate (16.2 g, 49.9 mmol) were added and the mixture was heated at 100° C. ON. The mixture was poured out into brine and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and was filtered and then evaporated to dryness. The residue was transferred to a silica gel column and eluded with EtOAc/heptanes 1:1 to give Compound 19 as a solid. This solid was dissolved in a mixture of THF (10 ml), EtOAc (20 mL) and heptanes (10 ml). The mixture was concentrated to approx. 15 mL in vacuo and this solution was cooled in an ice/water bath. A white precipitate formed. The solids was collected by filtration and dried in vacuo to give the title compound as colorless crystals (0.097 g, 4%). %). 1H-NMR (500 MHz, DMSO) δ 8.55 (d, 1H), 8.04 (s, 1H), 7.70 (d, 1H), 7.25 (m, 2H), 7.15 (m, 1H), 7.10 (d, 2H), 6.87 (d, 1H), 5.52 (m, 1H), 4.95 (m, 1H), 4.87 (m, 2H), 4.53 (m, 2H), 2.20 (m, 1H), 1.90 (m, 1H), 1.37 (m, 4H), 1.21 (m, 1H). LC-MS (m/z) 339.2 (MH+), tR=0.63 min (method B). Mp=151-153 C.