Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C.O>[N:18]1([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:9])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)CCCCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)CCCCN1CCCCC1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
5-Bromopentanoic acid methyl ester (1.22 g) was dissolved in acetonitrile (24.4 ml) and added with potassium carbonate (1.30 g), potassium iodide (0.104 g), and piperidine (0.928 ml) and the whole was stirred at 70° C. for 2.5 hours. The reaction solution was added with water and the whole was subjected to separation/extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was again dissolved in 18% hydrochloric acid (20 ml) and the whole was refluxed under heating for 3 hours. The reaction solution was concentrated under reduced pressure. Recrystallization was performed with acetone/acetic acid, thereby obtaining a hydrochloride (1.15 g) of the subject compound as a colorless crystal.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].C(O)(=O)C.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH:26]=O)=[CH:20][CH:19]=1>C(O)C>[CH2:1]([N:3]1[C:7]2[CH2:8][CH2:9][NH:10][CH:26]([CH2:25][CH2:24][C:21]3[CH:22]=[CH:23][C:18]([C:17]([F:16])([F:28])[F:29])=[CH:19][CH:20]=3)[C:6]=2[C:5]([CH3:11])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C)cc1CCN
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCn1nc(C)c2c1CCNC2CCc1ccc(C(F)(F)F)cc1
Yield: 34.5 %

Procedure:
2-(2-Ethyl-5-methyl-2H-pyrazol-3-yl)-ethylamine (148 mg, 0.97 mmol) was dissolved in ethanol (3 ml) and acetic acid (116.5 mg. 1.94 mmol) was added followed by the addition of 3-(4-trifluoromethyl-phenyl)-propionaldehyde (197 mg, 0.97 mmol). The mixture was sealed and put in the microwave oven (100 Watts; 130° C., 14 bar, 6 minutes). The solvents were removed under reduced pressure and the residue was purified by prep. HPLC to give 113 mg (34.5%) of 1-ethyl-3-methyl-4-[2-(4-trifluoromethyl-phenyl)-ethyl]-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine. LC-MS: tR=0.75 min; [M+H]+=338.22.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH3:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:27][C:28](=[S:29])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cc(C)cc(N=C=S)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(C)cc(C)c1
Yield: 25.8 %

Procedure:
Prepared according to the procedure described for Example 98 using 3-amino-4-methoxy-N-phenyl-benzamide (0.974 g, 4.01 mmol) and 3,5-dimethylphenyl isothiocyanate (0.66 g, 4.04 mmol) to afford the product (0.42 g); m.p. 203-205° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH3:12])[CH:10]=1)[N:7]([CH3:34])[N:6]=[CH:5]2.FC(F)(F)C(O)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:13][CH2:14][C:15]3([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[CH3:12])[CH:10]=1)[N:7]([CH3:34])[N:6]=[CH:5]2
Reactant: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cnn(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OCC1(c2ccccc2)CCNCC1)c1cc(Cl)cc2cnn(C)c12

Procedure:
(±)-tert-Butyl 4-((1-(5-chloro-1-methyl-1H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (22 mg, 0.06 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated to afford 17 mg (97%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.78 (s, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.31-7.37 (m, 4H), 7.20-7.23 (m, 1H), 6.89 (m, 1H), 4.91 (q, J=6.4 Hz, 1H), 4.16 (s, 3H), 3.40 (d, J=9.2 Hz, 1H), 3.35 (d, J=9.2 Hz, 1H), 2.89-2.95 (m, 2H), 2.71-2.79 (m, 2H), 2.12-2.20 (m, 2H), 1.94-2.03 (m, 2H), 1.44 (d, J=6.4 Hz, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 145.7, 144.3, 135.4, 128.3, 127.8, 127.3, 126.1, 123.2, 122.7, 122.4, 117.1, 78.4, 74.0, 42.8, 42.0, 40.5, 33.4, 22.6. Mass spec.: 384.17 (MH)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[CH:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][C:20]1=[O:28]>>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][CH:18]=[C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: Nc1ccc(OCCN2CCCCC2)cc1
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCN2CCCCC2)cc1
Yield: 79.5 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-piperidin-1-yl-ethoxy)-phenylamine (820 mg, 1.2 equiv.) and 3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 3.11 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (899 mg, 80%).
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[CH2:3][C@H:4]([NH:37]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:5]([NH:7][C@@:8]([C:23]1[CH:28]=[C:27]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:26]=[C:25]([F:36])[CH:24]=1)([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].N1CCCCC1>C(Cl)Cl>[NH2:37][C@@H:4]([CH2:3][C:2]([F:55])([F:56])[F:1])[C:5]([NH:7][C@@:8]([C:23]1[CH:28]=[C:27]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:26]=[C:25]([F:36])[CH:24]=1)([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6]
Reactant: O=C(N[C@@H](CC(F)(F)F)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: N[C@@H](CC(F)(F)F)C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.3 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl (S)-4,4,4-trifluoro-1-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-1-oxobutan-2-ylcarbamate (10 mg, 0.01 mmol) in DCM (0.5 mL) was added piperidine (20 mg, 0.1 mmol). The reaction mixture was stirred at rt for 1.5 h and concentrated. The residue was purified by preparative HPLC (Axia column, 30×100 mm, 30-100% MeOH/H2O with 0.1% TFA over 12 min, flow rate 40 mL/min, monitoring at 220 nm) to yield (S)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323A) as a white solid (6 mg, 82% yield). LCMS: RT=3.1 min [M+H] 565.22 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1H, s), 7.17-7.22 (1H, m), 7.12 (2H, t, J=7.33 Hz), 7.03-7.08 (2H, m), 6.96-7.02 (2H, m), 6.88 (3H, s), 6.59 (2H, d, J=7.07 Hz), 5.85 (1H, t, J=2.53 Hz), 4.09 (1H, s), 3.91 (1H, d, J=13.14 Hz), 3.71 (1H, d, J=13.39 Hz), 2.66 (2H, m). (R)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323B) was prepared in the same method here and isolated as a white solid (6 mg, 82% yield). LCMS: RT=3.1 min [M+H] 565.22 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (1H, s), 7.19 (1H, t, J=7.33 Hz), 7.08-7.15 (4H, m), 6.93-7.00 (2H, m), 6.84-6.92 (2H, m), 6.81 (1H, s), 6.58 (2H, d, J=7.07 Hz), 5.84 (1H, t, J=2.65 Hz), 4.26 (1H, d, J=5.56 Hz), 3.76-3.86 (2H, m), 2.53 (1H, d, J=10.61 Hz), 2.43-2.49 (1H, m). The stereochemistry of (S)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323A) and (R)-2-amino-4,4,4-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)butanamide (Example 323B) was assigned arbitrarily.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[CH:18]1([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:24])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(N)CO
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Product: Cc1onc(C2CCCCC2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 58 %

Procedure:
As described for example 31e, 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (708 mg, 1.5 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (340 mg, 58%) which was obtained as a white solid after purification by chromatography (silica, 0 to 4% methanol in dichloromethane). MS: m/e=388.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([S:18](Cl)(=[O:20])=[O:19])=[CH:10][CH:9]=1)=[O:6].[N:28]([CH:31]([CH3:33])C)=[C:29]=[O:30]>C(N(CC)CC)C>[C:29]([N:28]1[CH2:31][CH2:33][CH:5]([NH:7][S:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=3[C:2]([F:27])([F:26])[F:1])=[CH:9][CH:10]=2)(=[O:20])=[O:19])[CH2:4][CH2:3]1)(=[O:30])[CH2:9][CH2:8][CH3:17]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3C(F)(F)F)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-trifluoromethyl-benzoylamino)-naphthalene-1-sulfonyl chloride and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.91(s, 1H), 8.68 (d, 1H), 8.25 (m, 2H), 8.11 (d, 1H), 7.85 (m, 4H), 7.76 (m, 3H), 4.06 (m, 1H), 4.01(m, 1H), 3.62 (d, 1H), 2.94 (t, 1H), 2.59 (t, 2H), 1.48 (m, 2H), 1.41 (m, 2H), 1.19 (m, 2H), 0.82 (t, 3H); LC/MS m/z 546 (M−H)−, 548 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:3]=1.[OH:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][CH:31]=[N:32]2)=[CH:27][CH:26]=1.[H-].[Na+]>CN(C=O)C>[C:8]1([C:5]2[N:6]=[N:7][C:2]([O:24][C:25]3[CH:34]=[C:33]4[C:28]([CH:29]=[CH:30][CH:31]=[N:32]4)=[CH:27][CH:26]=3)=[CH:3][C:4]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3ccc4cccnc4c3)nnc2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 6-chloro-3-phenyl-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 13(e)), (106 mg, 0.3 mmol) and 7-hydroxyquinoline (55 mg, 0.4 mmol, Acros) in DMF (2.5 mL) was added NaH (22 mg, 0.6 mmol, 60% suspension in mineral oil, Aldrich) and the mixture was stired at room temperature for 15 h. The reaction mixture was then heated at 50° C. for another 28 h, allowed to cool to room temperature and the solvent removed in vacuum. The residue was partitioned between EtOAc/H2O and the aqueous layer was extracted with EtOAc. The combined organic layers were evaporated onto SiO2 and purified by flash silica gel chromatography with EtOAc/hexanes (0:1→3:7) as eluant to give the title compound as an off-white amorphous solid. Mp: 178–183° C. MS (ESI, pos ion.) m/z: 444 (M+1).
Reaction SMILES: [C:1]12([C:7]3=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=[C:6]3[O:5][CH2:4]1)[CH2:3][CH2:2]2.CN(C)C=O.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([O:12][C:8]2[C:7]3[C:1]4([CH2:4][O:5][C:6]=3[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]4)=[N:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1cccc2c1C1(CC1)CO2
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a solution of spiro[1-benzofuran-3,1′-cyclopropan]-4-ol (Intermediate 85, 70 mg) in dry N,N-dimethylformamide (2 ml) potassium carbonate (89 mg, 0.647 mmol) and then 2-chloro-5-nitropyridine (75 mg, 0.475 mmol) were added and the reaction mixture was stirred for 3 hours at 100° C. The reaction was quenched with brine (1 ml), diluted with water (2 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 9:1 as eluents affording the title compound as a white solid (100 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[N:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](OC)=[O:38])=[C:29]=[S:30]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]3[C:37](=[O:38])[C:32]4[C:31](=[CH:36][CH:35]=[CH:34][CH:33]=4)[NH:28][C:29]3=[S:30])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1N=C=S
Reactant: NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: O=c1c2ccccc2[nH]c(=S)n1CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 1 h
Yield: 46 %

Procedure:
To a stirred mixture of 5.5 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidineethanamine and 90 parts of tetrahydrofuran was added dropwise a solution of 3.8 parts of methyl 2-isothiocyanatobenzenecarboxylate in 18 parts of tetrahydrofuran (exothermic reaction). Upon completion, stirring was continued for 1 hour. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and recrytallized from methanol. The product was filtered off and dried, yielding 3.6 parts (46%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-2,3-dihydro-2-thioxo-4(1H)-quinazolinone; mp. 218.2° C. (460).
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[NH2:14].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=1>C(OCC)(=O)C>[NH2:14][C:13]1[CH:12]=[CH:11][C:10]([O:15][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=2)=[CH:9][C:8]=1[F:7]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Potassium tert-butoxide (5 g, 23.47 mmol, 1.4 eq) was dissolved in N,N-dimethylacetylamide (DMA, 12 mL). A solution of 3-fluoro-4-aminophenol (4.2 g, 32.86 mmol, 1.4 eq) in DMA (15 mL) was slowly added dropwise at 0° C. After the addition, the mixture was stirred at room temperature for 30 min. The mixture was heated to 100° C. and a solution of tert-butyl 4-chloropicolinate in DMA (18 mL) was slowly added dropwise, and then the mixture was stirred for 1 h. After being cooled to room temperature, ethyl acetate (500 mL) was added, and the resulted mixture was filtered to remove the undissolved material. The filtrate was washed with saturated brine (200 mL×3), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a brown solid. The crude was purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give the title compound (1.38 g, purity 98%, yield 20%) as a light brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][N:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[C:24]2[CH:36]=[CH:37][N:38]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:23]=2[C:22]1=[O:49]>>[CH3:20][N:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=3[C:12]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:24]2[CH:36]=[CH:37][N:38]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C:23]=2[C:22]1=[O:49]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: O=C1COc2ccc(Br)c(Oc3ccccc3)c2N1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(c4Oc4ccccc4)NC(=O)CO5)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 6-bromo-5-phenoxy-2H-1,4-benzoxazin-3(4H)-one and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C29H24N3O6S (M+H)+: m/z=542.1. found: 542.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH:7]=[C:6]([C:26]([OH:28])=[O:27])[C:5]2=[O:29].[CH2:30]=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:30])[CH2:14][CH2:13]1)[N:8]([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[CH:7]=[C:6]([C:26]([OH:28])=[O:27])[C:5]2=[O:29]
Reactant: C=O
Reactant: O=C(O)c1cn(-c2ccc(O)cc2)c2c(F)c(N3CCNCC3)c(F)cc2c1=O
Solvent: O=CO
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(O)cc4)c3c2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6,8-Difluoro-1-(4-hydroxyphenyl)-7-(1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.80 g) is added slowly to a mixture of 90% formic acid (4 ml) and 37% formaline (4 ml) under ice-cooling. After the addition, the mixture is refluxed for 5 hours. The reaction mixture is distilled to dryness under reduced pressure. The residue is suspended in saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture is stirred at room temperature for 30 minutes. The precipitated crystals are separated by filtration, washed with water, dried, and then recrystallized from DMF to give 6,8-difluoro-1-(4-hydroxyphenyl)-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.52 g) as pale yellowish white crystals, m.p. 300° C.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[C:22]([O:26][CH3:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)[C@H](C)O)C4)c[nH]c23)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A169) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:11]3([C:16]([F:18])([F:17])[CH2:15][O:14][C:13]([NH2:19])=[N:12]3)[CH2:10][C:9]([CH3:21])([CH3:20])[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[N:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[C:4]3[C@@:11]4([C:16]([F:17])([F:18])[CH2:15][O:14][C:13]([NH2:19])=[N:12]4)[CH2:10][C:9]([CH3:21])([CH3:20])[O:8][C:5]3=[CH:6][CH:7]=2)[CH:26]=[N:27][CH:28]=1
Reactant: CC1(C)C[C@@]2(N=C(N)OCC2(F)F)c2cc(Br)ccc2O1
Reactant: OB(O)c1cncc(Cl)c1
Product: CC1(C)C[C@@]2(N=C(N)OCC2(F)F)c2cc(-c3cncc(Cl)c3)ccc2O1
Yield: 78 %

Procedure:
In a manner analogous to that described in Example 19, the cross coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,2-dimethyl-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazin]-2′-amine (intermediate B6.5) with 5-chloropyridin-3-ylboronic acid yielded the title compound (78% yield) as a white powder. MS (ISP): m/z=394.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:10]([CH2:20][CH2:21][OH:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[C:23]([O:22][CH2:21][CH2:20][N:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[C:9]1[CH3:8])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Cc1cc(-c2ccccc2)cn1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCCn1cc(-c2ccccc2)cc1C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
Triethylamine (0.5 mL, 3.59 mmol) was added dropwise to a solution of 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethanol (260 mg, 1.29 mmol) in dry dichloromethane (20 mL) at 0 to 5° C. followed by the addition of acetyl chloride (0.2 mL, 2.81 mmol). The reaction mixture was stirred for 30 min and then quenched into ice water (30 mL) and ethyl acetate (20 mL) and stirred for 15 min. The organic layer was separated and washed with water (2×25 mL), brine (2×25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to afford 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethyl acetate (300 mg, 96%) as a brown liquid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](Cl)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.[Cl:17][C:18]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1>CCOCC>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([NH:24][C:21]2[CH:22]=[N:23][C:18]([Cl:17])=[CH:19][CH:20]=2)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Solvent: CCOCC
Product: O=C(NC(Nc1ccc(Cl)nc1)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Yield: 65 %

Procedure:
A mixture of 4-bromoaniline 118 (5.0 g, 24.2 mmol) and chloral (4.7 mL, 48.2 mmol) in THF (4 mL) was heated for 30 minutes. Solvent was removed under vacuum. 4-Bromo-N-(2,2,2-trichloro-1-hydroxyethyl)benzamide 121 (1.26 g, 3.62 mmol) in chloroform (15 mL) and PCl5 (0.8 g, 3.65 mmol) was heated at 50° C. for 30 minutes. The product was isolated from a standard aqueous work-up and extraction to produce 4-bromo-N-(1,2,2,2-tetrachloroethyl)benzamide. 4-Bromo-N-(1,2,2,2-tetrachloroethyl)benzamide (1.21 mmol) in ether (50 mL) was reacted with 6-chloropyridin-3-amine (0.32 g, 2.44 mmol) at room temperature for 18 hours. The mixture was subjected to a standard aqueous work-up and extraction. Chromatography on silica gel (7:3 hexanes:CH2Cl2) gave 4-bromo-N-(2,2,2-trichloro-1-(6-chloropyridin-3-ylamino)ethyl)benzamide (Compound-42, 0.36 g, 65%). 1H NMR (300 MHz, d4-methanol): δ=7.99 (dd, J=3.0, 0.6 Hz, 1H), 7.74 (d, J=9.0 Hz, 2H), 7.65 (d, J=9.0 Hz, 2H), 7.36 (dd, J=9.0, 3.3 Hz, 1H), 7.26 (dd, J=8.7, 0.6 Hz, 1H), 6.36 (s, 1H).