Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:18][CH2:19]Cl)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:21][N:22]([CH3:31])[C:23]1[NH:24][CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:21][N:22]([CH3:31])[C:23]1[NH:24][CH:25]=[C:26]([CH2:19][CH2:18][N:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:27]=1[N+:28]([O-:30])=[O:29]
Reactant: ClCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)nc1
Reactant: CN(C)c1[nH]ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)c1[nH]cc(CCN(Cc2ccc(Cl)cc2)Cc2ccc(Cl)nc2)c1[N+](=O)[O-]

Procedure:
This compound was prepared in a manner analogous to that set forth in Step G of Example 1, using 0.47 gram (0.0014 mole) of [(6-chloro(3-pyridyl)methyl](2-chloroethyl)[(4-chlorophenyl)methyl]amine (prepared in Steps A and B of the present Example), 0.2 gram (0.0013 mole) of dimethyl(3-nitropyrrol-2-yl)amine and 0.45 gram (0.0032 mole) of potassium carbonate in 20 mL of DMF. The crude product was purified with column chromatography on silica gel. Elution was accomplished using 50% hexane in diethyl as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.05 gram of Compound 214. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>CS(C)=O.CCOC(C)=O>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:2]2[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=2)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:21][CH2:22]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of tert-butyl 2-chloro-6-(trifluoromethyl)isonicotinate (3.0 g, 11 mmol, Example 21, Step 1), tert-butyl 4-aminopiperidine-1-carboxylate (4.3 g, 21 mmol, Aldrich) and N,N-diisopropylethylamine (3.7 mL, 21 mmol) in dimethyl sulfoxide (9.2 mL) was heated to 100° C. for 20 hours. The mixture was cooled to room temperature and diluted with EtOAc. The combined organic extracts were washed with water (3 times) and brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography using a 120 g silica gel cartridge and eluting with a gradient from 0-15% EtOAc in hexanes afforded product as a white solid (3.4 g, 72%). LCMS (M+Na)+: 468.2.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49](B2OC(C)(C)C(C)(C)O2)[C:48]([CH3:61])=[N:47]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:41][C:42]1[CH:43]=[C:44]([CH:62]=[CH:63][CH:64]=1)[CH2:45][N:46]1[C:50]([CH3:51])=[C:49]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=4)[CH2:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:19][CH2:20]4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH3:38])=[CH:39][CH:40]=3)(=[O:33])=[O:32])[CH:3]=2)[C:48]([CH3:61])=[N:47]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 90.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-(3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperidine-1-carboxylate (intermediate 66G) (100 mg, 0.148 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (74 mg, 0.223 mmol) using Pd(PPh3)2Cl2 (6 mg, 0.007 mmol) and sodium carbonate (40 mg, 0.372 mmol) in toluene/ethanol/water (6/5/2 ml) to afford 100 mg (90.1% yield) of the titled compound after column purification using 50% ethyl acetate in hexane as eluent. MS: m/z=747.8 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:28])=[C:20]([CH:27]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:28][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:11]2[S:10][CH2:9][CH2:8][O:7][C:6]=2[CH3:5])=[O:14])=[CH:27][C:20]=1[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]
Reactant: CC1=C(C(=O)O)SCCO1
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC1=C(C(=O)Nc2ccc(Cl)c(C(=O)OC(C)C)c2)SCCO1
Reaction time: 4 h

Procedure:
Thionyl chloride (6.5 g, 0.055 mole) was added to a stirring slurry of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (8.0 g, 0.050 mole) in methylene chloride (50 ml). The mixture was stirred at 35°-40° C. for 4 hours, during which the solid completely dissolved. The solution was then evaporated under reduced pressure at about 35° C. to remove hydrogen chloride, sulfur dioxide and unreacted thionyl chloride. The residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, which solidified, was dissolved in methylene chloride (50 ml). The solution was chilled in ice and treated dropwise with a solution of 1-methylethyl 5-amino-2-chlorobenzoate (10.7 g, 0.050 mole) and triethylamine (5.5 g, 0.055 mole) in methylene chloride (50 ml). The addition was carried out over about 2 hours, after which the reaction mixture was left stirring overnight at room temperature.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][OH:11])[CH2:5][CH2:4]1.F[C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][N:14]=1>C1COCC1.O>[I:19][C:16]1[CH:17]=[CH:18][C:13]([O:11][CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)=[N:14][CH:15]=1
Reactant: OCCN1CCOCC1
Reactant: Fc1ccc(I)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Ic1ccc(OCCN2CCOCC2)nc1
Temperature: 60 °C
Yield: 60 %

Procedure:
To a suspension of sodium hydride (2.15 g, 60% dispersion in mineral oil, 54.0 mmol) in THF (100 mL) at 0° C. was added 2-morpholinoethanol (5.43 mL, 44.8 mL). After 30 min 2-fluoro-5-iodopyridine (10.0 g, 44.8 mmol) was added and the reaction mixture was heated to 60° C. for 16 hr and was then cooled and diluted with water (75 mL). The resulting mixture was extracted with EtOAc (2×75 mL) and the combined organic extracts were dried and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 120 g, 20-60% EtOAc in isohexane, gradient elution) to afford 4-(2-(5-iodopyridin-2-yloxy)ethyl)morpholine as a yellow oil (9.35 g, 60%); Rt 0.94 min (Method 2, acidic); m/z 335 (M+H)+, (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[CH2:15]O)[N:3]=1.CCN(S(F)(F)[F:23])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[CH2:15][F:23])[N:3]=1
Reactant: OCC1COCCN1Cc1nccc(Cl)n1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCC1COCCN1Cc1nccc(Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
{4-[(4-Chloropyrimidin-2-yl)methyl]morpholin-3-yl}methanol (200 mg, 0.821 mmol) was taken up in DCM (4 mL) and cooled to 0° C. DAST (0.119 mL, 0.903 mmol) was added and the resulting mixture stirred at 0° C. for 90 minutes. Saturated NaHCO3 was added and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (12-100% EtOAc-hexanes) followed by HPLC (10-40% MeCN—H2O) gave the title compound as a pale yellow gum.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].[C:19](=[S:21])=[S:20].[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>CS(C)=O>[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][S:20][C:19]([N:2]2[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:21])=[CH:25][CH:24]=1
Reactant: S=C=S
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: Cc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ccc(CSC(=S)N2Cc3[nH]c4ccccc4c3CC2C(=O)O)cc1

Procedure:
In the same manner as described in Example 16, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (4.22 g), 10N NaOH (3.9 ml), carbon disulfide (1.4 ml), dimethylsulfoxide (12 ml) and 4-methylbenzyl chloride (3.3 g) are reacted and treated. The product is crystallized from ethanol to give the title compound (3.13 g), m.p. 188°-190° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6](=[O:25])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15](I)=[CH:14][C:13]=2[F:24])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[F-].[Cs+].O.CCOC(C)=O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH2:4][O:5][C:6](=[O:25])[CH:7]([C:12]2[C:13]([F:24])=[CH:14][C:15]([C:31]3[CH:32]=[CH:33][C:28]([C:27]([F:38])([F:37])[F:26])=[CH:29][CH:30]=3)=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH:17]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH2:2]1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(OCC2CC2)c(I)cc1F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CC(C(=O)OCC1CC1)c1cc(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)cc1F

Procedure:
To a solution of 2-(5-cyclopropylmethoxy-2-fluoro-4-iodo-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.2 g, 0.43 mmol) in anhydrous DME (10 mL) under argon was added 4-trifluoromethylphenylboronic acid (0.1 g, 0.53 mmol), CsF (0.16 g, 1.05 mmol), and Pd(PPh3)4 (0.015 g, 0.013 mmol). The reaction mixture was refluxed for 18 h, a water/EtOAc 15/15 mL mixture was added and the organic phase was separated and dried over MgSO4. The solvent was then evaporated to give a yellow oil which was purified by column chromatography over silica gel (Heptane-EtOAc gradient) to give 0.18 of 2-(2-cyclopropylmethoxy-5-fluoro-4′-trifluoromethyl-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a light yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.70-7.64 (m, 4H), 7.05 (d, J=10.4 Hz, 1H), 7.01 (d, J=6.1 Hz, 1H), 4.09 (t, J=7.7 Hz, 1H), 4.02-3.87 (m, 2H), 3.78 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.74-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.25-1.05 (m, 2H), 0.95 (d, J=6.3 Hz, 6H), 0.60-0.40 (m, 4H), 0.30-0.10 (m, 4H). 13C NMR (75 MHz, CDCl3/TMS): δ 173.5, 154.3 (d, 1JCF=239.7 Hz), 151.9, 140.7, 132.0, 129.5, 126.6 (d, 2JCF=16.9 Hz), 124.8 (q, 3JCF=3.7 Hz), 124.0 (q, 1JCF=271.6 Hz), 117.0 (d, 2JCF=24.6 Hz), 113.6, 74.1, 69.6, 41.1, 41.5, 26.1, 22.7, 22.2, 10.2, 9.8, 3.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.Cl.N[C:32](N)=N.ClC1C2C(=CC=C(S(NC3(C(OC)=O)CCOCC3)(=O)=O)C=2)C(Cl)=CN=1.NC(N)=N>CS(C)=O.O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:23]([O:25][CH3:32])=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1
Reactant: N=C(N)N
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCOCC3)cc12
Agent: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCOCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCOCC1
Temperature: 50 °C
Yield: 16.6 %

Procedure:
4-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}tetrahydro-2H-pyran-4-carboxylic acid hydrochloride ##STR55## NaH (33.5 mg, 80% dispersion by wt in mineral oil, 1.12 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (176 mg, 1.84 mmol) in DMSO (3.0 mL) under N2 and the mixture was heated at 50° C. for 15 min. Methyl 4-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino}tetrahydro-2H-pyran-4-carboxylate (187 mg, 0.446 mmol) was added in one portion and the mixture heated at 80° C. for 8 h. A second portion of guanidine (0.45 mmol) [prepared from guanidine hydrochloride and NaH] in DMSO (1.0 mL) was added and the mixture heated at 90° C. for an additional 4 h. The cooled mixture was poured into water (100 mL), extracted with EtOAc (3×50 mL) and the combined organic extracts were washed with brine, dried (Na2SO4). The solvents were evaporated in vacuo and the residue purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880NH3 (95:5:0.5) as eluant, and then crystallised with EtOAc, to give to give methyl 4-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}tetrahydro-2H-pyran-4-carboxylate (83 mg, 0.186 mmol) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:26][C:27]1[C:32]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:31][CH:30]=[CH:29][N:28]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH2:11][N:36]2[CH2:37][CH2:38][CH:33]([C:32]3[C:27]([F:26])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:34][CH2:35]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: Fc1ncccc1C1CCNCC1
Product: COc1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(c2cccnc2F)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 86 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.38 g) was coupled to 4-(2-fluoro-3-pyridyl)piperidine (0.47 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.25 g); mp 99-148° C. (d); MS: m/z=542(M+1); NMR(CD3OD): 2.1 (m,4), 2.5-2.6 (m,2), 2.9 (m,1), 3.1-3.2 (m,5), 3.6-3.8 (m,6), 4.8 (d,1, J=4), 6.7-7.5 (m,6), 7.8-8.1 (m,3). Analysis for C28H30Cl2N3O2F.HCl.H2O: Calculated: C, 58.35; H, 5.57, N, 7.04; Found: C, 57.99; H, 5.47; N, 7.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].C([O-])([O-])=O.[K+].[K+].[CH2:18]=O.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=1>C(O)C>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH2:28][CH2:29][N:30]([CH2:18][NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:31][CH:32]=1
Reactant: C1=C(c2ccccn2)CCNC1
Reactant: COc1cccc(C(N)=O)c1
Reactant: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cccc(C(=O)NCN2CC=C(c3ccccn3)CC2)c1
Temperature: 25 °C
Yield: 27.8 %

Procedure:
3-Methoxybenzamide (1.13 g, 7.5 mmol), K2CO3 (345 mg, 2.5 mmol), paraformaldehyde (0.5 g, 16 mmol), and 1′,2′,3′,6′-tetrahydro-2,4′-bipyridine hydrochloride (393 mg, 2 mmol) were combined in ethanol (25 ml) and refluxed for 18 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (80 mL) and water (80 mL). The organic layer was washed with brine (2×50 mL), dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with ethyl acetate:ethanol, 9.0:1.0) to provide the title compound (180 mg, 49% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.58 (m, 2H), 2.76 (t, 2H, J=6 Hz), 3.29 (m, 2H), 3.80 (s, 3H), 4.27 (d, 2H, J=6 Hz), 6.70 (m, 1H), 7.09 (m, 1H), 7.22 (m, 1H), 7.42 (m, 4H), 7.72 (m, 1H), 8.51 (m, 1H), 8.83 (t, 1H, J=6 Hz); MS (DCI/NH3) m/e 324 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[CH:14]=[C:15]([C:20]2[S:24][C:23]([NH:25][C:26](=[O:28])[CH3:27])=[N:22][C:21]=2[CH3:29])[CH:16]=[N:17][C:18]=1[Cl:19]>C1COCC1>[Cl:19][C:18]1[N:17]=[CH:16][C:15]([C:20]2[S:24][C:23]([NH:25][C:26](=[O:28])[CH3:27])=[N:22][C:21]=2[CH3:29])=[CH:14][C:13]=1[NH:12][C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:11]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NC(=O)Nc3ccc(F)cc3F)c2)s1
Temperature: 50 °C

Procedure:
2,4-Difluorophenyl isocyanate (0.022 mL) was added to a stirred solution of N-[5-(5-amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (50 mg) in THF (1 mL) and the resultant solution was stirred and heated to 50° C. for 1 hour. The mixture was cooled to room temperature and concentrated by evaporation. The residue was purified by preparative HPLC. There was thus obtained the title compound as a white solid (20 mg); 1H NMR Spectrum: (DMSOd6) 2.16 (s, 3H), 2.39 (s, 3H), 7.05-7.08 (m, 1H), 7.33-7.37 (m, 1H), 8.09-8.14 (m, 1H), 8.17 (s, 1H), 8.67 (m, 1H), 8.67 (s, 1H), 9.48 (s, 1H); Mass Spectrum: M+H+ 438.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=2[Cl:41])[CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[CH:43]([N-]C(C)C)([CH3:45])[CH3:44].[Li+].IC(I)(C)C>C1COCC1>[CH3:1][O:2][C:3]([C:4]1([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[C:32]=3[Cl:41])[CH2:16][CH:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:6]=2)[CH2:45][CH2:43][CH2:44]1)=[O:42]
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)[N-]C(C)C
Agent: CC(C)(I)I
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of (3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetic acid methyl ester (100 mg, 0.17 mmol) in dry THF (50 ml) was added lithium diisopropylamide (1.26 ml, 0.5 mmol) dropwise with cooling to −78° C. After the reaction mixture was stirred at −78° C. for an additional 1 h, diiodo-propane (152 mg, 0.51 mmol) was added. The reaction was warmed to room temperature over 4 h followed by quenching with saturated ammonium chloride (10 ml). Solvent was removed and the residue was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatograph (EtOAc:Hexane/20:80) to give the title compound as an oil (40 mg, 50%). MS m/e 636.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH2:17]=O>O1CCOCC1>[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH:12]1[CH2:17][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: C=O
Reactant: CN1CCNCC1
Reactant: CC(=O)c1ccccc1
Solvent: C1COCCO1
Product: CN1CCNCC1CCC(=O)c1ccccc1

Procedure:
Acetophenone (120 mg), N-methylpiperazine (100 mg), and paraformaldehyde (36 mg) were reacted in dioxane (0.2 ml) at 150° C. for 2 hours.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][C:17]2([NH:20]C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H].[NH2:30][C:31]1[C:40]([F:41])=C(F)[C:38]([F:43])=[C:37]2[C:32]=1[C:33](=[O:51])[C:34]([C:48]([OH:50])=[O:49])=[CH:35][N:36]2[C@@H:44]1[CH2:46][C@@H:45]1[F:47]>CO.[Pd]>[NH2:30][C:31]1[C:40]([F:41])=[C:9]([N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]3([NH2:20])[CH2:18][CH2:19]3)[CH2:12]2)[C:38]([F:43])=[C:37]2[C:32]=1[C:33](=[O:51])[C:34]([C:48]([OH:50])=[O:49])=[CH:35][N:36]2[C@@H:44]1[CH2:46][C@@H:45]1[F:47]
Reactant: [H][H]
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC(C)(C)OC(=O)NC1(CC2CCN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1c(F)c(N2CCC(CC3(N)CC3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.1 %

Procedure:
1-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine (originated from F4 of Reference Example 4; 200 mg, 0.534 mmol) was dissolved in anhydrous methanol (20 ml), and the solution was mixed with 10% palladium on carbon catalyst (water content 50%, 200 mg) and stirred at room temperature for 1 hour in an atmosphere of hydrogen under atmospheric pressure. After filtration of the reaction solution through celite, the resulting filtrate was concentrated under a reduced pressure. The thus obtained residue and triethylamine (3 ml) were added to dry acetonitrile (15 ml), and the mixture was further mixed with 5-amino-6,7,8-trifluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (141 mg, 0.445 mmol) and heated under reflux for 16 hours. After cooling of the reaction solution, the thus precipitated crystals were collected by filtration, washed with acetonitrile, mixed with concentrated hydrochloric acid (10 ml) under ice-cooling and then stirred at room temperature for 5 minutes. This was mixed with distilled water (20 ml), and the thus obtained acidic aqueous solution was washed with dichloromethane (20 ml×2), adjusted to pH 11 with sodium hydroxide aqueous solution under ice-cooling and then washed with chloroform (20 ml). The resulting basic aqueous solution was adjusted to pH 7.4 with 1 N hydrochloric acid and extracted with chloroform (100 ml×4). After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. Thereafter, the resulting residue was purified by recrystallizing from ethanol-28% aqueous ammonia and then dried under a reduced pressure, thereby obtaining 138 mg (71.1%) of the title compound as yellow needle crystals.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=[C:11]([C:19]4[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH3:29])=[O:27])=[CH:21][CH:20]=4)[N:10]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.[CH3:30]N=C=O>>[CH:5]12[N:8]([C:9]3[CH:14]=[C:13]([CH2:15][N:16]([CH3:18])[CH3:17])[N:12]=[C:11]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:24]=4)[N:10]=3)[CH:1]([CH2:7][CH2:6]1)[CH2:2][O:3][CH2:4]2
Reactant: CN=C=O
Reactant: CNC(=O)Nc1ccc(-c2nc(CN(C)C)cc(N3C4CCC3COC4)n2)cc1
Product: CCNC(=O)Nc1ccc(-c2nc(CN(C)C)cc(N3C4CCC3COC4)n2)cc1
Yield: 21 %

Procedure:
A procedure similar to that used for the preparation of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-methylurea was used, substituting ethylisocyanate for methylisocyanate, to provide the mono-TFA salt of 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-ethylurea (0.014 g, 21%) as a white solid. MS: 411.4, M+H.