Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:63]([NH2:67])([CH3:66])([CH3:65])[CH3:64]>C(Cl)Cl>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:67][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CC(C)(C)N
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC(C)(C)C)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and t-butylamine (0.040 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (39 mg, 88%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([Cl:18])[C:7]=1[C:8]1[N:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:18][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]1[N:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1)[CH:19]=[O:20]
Reactant: OCc1cc(Cl)c(-c2nnc3ccc(F)cn23)c(Cl)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1cc(Cl)c(-c2nnc3ccc(F)cn23)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.2 %

Procedure:
A suspension of Intermediate 13b (0.57 g, 1.80 mmol) in DCM (18 mL) at 0° C. was treated with Dess Martin periodinane (0.85 g, 2.00 mmol) and the solution was stirred at 0° C. for 1 h. The mixture was diluted with a saturated aqueous sodium bicarbonate solution and the layers were separated. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM containing a few drops of MeOH and purified by FCC, using 0-5% MeOH in DCM, to give the title compound (0.66 g, quant). LCMS (Method 3): Rt 3.03 min, m/z 328, 330 [MH+].
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH3:12][CH:13]([CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH2:14][CH2:15]Br>CO>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:15][CH2:14][CH:13]([CH3:12])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: CC(C)=CCCC(C)CCBr
Agent: [Na]
Solvent: CO
Product: CC(C)=CCCC(C)CCSc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2 g. of sodium in 50 ml. of methanol at about 0° is added about 35 g. of p-nitrophenyl mercaptan. After about 0.5 hour, about 15 g. of 3,7-dimethyloct-6-enyl bromide is added and then the mixture refluxed for about 3 hours. Then the solvent is evaporated and the concentrate taken up in petroleum ether which is washed with water, dried over magnesium sulfate and evaporated to yield 3,7-dimethyloct-6-enyl p-nitrophenyl sulfide which is used as the starting material in the process of Example 2 to yield 7-ethoxy-3,7-dimethyloctyl p-nitrophenyl sulfide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([CH3:11])=[N:8][C:6]=2[N:7]=1.[Se](=O)=[O:19]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([CH:11]=[O:19])=[N:8][C:6]=2[N:7]=1
Reactant: O=[Se]=O
Reactant: Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: C1COCCO1
Product: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 105 °C
Yield: 49 %

Procedure:
To a solution of 5-chloro-2-methyl-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine (102 mg, 0.38 mmol) in 1,4-dioxane (5 mL) was added selenium dioxide (51 mg, 0.46 mmol) and the solution heated at 105° C. for 6 h. The reaction mixture was cooled to RT and partitioned between DCM and brine. The organic layer was isolated, then dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as an orange solid (53 mg, 49%).
Reaction SMILES: [Br:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[CH3:13][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[CH3:13][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([CH:2]([Br:1])[CH3:3])=[CH:5][CH:6]=1
Reactant: CC(Br)c1ccc(C(=O)O)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc(C(C)Br)cc1

Procedure:
A solution of 4-(1-bromo-ethyl)-benzoic acid (2.70 g, 11.8 mmol) in diethyl ether (20 mL) and methanol (5 mL) was cooled to 0° C. and treated with trimethylsilyldiazomethane (2 M in diethylether, 11.8 mL). After 1 h at 0° C. the solvents were removed under reduced pressure, the residue was re-dissolved in ethyl acetate (20 mL) and washed with aqueous NaHCO3 solution. The organic layer was collected, dried over MgSO4 and evaporated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH2:13][O:14][CH3:15])[C:9]([OH:11])=O)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[C:3]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[C:24]#[N:25])=[CH:4][C:5](=[O:16])[N:6]([CH:8]([CH2:12][CH2:13][O:14][CH3:15])[C:9]([NH:26][C:27]2[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=2)=[O:11])[CH:7]=1
Reactant: COCCC(C(=O)O)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COCCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
417 mg (purity 76%, 0.83 mmol) of 2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoic acid (racemate) were reacted with 177 mg (0.91 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate according to General Method 5A. Yield: 438 mg (92% of theory)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([CH3:41])[CH:35]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][C:36]=3[CH3:41])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 54.6 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.145 g, 0.318 mmol) obtained in Example 145, step 2 and 4-fluoro-2-methylphenylamine (0.041 mL, 0.372 mmol), the title compound (0.095 g, 54%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[CH:27]=O)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[CH2:27][N:32]3[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1cccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)c1
Reactant: OC1CCNC1
Product: OC1CCN(Cc2cccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)c2)C1

Procedure:
The title compound was prepared following the procedure described for Example 94, starting from 3-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (100 mg; 0.24 mmol) and 3-pyrrolidinol (32.7 mg; 0.48 mmol) to give Example 134 as an off-white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.97 (1H, s), 7.96-7.84 (2H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.6 Hz), 7.59-7.49 (4H, m), 4.74 (1H, d, J=4.4 Hz), 4.29-4.21 (1H, m), 3.75-3.63 (2H, m), 2.75 (1H, dd, J=9.6, 6.2 Hz), 2.63 (1H, q, J=7.8 Hz), 2.51-2.45 (1H, m), 2.36 (1H, dd, J=9.6, 3.8 Hz), 2.10-1.99 (1H, m), 1.64-1.55 (1H, m). LC/MS (Method C): 484 (M+H)+. HPLC (Method E) Rt 2.13 min (Purity: 97.8%).
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:16][C:17]#[N:18]>CS(C)=O>[CH2:1]1[CH:12]2[CH:4]([N:5]([CH2:16][C:17]#[N:18])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: N#CCCl
Reactant: c1ccc2c(c1)NC1CCCC21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCN1c2ccccc2C2CCCC21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole (22 mmol, 3.5 g) in DMSO (44 mL) was added 60% sodium hydride (24 mmol, 0.97 g) portionwise, followed by 2-chloroacetonitrile (33 mmol, 2.1 mL). The reaction mixture stirred at ambient temperature for 18 h and then additional 60% sodium hydride (22 mmol, 0.88 g) and 2-chloroacetonitrile (24 mmol, 1.5 mL) was added. The reaction was heated to 60° C. for 18 h. The reaction was concentrated and the diluted with ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash column chromatography through silica gel (elution with 60% ethyl acetate-hexanes) to afford the desired material.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:28]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1ccco1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 48.9 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (3 g, 9.1 mmol) and furan-2-sulfonyl chloride (1.81 g, 10.9 mmol) the title compound was obtained (2.0 g, 48.9% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.74-10.87 (br, 1H), 8.53 (d, J=5.3 Hz, 1H), 7.91-7.93 (m, 1H), 7.33-7.38 (m, 1H), 7.21-7.28 (m, 3H), 7.10-7.13 (m, 1H), 6.98 (d, J=5.3 Hz, 1H), 6.57-6.60 (m, 1H), 3.23-3.35 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (ES+): 661 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:20]=4[NH:21][C:22]=3[CH:23]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:36]>>[ClH:36].[ClH:36].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:27][NH:26][CH2:25][CH2:24][C:20]=4[NH:21][C:22]=3[CH:23]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc3c2C1
Agent: Cl
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c3c([nH]c2c1)CCNC3
Yield: 26 %

Procedure:
Prepared from tert-butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (150 mg, 0.32 mmol) according to the procedure of Example 1 (step d). Purification by flash column chromatography (4 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 85% methylene chloride over 30 min) provided the free-base as a yellow solid. This was converted to the bis-HCl salt (2 N HCl/Et2O in CH2Cl2) providing the title compound (36 mg, 26%) as a yellow solid: mp 240° C. dec.; 1H NMR (500 MHz, CD3OD) δ 7.65 (d, J=7.5 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.47 (d, J=7.2 Hz, 2H), 7.42-7.36 (m, 4H), 7.03 (d, J=8.5 Hz, 1H), 6.39 (dd, J=7.6, 2.5 Hz, 1H), 6.21 (d, J=2.5 Hz, 1H), 5.21 (s, 2H), 4.47 (s, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.20 (t, J=6.1 Hz, 2H); ESI MS m/z 372 [M+H]+; HPLC (Method A) 95.0% (AUC), tR=12.2 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)C(Cl)=O)([O-:26])=[O:25]>C(Cl)(Cl)Cl>[CH3:12][O:11][C:9]1[C:8]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:1][C:34]2[CH:33]=[CH:29][CH:28]=[C:27]([N+:24]([O-:26])=[O:25])[CH:35]=2)[CH:10]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COCCOc1cc(C(N)=O)c(N)cc1OC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COCCOc1cc(C(N)=O)c(Nc2cccc([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-amino-4-methoxy-5-(2-methoxyethoxyl)benzamide (1.78 g, 7.40 mmol) and pyridine (2.40 mL, 29.6 mmol) in CHCl3 (40 mL) was added 3-nitrobenzoyl chloride (1.44 g, 7.8 mmol). The mixture was stirred at RT for 2.5 h upon which the mixture was concentrated in vacuo to give the desired product, which was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH:11]1[CH2:13][C:12]1([F:15])[F:14])[OH:10].[C:16](OC(C1CC1(F)F)C1C=CC(C(F)(F)F)=CC=1)(=[O:18])[CH3:17]>>[C:16]([O:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH:11]1[CH2:13][C:12]1([F:15])[F:14])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(c1ccc(C(F)(F)F)cc1)C1CC1(F)F
Reactant: OC(c1ccc(Cl)cc1Cl)C1CC1(F)F
Product: CC(=O)OC(c1ccc(Cl)cc1Cl)C1CC1(F)F

Procedure:
The title compound was prepared starting from 8.20 g (32.4 mmol) of a mixture of the two diastereomers of the compound from Example 191A in analogy to the synthesis of the compound from Example 192A. 7.70 g (81% of theory) of the title compound were obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.Cl.[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([CH3:35])[C:26]([N:29]3[CH2:30][CH2:31][N:32]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:8][C:9]=4[O:16][CH3:17])=[O:13])[CH2:33][CH2:34]3)=[N:27][CH:28]=2)[CH2:22][CH2:21]1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 73 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (271 mg) described in Preparation Example 19 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 86, the title compound (343 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(OCC)=O)=NC(OCC)=O.O[C:26]1[CH:42]=[CH:41][C:29]2[CH2:30][CH:31]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:32](=[O:35])[NH:33][CH2:34][C:28]=2[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:26]1[CH:42]=[CH:41][C:29]2[CH2:30][CH:31]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:32](=[O:35])[NH:33][CH2:34][C:28]=2[CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: COC(=O)CC1Cc2ccc(O)cc2CNC1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)CC1Cc2ccc(OCCCNC(=O)OC(C)(C)C)cc2CNC1=O
Reaction time: 18 h
Yield: 67.7 %

Procedure:
A solution of 3-[(tert-butoxycarbonyl)amino]-1-propanol (0.14 g, 0.8 mmol) and diethyl azodicarboxylate (0.13 mL, 0.8 mmole) in anhydrous DMF (2 mL) was added dropwise to a solution of methyl (±)-8-hydroxy-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.10 g, 0.4 mmole) and triphenylphosphine (0.21 g, 0.8 mmol) in anhydrous DMF (1.4 mL) and dry THF (2 mL) at RT under argon. The resulting solution was stirred for 18 hr, then was concentrated under vacuum. Silica gel chromatography (1%-3% MeOH/CH2Cl2) gave the title compound (0.11 g): MS (ES) m/e 407.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:14]([O:16][P:17]([O-:21])[O:18][CH2:19][CH3:20])[CH3:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:16][P:17]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cccc(P(=O)(OCC)OCC)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(3-bromophenyl)acetate, 35i-b, (22.1 g, 90 mmol), diethylphosphite (25.1 g, 180 mmol) and triethylamine (27.5 g, 270 mmol) in toluene (300 mL) was added [1,1′-bis(diphenylphosphino) ferrocene]dicholoropalladium (3 g). The mixture was allowed to stir overnight at 110° C. and was filtered. The solution was concentrated to afford the crude product which was purified by column chromatography to give the title compound, 35i-c as yellow brown oil (26 g, crude). 1H NMR (300 MHz, CDCl3): δ 1.20-1.32 (m, 9H), 3.62 (s, 2H), 4.00-4.16 (m, 6H), 7.36-7.47 (m, 2H), 7.64-7.71 (m, 2H). LC-MS (M+H)+ 301.
Reaction SMILES: C1(O[C:8](=[O:19])[NH:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])C=CC=CC=1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)(=O)C>[CH:20]1([NH:26][C:8]([NH:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])=[O:19])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC1CCCCC1
Reactant: O=C(NOc1cccc(Cl)c1Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NOc1cccc(Cl)c1Cl)NC1CCCCC1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
4.00 g (13.4 mmole) of N-(2,3-dichlorophenoxy)carbamic acid phenyl ester synthesized in Reference Example 1 was dissolved in 60 ml of ethyl acetate. 3.32 g (33.5 mmole) of cyclohexylamine was added thereto, and the mixture was reacted at 60° C. for 12 hours. The reaction mixture was cooled to room temperature, and after an addition of 100 ml of ethyl acetate, it was washed with a 3% sodium hydroxide aqueous solution and then with a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane, whereby 2.84 g of the desired product was obtained as light brown crystals (yield: 70%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH2:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[N:20]#[C:21][NH2:22].C([O-])(=O)C>>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:21]([NH2:22])=[NH:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCOCCOC(=O)c1ccccc1
Reactant: N#CN
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: N=C(N)NCCOCCOC(=O)c1ccccc1
Temperature: 90 °C
Yield: 62.1 %

Procedure:
2.14 g (10.2 mmol) of 2-(2-aminoethoxy)ethyl benzoate and 0.624 g (10.4 mmol) of acetic acid were placed in a 50 ml two neck flask. While heating the flask in a 90° C. oil bath, 0.680 g (16.2 mmol) of cyanamide was added. After 6 hours of the reaction, the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=1/2 containing 0.5% acetic acid) to obtain 1.97 g of the title compound (wax-like, 6.33 mmol, 62.0% in yield) in the form of acetate. Results of the analysis of this compound are as follows.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[C:21]([C:24]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25])([OH:23])=[O:22].O.Cl>C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]2[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:21]([OH:23])=[O:22])[CH:32]=[CH:31][CH:30]=2)[CH:3]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 130 °C
Yield: 87.3 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (0.51 mmol) and 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid (0.61 mmol) in acetonitrile (2.5 mL) and aqueous sodium carbonate solution (0.4 M, 2.5 mL) is degassed with nitrogen for 5 minutes before addition of tetrakistriphenylphosphine palladium (0) (29.5 mg, 5 mol %). The reaction vessel is sealed and heated under microwave to 130° C. for 30 minutes. To the reaction mixture is added 2 mL of water, the pH is adjusted to about 7 using 2 N aqueous HCl and this mixture is extracted three times with ethyl acetate (30 mL). The combined extracts are washed with brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid as a solid (205 mg, 75%). LC/MS: RT=2.39 minutes, MS: 460 (M+H); 1H NMR [300 MHz, (CD3)2SO]: δ 12.38 (1H, s), 7.36-8.00 (7H, m), 6.58 (1H, s), 3.84 (3H, s), 3.58 (2H, m), 2.98 (2H, m), 1.54 (6H, s).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14](=[O:15])[CH:16]=[C:8]1[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
4-tert-Butylcyclohexanone (8.62 g, 56 mmol) was dissolved in toluene (200 ml). Methoxycarbonylmethylenetriphenylphosphorane (56.1 g, 168 mmol) was added with stirring and the reaction mixture was heated under reflux for 3 days. The solvent was removed in vacuo. The residue was dissolved in hot hexanes (100 ml) and cooled to room temperature. The precipitate was filtered off and the filtrate was evaporated in vacuo to afford a yellow oil which was then purified by chromatography (silica gel, hexane/ethyl acetate, 2:1 as eluant) to give the title compound as an oil (10.78g, 92%). 1H-NMR; δ (CDCl3) 5.60 (1H, s), 3.87 (1H, m), 3.69 (3H, s), 2.38-2.10 (2H, m), 2.03-1.77 (3H, m), 1.36-1.02 (3H, m) and 0.87 (9H, s).