Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[N:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[N:23]=1
Reactant: Nc1nccc(Cl)n1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2nccc(Cl)n2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 4-Chloro-pyrimidin-2-ylamine instead of 3-chloroaniline to yield the final compound as a light brown solid, MS (ISP): m/e=361.1, 363.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH2:12][CH3:13])=[CH:10][C:5]=2[N:4]=[CH:3]1.[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=O)=[CH:21][CH:20]=1>>[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:11](\[C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][C:5]=3[CH:10]=2)/[CH2:12][CH3:13])=[CH:21][CH:20]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CCC(=O)c1ccc2c(c1)ncn2C
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2c(c1)ncn2C

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(1-methyl-1H-benzo[d]imidazol-5-yl)propan-1-one (730 mg, 2.2 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (500 mg, 1.0 eq) to give the separated (Z)-isomer and (E)-isomer of the product. (Z)-isomer: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.62 (s, 1H), 7.11-7.15 (m, 3H), 7.01 (dd, J=8.4 Hz, 1.2 Hz, 1H), 6.83 (dd, J=6.8 Hz, 2.0 Hz, 2H), 6.79 (dd, J=6.8 Hz, 2.0 Hz, 2H), 6.49 (dd, J=6.8 Hz, 2.0 Hz, 2H), 4.05 (t, J=5.6 Hz, 2H), 3.79 (s, 3H), 3.69 (t, J=6.0 Hz, 2H), 2.53 (q, J=7.2 Hz, 2H), 0.91 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]1[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=1[C:12]([F:11])([F:26])[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1ccc(C(F)(F)F)cc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 26.5 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2,4-bis(trifluoromethyl)phenylboronic acid (Ryscor; 1.75 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 μL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2,4-bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (646 mg, 36%) as a solid.
Reaction SMILES: [S:1](N)(N)(=[O:3])=[O:2].[NH2:6][C:7]1[C:8]([CH:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[NH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2>N1C=CC=CC=1>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:17]2[C:8]3[CH:9]=[CH:10][C:11]4[C:16](=[N:15][CH:14]=[CH:13][CH:12]=4)[C:7]=3[NH:6][S:1](=[O:3])(=[O:2])[N:18]2[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=1
Reactant: NS(N)(=O)=O
Reactant: CN(C)CCNC(c1ccc(F)cc1)c1ccc2cccnc2c1N
Solvent: c1ccncc1
Product: CN(C)CCN1C(c2ccc(F)cc2)c2ccc3cccnc3c2NS1(=O)=O
Temperature: 120 °C
Yield: 18.6 %

Procedure:
Sulfamide (272 mg, 2.84 mmol) was added to a solution of N-[(8-amino-quinolin-7-yl)-(4-fluoro-phenyl)-methyl]-N′,N′-dimethyl-ethane-1,2-diamine 415 (160 mg, 0.47 mmol) in pyridine (1.5 ml) and the mixture was heated at 120° C. for 1.5 h in a sealed tube. After cooling, the solvent was removed in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (98:2) to give the title compound (35 mg, 18%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:16][C:15](=[O:17])[C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OCC)C>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:17])=[O:16])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)o2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccccc2)cc1
Yield: 8.9 %

Procedure:
To a stirred solution of 2-(4-tert-butylphenyl)-4H-3,1-benzoxazin-4-one (1.0 g, 3.6 mmol) in toluene (15 mL) was added aniline (0.33 g, 3.6 mmol). After refluxing for 8 h, the solution was allowed to cool, diethyl ether was added, and the precipitate was filtered and dried In vacuo to give 120 mg (9%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[C:29]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)[CH:28]=[CH:27][C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]

Procedure:
In an analogous procedure to that described in Example 15, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-5chloro-2-nitrobenzamide was reacted with 1-methylpiperazine to give the title compound; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 2.24 (s, 3H), 2.41-2.47 (m, 4H), 2.63-2.69 (m, 2H), 3.46-3.53 (m, 8H), 3.69-3.72 (m, 4H), 7.0 (s, 1H) 7.04-7.12 (m, 2H), 7.19 (d, 1H), 7.25 (s, 1H), 7.57 (d, 1H), 7.88 (s, 1H), 8.04 (d, 1H), 8.26 (d, 1H), 9.83 (s, 1H), 10.33 (s, 1H); Mass Spectrum: M+H+ 560.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>CC(O)C>[O:16]1[C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([CH3:19])=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]5)=[N:32][CH:31]=4)[N:7]=3)=[CH:18][C:13]=2[NH:14][C:15]1=[O:17]
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)nc2)nc1Nc1ccc2oc(=O)[nH]c2c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a vial with 5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (27.7 mg, 0.5 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4 mg, 1.0 mmol), i-PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vial was tightly closed, and the reaction mixture was stirred at 85° C. for 2 days. The solvents were removed in vacuo, and the crude product was purified by RP-HPLC. Purified compound (as a trifluoroacetate salt) was dissolved in MeOH—H2O (1:4, 2 mL) and was passed through a PL-HCO3-MP-SPE column, washing with same solvents (1 mL). The filtrate was collected and the solvent was removed by lyophilization. N4-(benzoxazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine was obtained as a purple solid, 23.1 mg (53% yield); 1H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.73 (s, 1H), 8.30-8.28 (m, 2H), 7.87-7.84 (m, 2H), 7.46-7.28 (m, 2H), 7.22 (d, J=8.5, 1H), 6.71 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H), 2.11 (s, 3H); LCMS (M+) m/z 433.52.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]([NH2:6])=[NH:5].Cl[C:8]1[N:13]=[C:12]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])[N:11]=[C:10]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:9]=1>O1CCOCC1>[C:28]([C:27]1[CH:30]=[CH:31][C:24]([NH:23][C:10]2[N:11]=[C:12]([CH2:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])[N:13]=[C:8]([NH:5][C:4]([NH2:6])=[NH:3])[N:9]=2)=[CH:25][CH:26]=1)#[N:29]
Reactant: N=C(N)N
Reactant: N#Cc1ccc(Nc2nc(Cl)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2nc(Cc3c(Cl)cccc3Cl)nc(NC(=N)N)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
NaOH (0.0128 mol), 1,4-dioxane (5 ml), and guanidine (0.0128 mol) were combined and stirred at RT for 5 minutes under argon. Then, intermediate (27) (0.00128 mol) was added and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was quenched with H2O, and stirred. The resulting precipitate was filtered off and the residue was stirred in refluxing methanol, cooled, and filtered, yielding 0.34 g (64.3%) of N-[4-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-guanidine (compound 20).
Reaction SMILES: Cl.[Br:2][C:3]1[S:4][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:10]=2[N:11]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:25][CH2:24][CH2:23]2)[CH2:18][CH2:17]1)=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:2][C:3]1[S:4][C:5]2[CH2:6][N:7]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH2:8][CH2:9][C:10]=2[N:11]=1
Reactant: Brc1nc2c(s1)CNCC2
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN1CCc2nc(Br)sc2C1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromo-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine hydrochloride (3.03 g, 11.86 mmol), 1-(chloroacetyl)-4-cyclobutylpiperazine (2.57 g, 11.86 mmol), K2CO3 (4.91 g, 35.58 mmol) and KI (166 mg, 1 mmol) in CH3CN (20 ml) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The layers are separated and the aqueous layer is extracted with EtOAc (3×30 mL). The combined extracts are washed with brine (50 μL), dried and evaporated. The resulting oil is purified by flash column with DCM/MeOH/NH4OH (100:5:0.5) to give the title compound as a light yellow solid. MS (M+1): 398.9; 1H NMR (δ, CDCl3): 3.72 (s, 2H), 3.56-3.65 (m, 4H), 3.41 (s, 2H), 2.81-2.95 (m, 4H), 2.67-2.76 (m, 1H), 2.27-2.32 (m, 4H), 1.65-2.08 (m, 6H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22](O)[C:23]4[S:24][CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:27]=4)[CH:20]=3)[NH:15][C:14](=[O:35])[C:13]=2[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:9]=[CH:10][CH:11]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]([Cl:3])[C:23]4[S:24][CH:25]=[C:26]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:27]=4)[CH:20]=3)[NH:15][C:14](=[O:35])[C:13]=2[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:9]=[CH:10][CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(O)c3nc(-c4ccccc4)cs3)ccc2[nH]c1=O
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2cccc(Cl)c2)c2cc(C(Cl)c3nc(-c4ccccc4)cs3)ccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (30 ml) was added dropwise to a mixture of intermediate (19) (0.0245 mol) in DCM (150 ml), previously cooled on an ice bath. The mixture was stirred at a low temperature for 1 hour and at room temperature overnight. The solvent was evaporated till dryness. The product was used without further purification, yielding (quant.) of ethyl 4-(3-chlorophenyl)-6-[chloro(4-phenyl-2-thiazolyl)methyl]-1,2-dihydro-2-oxo-3-quinolinecarboxylate (intermediate 20).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([NH2:12])=[N:8]1)#[N:2].[F:13][C:14]([F:20])([F:19])[CH2:15][N:16]=[C:17]=[S:18]>C(#N)C>[F:13][C:14]([F:20])([F:19])[CH2:15][NH:16][C:17](=[S:18])[NH:12][C:9]1[N:10]=[CH:11][N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[N:8]=1
Reactant: N#CCCCCn1cnc(N)n1
Reactant: FC(F)(F)CN=C=S
Solvent: CC#N
Product: N#CCCCCn1cnc(NC(=S)NCC(F)(F)F)n1
Yield: 42.3 %

Procedure:
The crude 1-(4-cyanobutyl)-3-amino-1,2,4-triazole (5.45 g.) in acetonitrile (80 ml.) was treated with 2,2,2-trifluoroethylisothiocyanate (4.4 g.) and the solution heated under reflux for 3.5 hours. Evaporation gave a white sticky solid which was triturated with ether/EtOH to give 5-(3-[3-(2,2,2-trifluoroethyl)thioureido]-1,2,4-triazol-1-yl)valeronitrile (4.04 g.) as a white solid, m.p. 136°-138°.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:11]1[CH:16]=[C:15]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[N:14]=[C:13]([N:18]([CH3:20])[CH3:19])[N:12]=1
Reactant: NCc1ccccc1F
Reactant: CN(C)c1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(C)c1nc(Cl)cc(NCc2ccccc2F)n1

Procedure:
Analogously to Example 12, 13.9 g (110 mmol) of 2-fluorobenzylamine, 21.3 g (110 mmol) of 4,6-dichloro-2-(N,N-dimethylamino)-pyrimidine and 11.5 g (114 mmol) of triethylamine are dissolved in 300 ml of absolute ethanol and the mixture is heated under reflux for 48 hours. After the ethanol has been removed by distillation, water is added to the residue, the product is filtered off with suction and recrystallisation from cyclohexane yields 4-chloro-2-(N,N-dimethylamino)-6-(2-fluorobenzylamino)-pyrimidine having a melting point of 71°-73°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[N:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=2[N:21]([CH2:36][CH3:37])[C:20]1=[O:38]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[N:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]3[CH:32]=[CH:33][CH:34]=[CH:35][C:22]=3[N:21]([CH2:36][CH3:37])[C:20]2=[O:38])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: CCN1C(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)N=C(c2ccccc2)c2ccccc21

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-2,3-dihydro-1-ethyl-5-phenyl-1H-1,4-benzodiazepin-2-one (prepared as described in Example 8-X using ethyl iodide), the title compound was prepared as a solid having a melting point of 155-158° C. The reaction was monitored by tlc on silica gel (Rf=0.48 in 10% methanol/dichloromethane) and purification was by silica gel chromatography using 10% methanol/dichloromethane as the eluant, followed by recrystallization from diethyl ether.
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6]C)=[O:5].O1CCOCC1.[OH-].[Na+]>CO>[OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCCCCCCCC[C@@H](O)CC(=O)O
Yield: 97.9 %

Procedure:
Under nitrogen and while stirring there were added dropwise to a solution of 129.2 g of methyl (R)-3-hydroxytetradecanoate, 1033 ml of dioxan and 122.9 g of 28 percent sodium hydroxide solution. 77.5 ml of methanol were added dropwise to the solution. After stirring for a further 1.5 hours the resulting suspension was filtered and the filter cake was washed with 1000 ml of dioxan and filtered off. The filter cake was adjusted to pH 0 by the addition of 650 ml of 1.5N hydrochloric acid. The suspension was stirred, filtered, the filter cake was washed with 3000 ml of water and the crystals were dried. 119.64 g (98%) of (R)-3-hydroxytetradecanoic acid, m.p. 70.6°-71.4°, were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18](Cl)=[O:19])[CH3:2].[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[O:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([NH2:36])=[C:31]([F:37])[CH:30]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Br:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[O:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([NH:36][C:18]([C:5]2[C:6](=[O:17])[N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH2:1][CH3:2])=[O:19])=[C:31]([F:37])[CH:30]=1
Reactant: Nc1cc(F)c(Oc2ccncc2Br)cc1F
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccncc2Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A suspension of 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride (freshly prepared from Example B2 (0.207 g, 0.747 mmol) using the method of Example 4) in THF (5 ml) was added to a 0° C. solution of Example A2 (0.15 g, 0.498 mmol) and N,N-diisopropylethylamine (0.870 ml, 4.98 mmol) in THF (5 ml). The mixture was allowed to warm to room temperature and stir overnight. Additional 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride [freshly prepared from Example B2 (0.207 g, 0.747 mmol)] was added and the mixture was stirred overnight at RT. Additional 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonyl chloride [freshly prepared from Example B2 (414 mg, 0.996 mmol)] was added to the reaction mixture. After stirring for 3 h, the mixture was partitioned between CH2Cl2 and sat. Na2CO3 (aq) and extracted with sat. Na2CO3 (aq) (2×). The organic extract was dried and evaporated. The crude product was purified by silica gel chromatography (hexanes/EtOAc) to yield N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.124 g, 44.4% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.24 (s, 1H), 8.74 (s, 1H), 8.37 (m, 2H). 7.92 (d, J=7.8 Hz, 1H), 7.59 (dd. J=10.9, 7.4 Hz, 1H), 7.48 (dd, J=8.8, 4.9 Hz, 2H), 7.36 (t, J=8.7 Hz, 2H), 6.88 (d, J=5.6 Hz, 1H); 6.55 (d, J=7.9 Hz, 1H); 4.28 (q, J=7.0 Hz, 2H); 1.33 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 560.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].CN(C)C1C=CC=CC=1.[Br:19][CH2:20][C:21](Br)=[O:22]>CC(C)=O>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][C:21](=[O:22])[CH2:20][Br:19]
Reactant: O=C(Br)CBr
Reactant: Nc1cc(Cl)ccc1O
Solvent: CN(C)c1ccccc1
Solvent: CC(C)=O
Product: O=C(CBr)Nc1cc(Cl)ccc1O
Reaction time: 0.75 h
Yield: 52.6 %

Procedure:
To a mixture of 2-amino-4-chlorophenol (19.50 g.) and N,N-dimethylaniline (19.90 g.) in dry acetone (200 ml.) was added dropwise bromoacetyl bromide (33.2 g.) over a period of 15 minutes under ice-cooling at below 10° C. with stirring and stirring was continued for 45 minutes at the same temperature. The reaction mixture was evaporated and to the residue were added ethyl acetate and water. The ethyl acetate layer was washed with 5% hydrochloric acid (twice), water, 5% aqueous solution of sodium bicarbonate, water (twice) and a saturated aqueous solution of sodium chloride successively, dried over magnesium sulfate, treated with activated charcoal and then evaporated. The residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give the title compound (18.91 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[N:10]([CH3:21])[C:9]=2[C:22]([OH:24])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:25][NH:26][CH3:27]>ClC(Cl)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11](=[O:20])[N:10]([CH3:21])[C:9]=2[C:22]([N:26]([CH3:27])[CH3:25])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC
Reactant: COc1ccc2c(=O)n(C)c(C(=O)O)c(-c3cccc(F)c3)c2c1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: COc1ccc2c(=O)n(C)c(C(=O)N(C)C)c(-c3cccc(F)c3)c2c1
Reaction time: 0.5 h

Procedure:
The acid chloride of 11 (80 mg, 0.mmol mmol) was added to a solution of excess dimethylamine in dichloroethane containing a catalytic amount of DMAP at room temperature. After stirring for 30 min the reaction mixture was washed with 1M HCl then brine. Drying (Na2SO4) and concentration gave the amide 12.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[N:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1>>[N:10]1[CH:15]=[CH:14][C:13]([CH:16]([OH:17])[C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)=[CH:12][CH:11]=1
Reactant: Ic1ncn2ccsc12
Reactant: O=Cc1ccncc1
Product: OC(c1ccncc1)c1ncn2ccsc12

Procedure:
7-[(Pyridin-4-yl)hydroxymethyl]imidazo[5,1-b]-thiazole (1.32 g) was prepared in the same manner as in step a) of Synthesis Example 1, except that 2.50 g of 7-iodoimidazo[5,1-b]thiazole and 1.05 ml of pyridine-4-aldehyde were used as the starting compounds.
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[S:18]([NH2:21])(=[O:20])=[O:19])C1C=CC=CC=1.O>[Pd].CO>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=1[S:18]([NH2:21])(=[O:19])=[O:20]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 55 °C
Yield: 93.6 %

Procedure:
A mixture of 2-benzylamino-5-nitro-benzenesulfonamide (15 g, 48.81 mmol) and 5% palladium on activated carbon powder (wet, nominally 50% water, 6 g) in methanol (500 mL) was heated to 55° C. The mixture was degassed while stirring and the flask was charged with hydrogen gas via balloon. After stirring for 16 h under 1 atmosphere of hydrogen gas, the reaction was filtered through Celite and concentrated in vacuo to afford the desired product, 2,5-diamino-benzenesulfonamide (8.55 g, 45.67 mmol, 93.6%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ: 4.56 (2H, bs), 4.98 (2H, bs), 6.58-6.59 (2H, m), 6.87 (1H, d, J=1.6 Hz), 7.00 (2H, s). LC-MS (ESI) calcd for C6H9N3O2S 187.04, found 188.2 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][P:17]([O:21]CC)[O:18][CH2:19][CH3:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:19]([O:18][P:17]([CH2:2][C:3]([O:5][CH3:6])=[O:4])([CH2:16][CH2:15][CH2:14][CH2:13][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:21])[CH3:20]
Reactant: COC(=O)CBr
Reactant: CCOP(CCCCc1ccccc1)OCC
Product: CCOP(=O)(CCCCc1ccccc1)CC(=O)OC
Reaction time: 0.75 h

Procedure:
A mixture of 16.9 g. (0.11 mole) of methyl bromoacetate and 5.0 g. (0.019 mole) of (4-phenylbutyl)phosphonous acid, diethyl ester was heated on a 140°-150° oil bath until distillation of ethyl bromide was detected. An additional 16 g. (0.063 mole) of (4-phenylbutyl)phosphonous acid, diethyl ester was then gradually added to the reaction mixture. Heating was then continued for 45 minutes. After cooling to 100°, excess reagent was removed in vacuo to give 25 g. of crude product (Rf =0.25 silica gel/ethyl acetate). Impurities with higher Rf values were separated by flash chromatography using ethyl acetate. As a result, 18.3 g. of [ethoxy(4-phenylbutyl)phosphinyl]acetic acid, methyl ester were obtained.