Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([N:9]1[CH:16]2[CH2:17][N:12]([C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[CH2:15]2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7]>S(=O)(=O)(O)O>[C:6]([N:9]1[CH:16]2[CH2:17][N:12]([C:13]3[CH:21]=[C:20]([N+:1]([O-:4])=[O:2])[CH:19]=[CH:18][C:14]=3[CH2:15]2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7]
Reactant: CC(=O)N1CCN2CC1Cc1ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)N1CCN2CC1Cc1ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 6.9 %

Procedure:
Potassium nitrate (13.14 g.) was added in portions to a solution of 4-acetyl-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (26.43 g.) in concentrated sulfuric acid (100 ml.). The mixture was stirred for about three days at room temperature, then quenched in ice (1500 ml.). The resulting mixture was basified with aqueous sodium hydroxide (35%) and extracted with chloroform. The chloroform extract was dried over potassium carbonate, treated with charcoal, filtered and stripped of solvent. Recrystallization of the residue from isopropyl alcohol afforded 4-acetyl-9-nitro-3,4,5,6-tetrahydro-2H-1,5-methano-1,4-benzodiazocine (2.2 g., m.r. 142°-144° C. with resolidification and remelting, m.r. 162°-164° C.), the compound of Formula III wherein Q* is acetyl.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.CO.C(Cl)(Cl)Cl>CCO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:24]2[CH:25]=[C:20]([Cl:19])[N:21]=[CH:22][N:23]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1ccc(Br)cc1F
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(Br)ccc1Nc1cc(Cl)ncn1
Yield: 37.4 %

Procedure:
A solution of 4-bromo-2-fluoroaniline (701 mg, 3.69 mmol), diisopropylethylamine (0.70 mL, 4.03 mmol), and 4,6-dichloropyrimidine (500 mg, 3.36 mmol) in EtOH (10 mL) was heated in an 85° C. oil bath for 5 d. Flash chromatography (2% MeOH/CHCl3) of the residue gave 380 mg (37%) of N-(4-bromo-2-fluorophenyl)-6-chloropyrimidin-4-amine as a pale yellow solid. MS (m/z): 304, 302. A suspension of N-(4-bromo-2-fluorophenyl)-6-chloropyrimidin-4-amine (0.37 g, 1.22 mmol) and tert-butyl 3-aminophenylcarbamate (0.28 g, 1.35 mmol) in n-BuOH (4 mL) was heated in an oil bath at 120-130° C. for 6 h. The reaction mixture was cooled and concentrated to give 0.68 g of a brown foam. Flash chromatography gave 0.16 g (28%) tert-butyl 3-(6-[4-bromo-2-fluorophenyl]aminopyrimidin-4-yl)aminophenylcarbamate as a white solid. MS (m/z): (M+H) 476, 474. tert-Butyl 3-(6-[4-bromo-2-fluorophenyl]aminopyrimidin-4-yl)aminophenylcarbamate (0.15 g, 0.32 mmol) was taken up in 4M HCl in dioxane (5 mL). After several minutes a white solid began to precipitate. The mixture was allowed to stand for 3 h and was concentrated via rotary evaporation. Saturated aqueous sodium bicarbonate (5 mL) was added and the mixture was sonicated for several minutes. The solid was collected by filtration, was washed with water (5 mL), and was dried overnight under vacuum to give 0.12 g (100%) of 3-[6-(4-bromo-2-fluorophenylamino)-pyrimidin-4-yl-amino]-phenylamine (IR-17) as a white powder. MS (m/z): (M+H) 376, 374.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13](=[S:18])[NH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:19]([NH:22][C:23]1[CH:28]=[C:27]([CH2:29]OS(C)(=O)=O)[CH:26]=[CH:25][N:24]=1)(=[O:21])[CH3:20].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[C:19]([NH:22][C:23]1[CH:28]=[C:27]([CH2:29][S:18][C:13]2[C:12]([C:10]([NH:9][C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[O:11])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:26]=[CH:25][N:24]=1)(=[O:21])[CH3:20]
Reactant: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Reactant: CC(=O)Nc1cc(COS(C)(=O)=O)ccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(CSc2ncccc2C(=O)Nc2cc(C)cc(C)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Or the compound is also synthesized in the following method. N-(3,5-Dimethylphenyl)-2-thioxo-1,2-dihydropyridine-3-carboxamide (Reference compound No. 10-1, 200 mg, 0.77 mmol) and 2-acetylamino-4-methanesulfonyloxymethylpyridine (Reference compound No. 13-1, 190 mg, 0.77 mmol) were suspended in N,N-dimethylformamide (2.0 mL) under ice-cooling and under nitrogen atmosphere, then triethylamine (0.22 mL, 1.5 mmol) was added thereto, and then the mixture was stirred for 2 hours at room temperature. Ethyl acetate (40 mL) was added to the reaction mixture, and then the whole was washed with water (30 mL) and brine (20 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was filtered off with the solvent mixture consisting of diisopropyl ether and ethyl acetate and dried under reduced pressure at 40° C. to give 250 mg of the target compound as a pale yellow solid. (Yield 81%)
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH3:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].CC1C=C(CC2OC2)C=CC=1C=O>[OH-].[Na+]>[CH3:6][C:7]1[CH:14]=[C:13]([O:15][CH2:1][CH:3]2[O:5][CH2:4]2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: ClCC1CO1
Reactant: Cc1cc(O)ccc1C=O
Agent: Cc1cc(CC2CO2)ccc1C=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCC2CO2)ccc1C=O
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To epichlorohydrin (20 g., 0.216 mole) heated at 55° C. is added dropwise a solution of 2-methyl-4-hydroxybenzaldehyde (9.0 g., 0.066 mole) in 2.5 N sodium hydroxide solution (40 ml.). After the addition, the solution is allowed to stir an additional 3 hours at 55° C. and then at room temperature overnight. The oil is distilled to give 8.3 g. of 2-methyl-4-(2,3-epoxypropyl)benzaldehyde, m.p. 160°-170° C. at 1 mm. Hg.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([O:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+]>>[O:11]1[C:6]2=[C:5]3[C:10](=[CH:9][CH:8]=[C:7]2[C:14](=[O:16])[CH:13]=[CH:12]1)[N:1]=[CH:2][CH:3]=[CH:4]3
Reactant: O=C(O)CCOc1cccc2ncccc12
Agent: [NH4+]
Agent: [OH-]
Product: O=c1ccoc2c1ccc1ncccc12
Temperature: 0 °C

Procedure:
Polyphosphoric acid (26 ml) was heated at 90°-95° C. and stirred while 3-(5-quinolinoxy)-propionic acid (2.60 g, 0.0120 mole) was added in small portions. After heating for 2 hours the mixture was poured into 200 ml ice water, basified to pH 10 with concentrated ammonium hydroxide and extracted with 3×200 ml ethyl acetate. The combined organic plasma were dried over magnesium sulfate, filtered, and evaporated in vacuo to a solid, which were recrystallized from toluene, m.p. 146°-147° C.
Reaction SMILES: [CH2:1]([NH:4][C:5](/[CH:7]=[CH:8]/[C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][C:20]=2[O:28][CH3:29])=[CH:11][CH:10]=1)=[O:6])[CH2:2][CH3:3].Cl.CN(C)CCCN=C=NCC.[CH3:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49]([NH2:52])(=[O:51])=[O:50].N=C=N>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([NH:4][C:5](/[CH:7]=[CH:8]/[C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:52][S:49]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[CH3:42])(=[O:50])=[O:51])=[O:25])=[CH:21][C:20]=2[O:28][CH3:29])=[CH:11][CH:10]=1)=[O:6])[CH2:2][CH3:3]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: CCCNC(=O)/C=C/c1ccc2ccn(Cc3ccc(C(=O)O)cc3OC)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCNC(=O)/C=C/c1ccc2ccn(Cc3ccc(C(=O)NS(=O)(=O)c4ccccc4C)cc3OC)c2c1
Reaction time: 18 h
Yield: 71 %

Procedure:
A mixture of E-4-[6-[2-(propylcarbamoyl)vinyl]indol-1-ylmethyl]-3-methoxybenzoic acid (0.76 g), 4-dimethylaminopyridine (0.26 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.41 g), and 2-methylbenzenesulfonamide (0.36 g) in methylene chloride (20 ml) was stirred under an atmosphere of nitrogen for 18 hr. Further quantities of 4-dimethylaminopyridine (0.026 g), the carbodiimide (0.041 g), and the sulfonamide (0.036 g) were added, and stirring was continued for a further 5 hr. The mixture was diluted with methylene chloride (40 ml); washed with 1M hydrochloric acid, water (twice) and brine; dried (MgSO4); and evaporated to give a foam. Crystallization from hot acetonitrile provided the title compound (0.75 g, 71%) as an off-white solid; mp 240°-242°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18](Cl)[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A mixture of di-tert-butyl(6-chloro-3-nitropyridin-2-yl)imidodicarbonate (700 mg, 1.87 mmol), phenylboronic acid (274 mg, 2.25 mmol) and tetrakistriphenylphosphine palladium (217 mg, 0.187 mmol) were blanketed with argon and taken up in THF (15.0 mL) and 2M aq. Na2CO3 (3.74 mL). The suspension was purged with bubbling argon for 20 min, then the reaction was sealed and heated via microwave to 120° C. for 2 h. The reaction was cooled, diluted with EtOAc and filtered through celite. The filtrate was washed with water, brine, dried (MgSO4) and concentrated to afford material purified via MPLC, silica cartridge, 5-20% EtOAc in heptanes to afford the product as a light yellow solid. 1H NMR (DMSO-d6, 600 MHz) d 8.68 (d, J=8.5 Hz, 1H), 8.29 (d, J=8.5 Hz, 1H), 8.16-8.12 (m, 2H), 7.57-7.54 (m, 3H), 1.35 (s, 18H); MS cal'd 438 (M+Na)+, exp 438 (M+Na)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([NH2:16])[C:13]3[C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=4[S:10][C:9]=3[NH:8][C:7]=2[CH:21]=1.[CH2:22]([C@H:30]1[CH2:35]N[CH2:33][CH2:32][NH:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.C1(C)C=CC=CC=1.C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]=[C:14]([N:16]3[CH2:33][CH2:32][NH:31][C@@H:30]([CH2:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:35]3)[C:13]3[C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=4[S:10][C:9]=3[NH:8][C:7]=2[CH:21]=1
Reactant: NC1=Nc2ccc(F)cc2Nc2sc3ccccc3c21
Reactant: c1ccc(CC[C@H]2CNCCN2)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1ccc2c(c1)Nc1sc3ccccc3c1C(N1CCN[C@@H](CCc3ccccc3)C1)=N2
Temperature: 115 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
Combine 9-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine hydrogen chloride (287 mg, 0.9 mmol), (S)-2-phenethyl-piperazine (340 mg, 1.80 mmol) and diisopropylethyl amine (116 mg, 0.9 mmol) in DMSO (0.5 mL) and toluene (2.0 mL), stir and microwave (300 W, 125 ° C.) for 8 h, then heat to 115 ° C. for 22 h. Cool the reaction to RT, dilute with CH2Cl2, wash with H2O and brine. Dry the organic layer with by Na2SO4. The crude material purify by chromatography on silica gel, gradient (100% CH2Cl2 to 100% CH2Cl2:2N NH3/MeOH=25:1), give 137 mg of title compound.
Reaction SMILES: [C:1]([C:3]([N:8]1[C:12](=[O:13])[CH:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21]=O)[C:9]1=[O:23])([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[CH:4]([C:3]([CH3:7])([N:8]1[C:12](=[O:13])[C:11]2[C:10](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:21]=2)[C:9]1=[O:23])[C:1]#[N:2])([CH3:6])[CH3:5]
Reactant: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2ccccc2C=O)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CC(C)C(C)(C#N)N1C(=O)c2cc3ccccc3nc2C1=O
Yield: 81 %

Procedure:
A solution of N-(1-cyano-1,2-dimethylpropyl)-2-(o-formylanilino)maleimide (7.19 g, 0.023 mol) in xylene (300 ml) containing p-toluenesulfonic acid (0.3 g, 0.0016 mol) is heated at reflux for 4 hours using a Dean-Stark trap to collect the eliminated water. The reaction is cooled, evaporated under reduced pressure and dissolved in hot ethyl acetate which is passed through a 3 inch silica gel column. The ethyl acetate fractions eluted are combined to give a solid, mp 195°-195.5° C., 5.51 g, (81%) of 1,3-dihydro-α-isopropyl-α-methyl-1,3-dioxo-2-H-pyrrolo[3,4-b]quinoline-2-acetonitrile.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]2[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[N:21]=1)=O)(C)(C)C>CO>[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][C:12]1[S:13][C:14]2[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[N:21]=1
Reactant: CC(C)(C)OC(=O)NCCc1nc2c(s1)NCCCC2
Agent: Cl
Solvent: CO
Product: NCCc1nc2c(s1)NCCCC2
Reaction time: 5 h
Yield: 70.5 %

Procedure:
A solution (3 ml) of 4.75N hydrochloric acid in methanol was added to a solution (10 ml) of 2-[2-(tert-butoxycarbonylamino)ethyl]-5,6,7,8-tetrahydro-4H-thiazolo-[5,4-b]azepine (1.00 g) in methanol, and the whole was stirred for 5 hrs. at room temperature. The solvent was distilled off under reduced pressure. The residue was washed with ethyl ether, and recrystallized from a mixture of methanol and ethyl ether to give the title compound (0.64 g, 70.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:20])[CH:15](Br)[CH2:16][CH2:17][CH3:18])[CH3:12].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:20])[CH:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: CCCC(Br)C(=O)OCC
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(Oc1ccc(Cl)cc1C=O)C(=O)OCC
Temperature: 140 °C
Yield: 84.3 %

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (15 g, 0.1 mol), 2-bromo-pentanoic acid ethyl ester (27 g, 0.13 mol) and K2CO3 (27 g, 0.2 mol) in DMF (100 mL) was heated at 140° C. for 1 h. After cooled to room temperature, the mixture was poured into water and the water phase was extracted with EtOAc thrice. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash column to give the title compound as a colorless oil (24 g).
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[C:41]([CH3:42])=[CH:40][C:38](=[O:39])[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1.CC(O)C>N>[C@H:11]1([N:34]2[C:41]([CH3:42])=[CH:40][C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: Cc1cc(=O)[nH]c(=O)n1[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: N
Solvent: CC(C)O
Product: Cc1cc(=O)[nH]c(=O)n1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A solution of 40 (4.50 g, 7.86 mmol) was dissolved in sat. methanolic ammonia (60 mL). The reaction mixture was heated at 100° C. for 17 h in a steel bomb. The reaction vessel was cooled to room temperature and concentrated to yield an oil. The reside was further purified by silica gel flash column chromatography using dichloromethane and methanol (9:1) as the eluent. Pure fractions were collected and evaporated to give a white solid. This was further recyrstallized from 2-propanol to afford 1.98 g (94%) of pure 41: mp 175-177° C.; 1H NMR (Me2SO-d6) δ 2.24 (s, 3H, CH3), 3.42-3.57 (m, 2H, C5′H), 3.68 (m, 1H, C4′H), 4.0 (m, 1H, C3′H), 4.53 (m, 1H, C2′H), 4.68, 4.94, 5.22 (m, 3H, 3 OH, D2O exchangeable), 5.43 (d, 1H, C1′H, J1′,2′=3.85 Hz), 5.56 (s, 1H, C5H) and 11.25 (s, 1H, NH). Anal. Calc. for C10H14N2O6 (258.23): C, 46.51; H, 5.46; N, 10.85. Found: C, 46.66; H, 5.26; N, 10.66.
Reaction SMILES: [CH:1]1([C:7]2[N:8]=[C:9](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=3)[S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]1(=[O:32])[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[CH2:22]1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[N:8]=[C:9](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:32])[CH2:22][C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[C:25]([OH:27])=[O:26])[CH:17]=[CH:18][CH:19]=3)[S:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc(/C=C/c2nc(C3CCCCC3)cs2)c1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1C(=O)O)Nc1cccc(/C=C/c2nc(C3CCCCC3)cs2)c1
Yield: 93.7 %

Procedure:
A solution of 2.8 g of (E)-3-[2-[4-(cyclohexyl)-2-thiazolyl]ethenyl]benzeneamine, 1.78 g of homophthalic anhydride and 30 ml of toluene were heated to reflux for 0.5 hr. Cooling and filtration yielded 4.12 g of (E)-2-[2-[3-[2-[4-(cyclohexyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid; m.p. 210°-211° C. from tetrahydrofuran.
Reaction SMILES: C1C2C(=CC=C(NC3N=C(C4C(C5C=C(NC(=O)C6C=CC=CC=6)C=CC=5)=NN5C=CC=CC=45)C=CN=3)C=2)CCN1.Cl[C:43]1[N:48]=[C:47]([C:49]2[C:50]([C:58]3[CH:59]=[C:60]([NH:64][C:65](=[O:74])[C:66]4[C:71]([F:72])=[CH:70][CH:69]=[CH:68][C:67]=4[F:73])[CH:61]=[CH:62][CH:63]=3)=[N:51][N:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=23)[CH:46]=[CH:45][N:44]=1.[CH3:75][S:76]([CH:79]([C:81]1[CH:82]=[C:83]([NH2:87])[CH:84]=[CH:85][CH:86]=1)[CH3:80])(=[O:78])=[O:77]>>[F:73][C:67]1[CH:68]=[CH:69][CH:70]=[C:71]([F:72])[C:66]=1[C:65]([NH:64][C:60]1[CH:61]=[CH:62][CH:63]=[C:58]([C:50]2[C:49]([C:47]3[CH:46]=[CH:45][N:44]=[C:43]([NH:87][C:83]4[CH:84]=[CH:85][CH:86]=[C:81]([CH:79]([S:76]([CH3:75])(=[O:78])=[O:77])[CH3:80])[CH:82]=4)[N:48]=3)=[C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][N:52]3[N:51]=2)[CH:59]=1)=[O:74]
Reactant: CC(c1cccc(N)c1)S(C)(=O)=O
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Product: CC(c1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)c5c(F)cccc5F)c4)nn4ccccc34)n2)c1)S(C)(=O)=O

Procedure:
The title compound is racemic and may be prepared by a procedure similar to Example 27, Step D using N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and racemic {3-[1-(methylsulfonyl)ethyl]-phenyl}amine. 1H NMR (400 MHz, DMSO-d6): δ 10.92 (s, 1H); 9.63 (s, 1H); 8.82 (d, 1H); 8.50 (d, 1H); 8.24 (d, 1H); 7.98 (s, 1H); 7.82 (d, 1H); 7.76 (br s, 2H); 7.56 (qt, 1H); 7.47 (t, 2H); 7.35 (d, 1H); 7.23 (m, 3H); 7.11 (t, 1H); 7.01 (d, 1H); 6.53 (d, 1H); 4.40 (m, 1H); 2.80 (s, 3H); 1.60 (d, 3H). HRMS (ESI): (M+H)+ calculated 625.1833, found 625.1828.
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:33]=[CH:32][C:9]2[S:10][C:11]([CH2:13][CH:14]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[CH:22][CH:21]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:8]=2[CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:35](=[NH:45])(OCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(#N)C1C=CC=CC=1.Cl>C(O)C.C(N(CC)CC)C>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:33]=[CH:32][C:9]2[S:10][C:11]([CH2:13][CH:14]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C@H:27]4[CH2:31][CH2:30][N:29]([C:35](=[NH:45])[C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH2:28]4)=[CH:22][CH:21]=3)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:12][C:8]=2[CH:7]=1)(=[NH:4])[NH2:5]
Reactant: CCOC(=N)c1ccccc1
Reactant: CCOC(=O)C(Cc1cc2cc(C(=N)N)ccc2s1)c1ccc(O[C@H]2CCNC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: N#Cc1ccccc1
Product: CCOC(=O)C(Cc1cc2cc(C(=N)N)ccc2s1)c1ccc(O[C@H]2CCN(C(=N)c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
1.0 g of ethyl 3-(5-amidinobenzo[b]thien-2-yl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride was dissolved in 15 ml of ethanol. To this solution was added 773 mg of ethyl benzimidate hydrochloride which has been prepared by allowing benzonitrile to react with ethanol in the presence of hydrogen chloride. 631 mg of triethylamine was added to the thus prepared solution during stirring under ice cooling, and the mixture was warmed up to room temperature, and stirred for 18 hours. Thereafter, the solvent was distilled off to obtain ethyl 3-(5-amidinobenzo[b]thien-2-yl)-2-[4-[((3S)-1-benzimidoyl-3-pyrrolidinyl)oxy]phenyl]propionate dihydrochloride. The thus obtained ester compound was dissolved in 60 ml of 3 N hydrochloric acid and refluxed under heating for 30 minutes. After distilling off the solvent, the resulting residue was subjected to column chromatography using a column packed with a highly porous polymer type synthetic adsorbent (styrene-divinylbenzene polymer: Diaion HP-20) and using a water/acetonitrile mixture as an elution solvent. Fractions of interest were pooled and concentrated, and the resulting residue was subjected to reversed phase high performance liquid chromatography using a column packed with octadecyl-bonded silica gel and using a water/acetonitrile mixture as an elution solvent. Thereafter, the thus eluted fractions of interest were pooled, mixed with dilute hydrochloric acid, and then concentrated to dryness. In this way, 350 mg of the title compound was obtained in the form of a light yellow solid.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][CH2:33][O:34][CH3:35])=[N:29][N:28]=3)=[CH:25][C:8]([C:9](N3CCC(C4C=CC(C#N)=CC=4)CC3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:38][C:39]([F:53])([F:52])[C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1.Cl.N1CCC(C2C=CC(C#N)=CC=2)CC1>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][CH2:33][O:34][CH3:35])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:49]3[CH2:48][CH2:47][CH:46]([C:43]4[CH:42]=[CH:41][C:40]([C:39]([F:38])([F:52])[F:53])=[CH:45][CH:44]=4)[CH2:51][CH2:50]3)=[O:10])=[C:7]([CH3:36])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Reactant: COCCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Agent: Cl
Agent: N#Cc1ccc(C2CCNCC2)cc1
Product: COCCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C(F)(F)F)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 153), using 4-(4-(trifluoromethyl)phenyl)piperidine hydrochloride salt instead of 4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5). m/z (ES+) 527 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 11.30-11.10 (br, 1H), 7.60-7.47 (m, 3H), 7.35-7.28 (m, 3H), 5.10-4.93 (m, 1H), 4.24-4.13 (m, 1H), 3.78 (t, 2H), 3.70 (d, 1H), 3.45 (s, 3H), 3.12 t, 2H), 3.15-3.05 (m, 1H), 2.90-2.75 (m, 2H), 2.44 and 2.35 (2 singlets, amide rotamers, ArCH3, 3H), 2.25-2.13 (m, 2H), 2.13-1.85 (m, 4H), 1.87-1.66 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:8](=O)[NH:7][CH:6]=[N:5][C:4]=2[P:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:8]1[C:9]2[NH:1][CH:2]=[P:3][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2pc[nH]c12
Product: Clc1ncnc2pc[nH]c12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 49 %

Procedure:
A mixture of 1,3-azaphospholo[4,5-d]pyrimidin-7(1H,6H)-one (compound 12, 5.0 g, 32.66 mmol) and phosphorus oxychloride (125 mL) was heated under reflux with stirring for 50 min under an argon atmosphere. The reaction mixture was cooled to room temperature and unreacted phosphorus oxychloride was removed under reduced pressure at 25° C. The residual syrup was cooled to 0° C. and carefully neutralized with 2 N aqueous ammonium hydroxide. The precipitate formed was collected by filtration, washed with cold water (2×25 mL) and dried over P2O5 under vacuum, first at 25° C. and then at 100° C. The dry solid was crystallized from acetonitrile to yield 2.73 g (49%) of the title compound, mp>300° C. (became black at 190° C.). 1H nmr (DMSO-d6): δ 8.81 (s, 1 H, C5H), 9.36 (dd, 1 H, JC2H, NH =4.8 Hz, JC2H,P =39.4 Hz, C2H), and 13.68 (br s, 1 H, NH). Anal. Calcd. for C5H3ClN3P: C, 35.02; H, 1.76; Cl, 20.67; N, 24.50; P, 18.05. Found: C, 35.36; H, 2.08; Cl, 21.10; N, 24.21; P, 17.78.