Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][N:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:15][CH3:16])[C:8](=[O:17])[C:7]([C:18]([OH:20])=O)=[CH:6]1.C(N(CC)C(C)C)(C)C.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C@H:39]([NH2:41])[CH3:40])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:22][O:21][CH:3]([O:2][CH3:1])[CH2:4][N:5]1[CH:6]=[C:7]([C:18](=[O:20])[NH:41][C@@H:39]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)[CH3:40])[C:8](=[O:17])[C:9]([O:15][CH3:16])=[C:10]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[C@@H](N)c1ccc(F)cc1
Reactant: COC(=O)c1c(OC)c(=O)c(C(=O)O)cn1CC(OC)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(OC)c(=O)c(C(=O)N[C@H](C)c2ccc(F)cc2)cn1CC(OC)OC
Reaction time: 2 h

Procedure:
1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.500 g, 1.59 mmol), was suspended in acetonitrile (6 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.550 mL, 3.17 mmol), (R)-1-(4-fluorophenyl)ethanamine (0.242 mg, 1.74 mmol) and HATU (0.661 g, 1.74 mmol). The reaction mixture was stirred for 2 hours and partitioned between ethyl acetate and water. The organic layer was separated and washed with HCl (10% aq), sodium bicarbonate (1M aq), dried over sodium sulfate, filtered and concentrated to afford crude (R)-methyl 1-(2,2-dimethoxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate which was used without purification in the next step: LCMS-ESI+ (m/z): [M+H]+ calculated for C21H26FN2O2: 437.17; found: 437.1.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH2:29])=[CH:24][CH:23]=2)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH:29][C:12]([C:10]1[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=1)=[O:14])=[CH:24][CH:23]=2)=[O:19])[CH3:16]
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccc(-c4ccccc4)o3)ccc2[nH]1

Procedure:
5-Phenyl-furan-2-carboxylic acid (56) (35 mg, 0.19 mmol) was coupled to 5-amino-1H-indole-2-carboxylic acid ethyl ester (42 mg, 0.20 mmol) using Method D to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C.C(O)(C)(C)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:12][C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)c1cccc(N)c1
Reactant: Clc1cc(Cl)n2nccc2n1
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cccc(Nc2cc(Cl)nc3ccnn23)c1
Temperature: 100 °C

Procedure:
To the reaction flask, 5,7-dichloropyrazolo[1,5-a]pyrimidine (1.6 g, 8.2 mmol) was added along with tert-butyl 3-aminobenzoate (1.7 g, 8.7 mmol), triethylamine (1.2 mL, 8.6 mmol), and t-butyl alcohol (22 mL). The reaction was heated at 100° C. for 6 hours then diluted with water, filtered and washed with water. The product, tert-butyl 3-(5-chloropyrazolo[1,5-a]pyrimidin-7-ylamino)benzoate, was collected as a solid in quantitative yield after drying under vacuum overnight. LCMS (M+1=345)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:23]([O:25]C)=[O:24])=[CH:15]2.[OH-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:23]([OH:25])=[O:24])=[CH:15]2
Reactant: CCCCCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 891.9 %

Procedure:
To a solution of methyl 2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)octanoate (0.04 g, 0.09 mmol), as prepared in the preceding step, in methanol (5.0 mL) was added a solution of NaOH (0.1 g, 2.5 mmol) in H2O (0.3 mL), and the reaction was stirred at ambient temperature overnight. After evaporating the solvent in vacuo, the residue is taken up in H2O (5 mL) and acidified to pH 4-5 with 10% HCl, and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (4% methanol in methylene chloride) to give the title compound as an oil (0.34 g, 90%). 1H-NMR (400 MHz, CDCl3) δ 7.72 (m, 1H), 7.48 (m, 1H), 7.26 (d, 8.9 Hz, 1H), 7.02 (d, J=2.7 Hz, 2H), 6.77 (dd, J=8.9, 2.4 Hz, 1H), 6.50 (m, 2H), 6.28 (d, J=2.9 Hz, 1H), 4.27 (dd, J=14.2, 8.6 Hz, 1H), 3.99 (m, 3H), 3.32 (t, J=6.7 Hz, 2H), 2.85 (br s, 1H), 1.95 (m, 2H), 1.67 (m, 1H), 1.30 (m, 9H), 0.84 (t, J=6.6 Hz, 3H). Mass spectrum (LCMS, ESI pos.) Calcd. for C25H33N3O3 424.2 (M+H); Found: 424.7.
Reaction SMILES: [C:1]([O:4][N:5]=[C:6]([NH2:32])[C:7]1[CH:8]=[C:9]([C:18]2[NH:19][C:20](=[O:31])[C:21]3[C:22](=[C:24]([CH2:28][CH2:29][CH3:30])[N:25]([CH3:27])[N:26]=3)[N:23]=2)[C:10]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[N:11][CH:12]=1)(=O)[CH3:2].C1C2C(C3ON=C(N)N=3)CN(C2)C1>>[CH2:14]([O:13][C:10]1[C:9]([C:18]2[NH:19][C:20](=[O:31])[C:21]3[C:22](=[C:24]([CH2:28][CH2:29][CH3:30])[N:25]([CH3:27])[N:26]=3)[N:23]=2)=[CH:8][C:7]([C:6]2[N:32]=[C:1]([CH3:2])[O:4][N:5]=2)=[CH:12][N:11]=1)[CH:15]([CH3:16])[CH3:17]
Reactant: CCCc1c2nc(-c3cc(C(N)=NOC(C)=O)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Agent: Nc1noc(C2CN3CCC2C3)n1
Product: CCCc1c2nc(-c3cc(-c4noc(C)n4)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Yield: 38.1 %

Procedure:
5-{5-[[(Acetyloxy)imino](amino)methyl]-2-isobutoxy-3-pyridinyl}-2-methyl-3-propyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 40) (55 mg, 0.13 mmol) was heated at 190° C. for 3 h. After cooling the oxadiazole was purified by flash column chromatography (elution with 50:1 dichloromethane:methanol) to give 21 mg of a yellow solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>C1COCC1.CCOC(C)=O>[CH3:25][N:26]([CH3:30])[C:27](=[O:28])[NH:1][C@@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:3]1
Reactant: CN(C)C(=O)Cl
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)N(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.7 %

Procedure:
Commercial (3R,4R)-tert-butyl 3-amino-4-methylpiperidine-1-carboxylate (427, 250 mg, 1.16 mmol) was dissolved in 10 mL dry THF. To it were added DIEA (610 μL, 3.50 mmol) and dimethylcarbamoyl chloride (214 μL, 2.32 mmol). The mixture was stirred at RT for 2 hours, diluted with 100 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to silica flash column using 0 to 5% MeOh in DCM to isolate (3R,4R)-tert-butyl 3-(3,3-dimethylureido)-4-methylpiperidine-1-carboxylate (428, 350 mg) in quantitative yield as a white solid. It was treated with 15 mL commercial 4N HCkl in dioxane at RT for 40 min to yield 1,1-dimethyl-3-((3R,4R)-4-methylpiperidin-3-yl)urea hydrochloride (429).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[NH:13][CH:14]=[CH:15][N:16]=3)[S:7][C:6]=2[CH:17]=1.O.[CH3:19][N:20](C)C=O>>[NH:16]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:11][C:8]1[S:7][C:6]2[CH:17]=[C:2]([C:19]#[N:20])[CH:3]=[CH:4][C:5]=2[C:9]=1[CH3:10]
Reactant: CN(C)C=O
Reactant: Cc1c(Cc2ncc[nH]2)sc2cc(Br)ccc12
Solvent: O
Product: Cc1c(Cc2ncc[nH]2)sc2cc(C#N)ccc12

Procedure:
A mixture of 6-bromo-2-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene (1.01 g) and cuprous cyanide (1.80 g) in N,N-dimethylformamide (20 ml) was heated under reflux for 22 hours and then cooled and poured into water. The solid was filtered off, washed with water and then suspended in a mixture of concentrated aqueous ammonia solution (100 ml) and ethyl acetate (150 ml) and the mixture was stirred until no solid remained. The organic layer was separated, washed with water, dried (Na2SO4) and evaporated. The residue was crystallised from ethyl acetate/petrol (b.p. 60°-80°) to give 2-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-6-carbonitrile (0.58 g), m.p. 154°-155°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=1[CH3:22].C(N(CC)CC)C.C(OCC)(=O)C>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=2[CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(/C=C/C#N)cc(C)c1N
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Cl)n1
Temperature: 145 °C
Yield: 68.1 %

Procedure:
To a mixture of 2,4-dichloropyrimidine (25 gm) and (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (28 gm) was added triethylamine (300 ml) under stirring. The mixture was then heated to 140 to 150° C. and stirred for 55 to 60 hours. The solution was then cooled to room temperature and the solvent was distilled off under reduced pressure to provide a residual solid. To the residual solid was added ethyl acetate (1500 ml) and water (1000 ml). The reaction mass was stirred for 30 minutes at room temperature and then the layers were separated. The organic layer was dried with sodium sulfate and then concentrates to provide 26 gm of (E)-3-(4-(2-chloropyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27](OCC)[O:28]CC)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[O:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
To a solution of diethyl 2-methyl-4-(3-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (462.5 mg) in acetone (4 ml) was added 6 N-hydrochloric acid (0.4 ml) and stirred at room temperature for an hour. After the reaction, the solvent was removed from the resultant solution. To the residue was added water, and the residue was pulverized. The powder was collected by filtration, washed with water and dried to give diethyl 2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (360 mg), m.p. 130° to 133° C.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([N:10]1[C:14]([CH:15]=[N:16][N:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[CH2:22][O:23][CH3:24])=[CH:13][N:12]=[C:11]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][CH2:8][CH3:9]>C1COCC1>[CH2:6]([N:10]1[C:14]([C@@H:15]([NH:16][N:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[CH2:22][O:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:13][N:12]=[C:11]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][CH2:8][CH3:9]
Reactant: [Li]CCCC
Reactant: CCCCn1c(C=NN2CCC[C@@H]2COC)cnc1-c1ccccc1
Solvent: C1CCOC1
Product: CCCC[C@H](NN1CCC[C@@H]1COC)c1cnc(-c2ccccc2)n1CCCC
Temperature: 25 °C

Procedure:
To a solution of BuLi (2.5 M in hexane, 12.5 ml, 31 mmol) under argon in anhydrous THF (15 mL) at −78° C. is slowly added a solution of crude 192 (14 mmol) in THF (15 mL). The mixture is allowed to warm to room temperature over a period of 15 h and quenched with saturated sodium bicarbonate. The aqueous phase is extracted with ethyl acetate and the combined organic phases were washed with water and dried over sodium sulfate. Removal of solvents under reduced pressure and purification of the residue by column chromatograpy affords the desired product as a colorless syrup. Yield: 5.1 g; [α]D−72 (c=1.2, CHCl3); LC-MS (MH+): 399.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:30](COCC[Si](C)(C)C)[N:29]=[C:28]3[NH:48][C:49](=[O:53])[CH2:50][CH2:51][CH3:52])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[C:19]1([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:30][N:29]=[C:28]3[NH:48][C:49](=[O:53])[CH2:50][CH2:51][CH3:52])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccccc3)c(-c3ccccc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccccc3)c(-c3ccccc3)cc12
Yield: 9.1 %

Procedure:
17.2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.5 g of N-[5,6-diphenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 40 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed with 75 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 1.5 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the product, which is still impure, is purified by HPLC (Hypersil column; C18, 5 μm; length 250 mm, diameter 21 mm, eluent: methanol/water (70/30 by volume) containing 0.1% trifluoroacetic acid; flow rate 10 cm3/min); after concentrating to dryness the fractions containing the expected product, the residue is taken up in 10 cm3 of diisopropyl ether, filtered off, washed with 2×5 cm3 of diisopropyl ether and dried (90 Pa; 45° C.) to give 100 mg of N-[5,6-diphenyl-1H-indazol-3-yl]butanamide in the form of white crystals melting at 210° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[S:24][C:23]4[C:18](=[N:19][CH:20]=[CH:21][C:22]=4[O:25][C:26]4[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=4)[CH:17]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.FC1C=C(N[C:66]([NH:68][C:69](=[O:77])[CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)=[S:67])C=CC=1OC1C=CN=C2C=C(C3C=CC=C(OCCN4CCOCC4)C=3)SC=12>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[S:24][C:23]4[C:18](=[N:19][CH:20]=[CH:21][C:22]=4[O:25][C:26]4[CH:27]=[CH:28][C:29]([NH:32][C:66]([NH:68][C:69](=[O:77])[CH2:70][C:71]5[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=5)=[S:67])=[CH:30][CH:31]=4)[CH:17]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cccc(OCCN5CCOCC5)c4)sc23)c(F)c1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)cc4)sc23)cc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(OCCN5CCOCC5)cc4)sc23)cc1
Yield: 30 %

Procedure:
Starting from the compound 202 and following the procedure described above for the compound 163a (scheme 31), title compound 203 was obtained in 30% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.38 (s, 1H), 11.73 (s, 1H), 8.47 (d, 1H, J=5.5 Hz), 7.90 (s, 1H), 7.79 (s, 2H, J=9.0), 7.36 (d, 2H, J=9.0 Hz), 7.43-7.27 (m, 7H), 7.05 (d, 2H, J=9.0 Hz), 6.63 (d, 1H, J=5.3 Hz), 4.15 (t, 2H, J=5.6 Hz), 3.82 (s, 2H), 3.58 (t, 4H, J=4.6 Hz), 2.71 (t, 2H, J=5.7 Hz), 2.51-2.46 (m, 4H). LRMS (M+1) 625.2 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[C:9]=[O:10])=[CH:5][CH:4]=1.[C:13](=O)([O-])[O-].[K+].[K+].[NH2:19][C:20]1[C:24]([C:25]#[N:26])=[C:23]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28]2)[N:22]([CH2:41][C:42]2[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=2[Cl:49])[C:21]=1[C:50]([O:52]CC)=O>N1C=CC=CC=1>[Cl:49][C:43]1[CH:44]=[CH:45][C:46]([F:48])=[CH:47][C:42]=1[CH2:41][N:22]1[C:21]2[C:50](=[O:52])[N:8]([CH2:7][C:6]3[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:9](=[O:10])[N:19]([CH3:13])[C:20]=2[C:24]([C:25]#[N:26])=[C:23]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:35])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:28]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN=C=O)cc1
Reactant: CCOC(=O)c1c(N)c(C#N)c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1Cc1cc(F)ccc1Cl
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc(Cn2c(=O)c3c(c(C#N)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)n3Cc3cc(F)ccc3Cl)n(C)c2=O)cc1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
4-Methoxybenzyl isocyanate (0.5 ml) and potassium carbonate (486 mg) were added to a solution of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chloro-5-fluorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (920 mg) in pyridine (1 ml), and the resulting mixture was stirred at 130° C. for 6 hours. 4-Methoxybenzyl isocyanate (2.0 ml) was added thereto, followed by stirring with heating for another 24 hours. The reaction solution was cooled to 25° C. and then concentrated under reduced pressure and water was added to the residue, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (15 ml), followed by adding thereto potassium carbonate (486 mg) and methyl iodide (0.33 ml), and the resulting mixture was stirred at 25° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (750 mg) as a light-yellow amorphous substance.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:39])[C:19]2[CH:20]=[C:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:22]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:19]2[CH:20]=[C:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:22]=[C:23]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=2)=[O:39])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCc1cc(CCC(=O)OCC)cc(C(O)c2ccc(F)cc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1cc(CCC(=O)OCC)cc(C(=O)c2ccc(F)cc2)c1
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
Dimethylsulphoxide (16.2 ml) was added dropwise to a stirred solution of oxalyl chloride (11.55 g) in dry dichloromethane (500 ml) at -78° C. under an atmosphere of dry nitrogen. The mixture was stirred for 10 minutes and then a solution of diethyl 5-[(4-fluorophenyl)hydroxymethyl]-1,3-benzenedipropanoate (30.65 g) in dry dichloromethane (150 ml) was added dropwise. The mixture was stirred at -78° C. for 30 minutes, triethylamine (23.03 g) was added, and stirring was continued for a further 10 minutes. The temperature was allowed to rise to room temperature, and the mixture was washed with water. The organic layer was separated, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel. Elution with dichloromethane followed by dichloromethane/methanol (50:1) gave the title compound as an oil (28.92 g), Rf 0.75 (SS 4). Found: C,69.08; H,6.46. C23H25FO5 requires: C,68.98; H,6.29%.
Reaction SMILES: [ClH:1].[C:2](=[NH:12])(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([OH:28])=[O:27]>O.O1CCOCC1>[ClH:1].[C:26]([C:25]1[CH:24]=[C:23]([NH:22][C:2](=[NH:12])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:31]=[CH:30][CH:29]=1)([OH:28])=[O:27]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N=C(Nc1cccc(C(=O)O)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 15.8 %

Procedure:
To ethyl benzimidate hydrochloride (3 g, 0.016 mole)(Fluka) and (2.1 g, 0.016 mole) diisopropylethylamine in H2O (15 ml) and dioxane (15 ml) was added 3-aminobenzoic acid (2.22 g, 0.016 mole) (Aldrich). The reaction mixture was stirred at room temperature for 4 days. The resulting precipitate was filtered, washed with dioxane/H2O and dried. The precipitate was slurried in H2O and acidified with concentrated HCl. The solvent was removed under vacuum and the residue was slurried in ether. The ether was decanted off and the residue dried under vacuum to yield N-(3-carboxyphenyl)benzamidine hydrochloride (700 mg) as a white solid. MS and NMR were consistent with the desired structure.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=[C:27]2[Cl:38].[C:39](=[O:42])([O-])[O-:40].[Cs+].[Cs+]>>[F:19][C:18]([F:21])([F:20])[C:39]([OH:40])=[O:42].[Cl:38][C:27]1[C:26]2[C:31](=[CH:32][CH:33]=[C:24]([CH2:23][N:3]3[C:4]4=[N:9][C:8]([N:10]5[CH2:11][CH2:12][O:13][CH2:14][CH2:15]5)=[CH:7][C:6](=[O:16])[N:5]4[CH2:17][C@@:2]3([CH3:1])[C:18]([F:21])([F:19])[F:20])[CH:25]=2)[N:30]=[C:29]([C:34]([F:37])([F:35])[F:36])[CH:28]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1cc(Cl)c2cc(CBr)ccc2n1
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1Cc1ccc2nc(C(F)(F)F)cc(Cl)c2c1
Product: O=C(O)C(F)(F)F

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 95 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (Example 1j) and 101 mg of 6-(bromomethyl)-4-chloro-2-(trifluoromethyl)quinoline, replacing the sodium hydride with 203 g of caesium carbonate. After purification by preparative HPLC/MS (method C), 40 mg of (2S)-1-{[4-chloro-2-(trifluoromethyl)quinolin-6-yl]methyl}-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one, in the form of a trifluoroacetic acid salt, are obtained in the form of a beige powder, the characteristics of which are the following: