Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH2:42][NH2:43].C(N(C(C)C)CC)(C)C.O>CC(O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:43][CH2:42][C:38]2[O:37][CH:41]=[CH:40][N:39]=2)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1Cl)C1CN(C(=O)OC(C)(C)C)Cc2ccccc21
Reactant: NCc1ncco1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ncco1)C1CN(C(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 75.7 %

Procedure:
tert-Butyl 4-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](2-methylpropyl)amino}-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg), 1-(1,3-oxazol-2-yl)methanamine hydrochloride (54 mg) and diisopropylethylamine (0.14 ml) were dissolved in 2-propanol (2 ml), and the mixture was stirred at 80° C. for 6 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with hexane-ethyl acetate (3:1) was concentrated under reduced pressure to give the object compound (85 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].C1N=CN([C:26](N2C=NC=C2)=[S:27])C=1>CC#N>[N:1]([C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:18])([F:19])[F:20])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[C:26]=[S:27]
Reactant: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)c(N)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)c(N=C=S)c1

Procedure:
A mixture of N-(3-amino-4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide (200 mg, 0.69 mmol), TCDI (133 mg, 0.746 mmol) and MeCN (3 mL) was refluxed for 1 h. Concentration and purification by column chromatography gave the sub-title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br:9]Br>>[C:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH:1]([Br:9])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)OCC
Product: CCOC(=O)OC(C)Br
Yield: 68.5 %

Procedure:
585 g Diethylcarbonate (4.92 mole) was heated by an external 1500 w iodine quartz lamp. The mixture was allowed to reflux (temperature 125°) by the heat evolved from the lamp. 318.2 g (2.0 mole) of bromine is added slowly during 3 hours through a dip-pipe at such a rate that the solution colour was yellow to light orange. The temperature dropped to ca. 120° at the beginning of the addition, but rose again slowly. When all the bromine was consumed the temperature was 137°. The reaction mixture was cooled and treated as described in Example 2. Fractional distillation afforded 1-bromoethyl ethyl carbonate in a 68.5% yield. The earlier fraction contained about 6.5% more of 1-bromoethyl ethyl carbonate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][CH:10]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:11](OCC)=[O:12].Cl>ClCCl>[CH3:9][C:10]1[C:11](=[O:12])[C:7]2[C:2](=[CH:3][CH:4]=[C:5]([CH3:8])[CH:6]=2)[NH:1][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(=O)C(=O)C(C)C(=O)OCC
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccc(C)cc2c(=O)c1C
Yield: 71.2 %

Procedure:
A mixture of p-toluidine (10 g) and diethyl 2-methyl-3-oxosuccinate (18.9 g) in dichloromethane (50 ml) was refluxed for 2 days. The reaction mixture was poured onto 0.5N hydrochloric acid (200 ml) and extracted with dichloromethane. The organic layer was washed with water, 0.5N sodium hydroxide solution and brine, dried over magnesium sulfate, and concentrated. The obtained residue was added to heated diphenyl (80 g) and the mixture was refluxed for 15 minutes. The reaction mixture was allowed to stand at ambient temperature, and the resulting precipitates were collected by filtration to give ethyl 1,4-dihydro-3,6-dimethyl-4-oxoquinoline-2-carboxylate (16.3 g).
Reaction SMILES: [CH2:1]([C:3]([CH3:5])=O)[CH3:2].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:11]([NH2:6])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:2][CH2:1][CH2:3][CH2:5][CH2:2][CH2:1][CH2:3][CH2:5][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: c1ccncc1
Reactant: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCN
Yield: 1584.9 %

Procedure:
A mixture of 31 g of the white solid obtained in Intermediate Preparation Example 4, 27 g of n-octadecylamine, 130 g of methyl ethyl ketone and 1.0 g of pyridine was heated at a temperature of 70° C. and reacted with stirring for 10 hours. After cooling, the reaction mixture was added in 1.0 L of methanol with stirring over 15 minutes, and the mixture was further stirred for one hour. A deposited solid was collected by filtration and dried in vacuo to obtain 48 g of a pale whitish yellow solid. The resulting compound had a molecular weight measured by high performance liquid chromatography of 15,000.
Reaction SMILES: Cl.[CH2:2](NC(N1CCN(C(C2CCCC2)=O)CC1)=O)C.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][C:25]([C:26]#[N:27])=[C:24]([NH2:32])[CH:23]=1.[H-].[Na+]>O>[CH3:31][O:30][C:29]1[CH:28]=[C:25]2[C:24](=[CH:23][C:22]=1[O:21][CH3:20])[N:32]=[CH:2][N:27]=[CH:26]2
Reactant: CCNC(=O)N1CCN(C(=O)C2CCCC2)CC1
Reactant: COc1cc(N)c(C#N)cc1OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc2cncnc2cc1OC
Reaction time: 0.5 h

Procedure:
Ethyl-4-(cyclopentylcarbonyl)piperazin-1-yl-formamidate hydrochloride (0.01 mole) is added to a solution of 4,5-dimethoxy-2-aminobenzonitrile (0.01 mole) in 30 ml. of N1N-dimethylformamide. Sodium hydride (0.02 mole of a 56% suspension in mineral oil) is added and the mixture stirred 0.5 hr. at room temperature and then at 100° C. for a period of 12 hr. When the reaction period is complete, water is added providing 4-amino-2-[4-cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[NH:20][CH2:19][C:18]2[CH:21]=[CH:22][O:23][C:17]=2[CH2:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH:15]([CH3:14])[CH2:16][C:17]4[O:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1Cc2occc2CN1
Product: CC1Cc2occc2CN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-methyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C@@:20]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)[CH:18]=3)[O:13][C:10]2=[CH:11][CH:12]=1)(=O)=O.CN(C=O)C.C(NC(C)C)(C)C.[CH3:47][C:48]([OH:52])([C:50]#[CH:51])[CH3:49]>CCOC(C)=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:25][C:22]1[O:23][CH2:24][C@:20]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)[CH:18]=3)[O:13][C:10]3[C:9]2=[CH:8][C:7]([C:51]#[C:50][C:48]([CH3:49])([OH:52])[CH3:47])=[CH:12][CH:11]=3)[N:21]=1
Reactant: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)cc1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: Cc1ccc(-c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(C#CC(C)(C)O)ccc2O3)cc1

Procedure:
A vial was charged with (S)-2′-amino-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (209 mg, 0.426 mmol), copper(i) iodide (8.11 mg, 0.043 mmol), and tetrakis(triphenylphosphine)palladium (49.2 mg, 0.043 mmol). The vial was flushed with Ar (g), then DMF (1704 μL, 0.426 mmol), diisopropylamine (1194 μL, 8.52 mmol), and 2-methylbut-3-yn-2-ol (208 μL, 2.130 mmol) were added in sequence. The vial was sealed and placed in a 70° C. oil bath for 2 hours. The mixture was diluted with EtOAc (15 mL), washed with water (10 mL), washed with brine (15 mL), dried over sodium sulfate, filtered, and evaporated. The residue was taken up in DCM/MeOH (not completely soluble) and chromatographed on a 40-g Redi-Sep column, eluting with 0-8% MeOH/DCM (product came out in a streak) to give (S)-4-(2′-amino-3-p-tolyl-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl)-2-methylbut-3-yn-2-ol as a light yellow solid
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=[C:4]([C:37](=[O:40])[NH:38][CH3:39])[CH:3]=1.Cl[C:42]1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1.NC1C=CC=CC=1C(NCC)=O>>[CH2:39]([NH:38][C:37]([C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[C:14]([C:15]([F:17])([F:18])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:22][C:21]=2[O:35][CH3:36])[N:10]=1)=[O:40])[CH3:42]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CCNC(=O)c1ccccc1N
Product: CCNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCC)OCC)cc2OC)ncc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)-phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-amino-N-ethylbenzamide. MS (ES+): m/z 582.25 (100) [MH+]; HPLC: tR=1.09 min (UPLC, purity).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(Cl)([Cl:16])=O.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 26 °C

Procedure:
A mixture containing 1200 g. (5.95 moles) of 4-chloro-2-nitrobenzoic acid, 5000 ml. (69 moles) of thionyl chloride and 40 ml. of N,N-dimethylformamide was stirred 4 hours while the temperature was maintained at 26° C. When the evolution of hydrogen chloride subsided, the temperature was raised to 65° C. and stirring was continued an additional hour. After removing excess thionyl chloride by vacuum distillation, the residue was dissolved in 1 l. of 1,2-dichloroethane and the solution was evaporated under reduced pressure. The residue which was essentially free of thionyl chloride was dissolved in 5 l. of 1,2-dichloroethane and the solution was twice treated with decolorizing carbon and filtered to give a final solution of 4-chloro-2-nitrobenzoyl chloride in 1,2-dichloroethane which was used directly in the next step.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])=[O:14].[OH-].[Na+]>CO>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6](/[CH:7]=[CH:12]/[C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[O:23][CH3:24])=[O:14])=[CH:5][C:4]=2[O:9]1
Reactant: COc1ccc(C(C)=O)c(OC)c1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)/C=C/c2ccc3c(c2)OCO3)c(OC)c1
Reaction time: 2 h

Procedure:
To a stirred solution of piperonal (1 g, 6.7 mmol) and 2,4-dimethoxyacetophenone (1.21 g, 6.7 mmol) in methanol (30 ml) was added 20 equivalents of aqueous sodium hydroxide (˜11 ml, 50% w/v) and the mixture stirred for 2 h. The resultant solid was collected by filtration and then recrystallised from methanol as pale yellow crystals (0.86 g, 41%): mp 137° C.; 1H NMR δ (CDCl3) 3.9 (3H, s, OCH3), 3.92 (3H, s, OCH3), 6.01 (2H, s, CH2O), 6.50 (2H, dd, ArH), 6.80 (1H, d, ArH), 7.00 (2H, m, ArH), 7.25 (1H, d, J=15.7 Hz, ArH), 7.59 (1H, d, J=15.7 Hz, ArH), 7.70 (1H, d, ArH); 13C NMR δ 101.45, 122.35, 129.93, 148.23, 149.37, 160.29, 164.05, 190.34; Infra red νMAX (KBr)/cm−1 1659.6 (C═O); MS (rel intensity) m/z 313 ([M+H]+, 37%); Anal. Calcd (CO18H16O5): C, 69.23; H, 5.13. Found C, 68.97; H, 5.26.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:25][CH:26]=2)=[CH:34][CH:35]=1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a mixture of ethyl 3-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (0.30 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added a 1N aqueous sodium hydroxide solution (1.3 mL) and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.25 g, 89%) of 3-[4-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 177-178° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:41])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH3:25])[CH2:23][OH:24])[CH:17]=[C:16]([C:26]([O:28]CC)=[O:27])[C:15]3=[O:31])=[C:8]([C:32]2[S:33][CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[N:36]=2)[CH:7]=1)[CH3:2].[OH-].[Li+].Cl>O1CCCC1.CO.O>[CH2:1]([NH:3][C:4](=[O:41])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([C@@H:22]([CH3:25])[CH2:23][OH:24])[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[C:15]3=[O:31])=[C:8]([C:32]2[S:33][CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[N:36]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3[C@@H](C)CO)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3[C@@H](C)CO)cn1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To a solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxypropan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 97, 200 mg, 0.34 mmol, 1 equiv.) in tetrahydrofuran (1 mL) and methanol (1 mL) was added 2 M lithium hydroxide (0.339 mL). The mixture was stirred in the microwave at 100° C. for 15 min The reaction mixture was cooled to room temperature and diluted with water. 1 N HCl was added until pH 3-4 was reached. The reaction mixture was partitioned between ethyl acetate (5 mL) and water (5 mL). The aqueous layer was extracted with ethyl acetate (2×5 mL), and the organics were washed with brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure. Purification via reverse phase HPLC (C18 column, acetonitrile/water 0-95% gradient) and concentrated under reduced pressure to provide (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxypropan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as a light yellow solid (92 mg, 48%).
Reaction SMILES: [OH-].[Na+].F[C:4]1[CH:9]=[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])[C:7]([F:20])=[CH:6][C:5]=1[C:21]1[N:25]([C@H:26]2[CH2:30][CH2:29][O:28][CH2:27]2)[N:24]=[CH:23][C:22]=1[C:31]([NH2:33])=[O:32].O.C(O)(=O)C>CS(C)=O>[F:20][C:7]1[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=2[CH3:19])=[CH:9][C:4]2[NH:33][C:31](=[O:32])[C:22]3[CH:23]=[N:24][N:25]([C@H:26]4[CH2:30][CH2:29][O:28][CH2:27]4)[C:21]=3[C:5]=2[CH:6]=1
Reactant: COc1ncc(C)c(-c2cc(F)c(-c3c(C(N)=O)cnn3[C@H]3CCOC3)cc2F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1ncc(C)c(-c2cc3[nH]c(=O)c4cnn([C@H]5CCOC5)c4c3cc2F)c1C
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
Sodium hydroxide (powder, 82 mg) was added to a solution of 5-(2,5-difluoro-4-(2-methoxy-3,5-dimethylpyridin-4-yl)phenyl)-1-[(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxamide (186 mg) in DMSO (1.5 mL), and the mixture was stirred at 75° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and water (5.5 mL) was then added with stirring. Acetic acid (0.12 mL) was further added, followed by stirring for 30 minutes. The generated solid was filtered, washed with water (5 mL) and then dried under reduced pressure at 60° C. for one hour to give the title compound (155 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:25][C:24]1[CH:23]=[C:22]([CH3:26])[NH:21][C:20](=[O:27])[C:19]=1[CH2:18][NH:17][C:15]([C:4]1[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:32]2[CH:31]=[N:30][C:29]([CH3:28])=[CH:34][CH:33]=2)[CH:3]=1)=[O:16]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Product: Cc1ccc(-c2cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c3c(C)nn(C(C)C)c3c2)cn1

Procedure:
The title compound was prepared in the same manner as described for example 76 from 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide (300 mg, 0.696 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (183 mg, 0.835 mmol). The title compound was collected as 75 mg (24%); H NMR (DMSO-d6, 400 MHz): δ 1.45 (d, J=6.4 Hz, 3H), 2.11 (s, 3H), 2.24 (s, 3H), 2.49 (s, 3H), 2.51 (s, 3H), 4.36-4.38 (m, 2H), 5.03-5.09 (m, 1H), 5.87 (s, 1H), 7.36 (s, 1H), 7.38 (s, 1H), 8.01 (s, 1H), 8.11 (d, J=2.4 Hz, 1H), 8.45 (s, 1H), 8.89 (s, 1H), 11.48 (s, 1H); LCMS (ES+) m/z: 444.21.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COc1ccc(F)cc1F
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccc(F)cc2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(2,4-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH:5]=[CH:6][N:7]=1.[CH2:8](I)[CH2:9][CH3:10].C(OCC)(=O)C.[OH-].[K+]>CN(C)C=O.CO>[CH2:8]([N:7]1[CH:6]=[CH:5][CH2:4][S:3][C:2]1=[NH:1])[CH2:9][CH3:10]
Reactant: CCCI
Reactant: NC1=NC=CCS1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN1C=CCSC1=N
Temperature: 50 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
1.3 g (11.4 mmol) of 2-amino-6H-1,3-thiazine was dissolved in 4 ml of dimethylformamide, and 2.4 g (14.1 mmol) of n-propyl iodide was added thereto. The mixture was heated at 50° C. for one hour and then stirred at room temperature overnight. To the reaction solution, 100 ml of ethyl acetate was added, and the mixture was stirred and then left to stand still. Then, the ethyl acetate layer was separated and removed by decantation. Then, the residual oily substance was dissolved in 50 ml of methanol, and 30 ml of a methanol solution containing 0.75 g (11.4 mmol) of 85% potassium hydroxide, was added thereto at room temperature. The mixture was further stirred at the same temperature for one hour, and then methanol was distilled off under reduced pressure. To the residue, 60 ml of chloroform was added, and insoluble matters were removed by filtration. Then, the filtrate was concentrated under reduced pressure. The residual oily substance was purified by alumina column chromatography (eluent: chloroform) to obtain 0.4 g of 3,6-dihydro-3-n-propyl-2H-1,3-thiazin-2-imine as an oily substance.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:18][CH2:19][F:20]>CN(C)C=O>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]([CH2:18][CH2:19][F:20])([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: FCCBr
Reactant: N#Cc1ccc(CC(C#N)C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC(C#N)(C#N)CCF)cc1
Yield: 24.9 %

Procedure:
Using 0.32 g of (4-cyanobenzyl)malononitrile, 7 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.10 g of 2-(4-cyanobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (46)).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C@H:15]1[C:19](=O)[O:18][CH2:17][N:16]1[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].[SiH](CC)(CC)CC.ClC(OC(C)(C)C)=O.Cl>C(Cl)Cl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][CH2:14][C@H:15]([N:16]([CH3:17])[C:21](=[O:22])[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:19][OH:18]
Reactant: O=C1OCN(C(=O)OCc2ccccc2)[C@H]1CCCN1C(=O)c2ccccc2C1=O
Agent: CC(C)(C)OC(=O)Cl
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Product: CN(C(=O)OCc1ccccc1)[C@H](CO)CCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a solution of (S)-benzyl 4-(3-(1,3-dioxoisoindolin-2-yl)propyl)-5-oxooxazolidine-3-carboxylate (11.6 g, 28.40 mmol) in DCM (30.0 mL) was added Et3SiH (13.6 mL, 85.3 mmol). The reaction mixture was stirred overnight, concentrated under reduced pressure, and dissolved in THF (100 mL). To the resulting solution was added tert-butyl chloroformate (4.4 mL, 34.08 mmol) and TEA (12.0 mL, 85.2 mmol) at 0° C. The reaction mixture was stirred at RT for 30 min. The precipitate was filtered off and the filtrate was added into a suspension of NaBH4 in water (1.0 mL) at 0° C. The reaction mixture was stirred at RT for 30 min. LCMS indicated the completion of the reaction. The reaction mixture was acidified to pH 3 by HCl (1N) and extracted with EtOAc (300 mL×2). The combined organic layers were washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel using a mixture of EtOAc and hexanes to give (S)-benzyl 5-(1,3-dioxoisoindolin-2-yl)-1-hydroxypentan-2-yl(methyl)carbamate (5.01 g, 45%). LRMS (M+H+) m/z 397.3.