Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([Cl:11])=[CH:4][C:3]=1[CH3:12].C(O)(=O)C.C(N)=N>[Ni].CO>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([Cl:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])cc1Br
Agent: [Ni]
Agent: N=CN
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(Cl)c(N)cc1Br
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In an autoclave, a mixture of 253 mmol of 1-bromo-4-chloro-2-methyl-5-nitro-benzene [10289-13-1], 2 g of Raney nickel (60% aqueous) and 1.5 g of formamidine acetate in 102 ml of methanol is stirred under an atmosphere of hydrogen (pressure 12 bars) at 80° C. for 1 hour. The mixture is cooled to room temperature, filtered and evaporated. The residue is partitioned between aqueous saturated sodium bicarbonate-solution and tert-butyl-methyl ether. The aqueous phase is extracted with tert-butyl-methyl ether. The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO2 60 F) to afford the title compound which is identified based on the Rf value.
Reaction SMILES: CC([S@]([NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])=O)(C)C.CO.[ClH:31]>CCOCC>[ClH:31].[CH3:11][CH:10]([CH3:12])[CH2:9][C@H:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[NH2:7]
Reactant: CC(C)C[C@@H](N[S@](=O)C(C)(C)C)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)C[C@@H](N)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A round bottom flask was charged with (R)-2-methyl-N—((R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butyl)propane-2-sulfinamide (47.5 g, 115.5 mmol) and methanol (300 mL). The mixture was cooled to 0° C. and 2.0N HCl in ether (150 mL) was added. The reaction was stirred for 20 minutes. The reaction was then concentrated under reduced pressure. Trituration with ether provided (R)-3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine hydrochloride (35.3 g, 89%), as a white solid. 1H NMR (400 MHz, CD3OD, δ): 0.95 (d, 3H) 0.99 (d, J=6.44 Hz, 3H) 1.38-1.51 (m, 1H) 1.78-1.91 (m, 1H) 1.92-2.03 (m, 1H) 4.40 (dd, J=10.15, 5.66 Hz, 1H) 7.56-7.63 (m, 2H) 7.74-7.88 (m, 6H). MS (M+1): 291.2. [α]D=−11.9, c=1.8 (MeOH).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:9][NH2:10]>C(O)C>[Cl:1][C:2]1[C:7]([NH:9][NH2:10])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccnc1Cl
Reactant: NN
Solvent: CCO
Product: NNc1nccnc1Cl
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
2,3-Dichloropyrazine (2 g, 13.42 mmol), hydrazine (1.324 g, 26.8 mmol) and ethanol (40 ml) were combined and the reaction mixture was stirred at 80° C. for 1.5 h. The mixture was cooled to room temperature and the yellow flakes were filtered off. The solid was washed with a small amount of water and dried. The mother liquor was concentrated to afford a yellow solid triturated with a small amount of water and dried. The 2 solids were combined to afford title product 471 (1.15 g, 59%) as yellow solid. MS (m/z): 145.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH2:18][CH3:19])[C:13]=3[C:12]([C:20]([O:22]CC)=[O:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[CH:15]=[CH:16][N:17]([CH2:18][CH3:19])[C:13]=3[C:12]([C:20]([OH:22])=[O:21])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(Nc2cccc(Cl)c2)c2ccn(CC)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1ccc2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c21
Yield: 13.6 %

Procedure:
A mixture of ethyl 4-[(3-chlorophenyl)amino]-1-ethyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (0.160 g) and 2M sodium hydroxide (0.5 ml) in methanol (1.5 ml) was irradiated at 120° C. for 3 minutes with microwaves. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The aqueous layer was removed, acidified to pH1 and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a white oil (0.020 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O.N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][Cl:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCc1ccc(OCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: ClCCCc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
3-(4-Benzyloxyphenyl)propanol produced in Example 193-(1) (1.5 g) was dissolved in toluene (30 ml). To the solution were added thionyl chloride (0.88 g) and pyridine (0.1 ml). The mixture was stirred for 2 hours at 80° C. The reaction mixture was cooled, to which was added saturated sodium hydrogencarbonate to cause decomposition, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to leave 3-(4-benzyloxyphenyl)propyl chloride (1.3 g) as a colorless crystalline product. m.p.: 34-35° C.
Reaction SMILES: Cl.C(O)(=O)C.[Br:6][C:7]1[C:8]([F:36])=[C:9]([F:35])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([NH:24]C(C)(C)C)[N:18]=1)[CH:14]=[C:13]([C:29]([O:31]CC)=[O:30])[C:12]2=[O:34]>O>[NH2:24][C:19]1[N:18]=[C:17]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([F:35])=[C:8]([F:36])[C:7]=3[Br:6])[C:12](=[O:34])[C:13]([C:29]([OH:31])=[O:30])=[CH:14]2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CCOC(=O)c1cn(-c2ccc(F)c(NC(C)(C)C)n2)c2c(Br)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)ccc1F
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To 4 ml of the mixed solution (1:1) of 4N hydrochloric acid and acetic acid was added 480 mg of ethyl 8-bromo-1-[6-(t-butylamino)-5-fluoropyridin-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 2 hours. After adding 4 ml of distilled water, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 345 mg of the title compound as a colorless powder.
Reaction SMILES: [C:1]1([C:7]2([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:18]>O1CCCC1>[CH3:18][O:14][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: OC1(c2ccccc2)CCCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccccc2)CCCCCC1
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 138.6 %

Procedure:
1-Phenyl-cycloheptanol (Example 1a) (7.6 g) was dissolved in tetrahydrofuran (100 mL) and sodium hydride (60% in oil, 2.0 g) added. The reaction was stirred at 60° C. for 5 minutes and iodomethane (7.1 g) added. The mixture was maintained at 60° C. overnight and then further quantities of sodium hydride (60% in oil, 2.0 g) and iodomethane (7.1 g) were added and the reaction was refluxed for 70 hours. The reaction mixture was partitioned between water (100 mL) and isohexane (100 mL) and the organic layer separated, dried (MgSO4) and evaporated to afford the sub-titled compound (11.31 g).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:18])=[C:15]([O:30][CH3:31])[CH:14]=1.Br.C([O-])(O)=O.[Na+]>CC(O)C.O>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:12][C:13]2[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:18])=[C:15]([O:30][CH3:31])[CH:14]=2)=[N:4][CH:3]=1
Reactant: COc1cc(N)ccc1C(=O)NCc1ccc(C)nc1
Reactant: Brc1ncc(Br)n2ccnc12
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: COc1cc(Nc2ncc(Br)n3ccnc23)ccc1C(=O)NCc1ccc(C)nc1
Yield: 41.7 %

Procedure:
5,8-dibromoimidazo[1,2-a]pyrazine (285 mg, 1.03 mmol) and 4-amino-2-methoxy-N-[(6-methylpyridin-3-yl)methyl]benzamide (280 mg, 1.03 mmol) are stirred in iPrOH (5 mL) and HBr (48% aq., 380 μL) is added. The mixture is heated at reflux for 24 hours. The cooled suspension is poured into NaHCO3 (sat. aq., 25 mL) and water (25 mL) and extracted with CDCl3 (3×40 mL). The extracts are dried over MgSO4 and evaporated. The residue is purified by column chromatography, eluting with 10% -20% DCM/MeOH to afford the title compound as a pale yellow solid (200 mg, 0.43 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)C>>[CH:10]([S:9][C:4]1[C:3]([CH2:2][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:28])=[O:15])=[CH:20][C:21]=2[O:26][CH3:27])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:12])[CH3:11]
Reactant: CC(C)Sc1ncccc1CCl
Reactant: CCOC(=O)CCc1ccc(O)c(OC)c1
Product: COc1cc(CCC(=O)O)ccc1OCc1cccnc1SC(C)C
Yield: 58.8 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (33 mg, 0.16 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-3-methoxy-phenyl]-propionic acid ethyl ester (40 mg, 0.17 mmol) obtained in Step C of Preparation Example 38 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (34 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:18]=[CH:19][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: COc1ccc(CNc2cc(Br)ccc2N)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Product: COc1ccc(Cn2cnc3ccc(Br)cc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 886.7 %

Procedure:
To a solution of 5-bromo-N-(4-methoxybenzyl)benzene-1,2-diamine (550 mg, crude) in HC(OMe)3 (20 mL) was added TsOH.H2O (30 mg, 0.16 mmol). The mixture was stirred at 100° C. for 4 h. The reaction solution was then concentrated and the residue was washed with water and extracted with EtOAc. The organic layer was concentrated to give the desired product (450 mg, 79% yield) and the crude product used in next step without further purification. LCMS (m/z): 318.1 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:10]1[C:11]([O:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21])[C@@H:15]([CH3:25])[CH2:14][CH2:13]2.[OH-].[Na+].[CH3:33][S:34](Cl)(=[O:36])=[O:35].Cl>O1CCOCC1>[CH:27]1([O:26][C:11]2[C:10]([C:3]3[CH:4]=[N:5][N:6]([CH:7]4[CH2:9][CH2:8]4)[C:2]=3[NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C@H:15]([CH3:25])[N:16]3[C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])[CH2:28][CH2:29][CH2:30]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CCc2c(ccc(-c3cnn(C4CC4)c3N)c2OC2CCC2)N1C(=O)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@H]1CCc2c(ccc(-c3cnn(C4CC4)c3NS(C)(=O)=O)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 8-mL round-bottom flask was charged with ((2S)-6-(5-amino-1-cyclopropyl-1H-pyrazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.020 g, 0.05 mmol), 1,4-dioxane (1 mL) and 4 M aqueous sodium hydroxide solution (1 mL). Methanesulfonyl chloride (0.028 g, 0.019 mL, 0.24 mmol) was added, and the resulting solution stirred overnight at room temperature. The pH of the reaction mixture was adjusted to 7 with 1 N aqueous HCl solution, and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, Water (0.05% ammonium bicarbonate) and acetonitrile (20% to 80% acetonitrile in 10 min, flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded N-(4-((2S)-5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1-cyclopropyl-1H-pyrazol-5-yl)methanesulfonamide (0.010 g, 42%) as yellow oil. 1H NMR (300 MHz, CD3OD) δ ppm 0.63-0.75 (m, 1H), 0.80-1.00 (m, 2H), 1.00-1.18 (m, 8H), 1.25-1.34 (m, 2H), 1.51-1.68 (m, 1H), 1.85-2.11 (m, 5H), 2.25-2.42 (m, 2H), 2.99-3.08 (m, 1H), 3.13 (s, 3H), 3.65-3.75 (m, 1H), 3.96-4.17 (m, 1H), 4.66-4.74 (m, 1H), 7.15 (d, J=8.10 Hz, 1H), 7.38 (d, J=8.40 Hz, 1H), 7.82 (s, 1H). MS (ESI, pos. ion) m/z 485 [M+H]+.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].C1C=CC=CC=1.S(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29][CH:28]=1)(C1C=CC(C)=CC=1)(=O)=O>O>[CH2:34]([O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:32][CH:31]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(OCc3ccccc3)cc2)cc1
Reactant: OC1CCCC1
Agent: [Na]
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(COc2ccc(CCOC3CCCC3)cc2)cc1
Temperature: 80 °C

Procedure:
24.11 g of cyclopentanol and then 1.63 g of sodium are introduced into a 250 ml round-bottomed flask. The mixture is heated at 110°-120° C. until the sodium has disappeared. The mixture is then cooled and 80 cc of benzene are added. 26.77 g of 2-(4-benzyloxyphenyl)ethanol tosylate are then introduced in portions. The mixture is heated at 80° C. for 3 hours. The benzene is driven off, the residue is taken up in water and the solution is extracted with ethyl acetate. This gives an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][N:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH:11]=[C:10]([C:20]([NH:32][C@@H:30]([C:27]3[CH:26]=[N:25][C:24]([CH3:23])=[N:29][CH:28]=3)[CH3:31])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)cc1
Reactant: Cc1ncc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(thiazol-2-yloxy)biphenyl-3-carboxylic acid (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (45 mg, 0.33 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford a light color solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)[C:6]([F:22])=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42](Cl)=[O:43])[C:37]2=[O:45])=[CH:32][CH:31]=1>CCOC(C)=O.O.C(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)[C:6]([F:22])=[CH:5][C:3]=1[NH:4][C:42]([C:38]1[C:37](=[O:45])[N:36]([C:33]2[CH:32]=[CH:31][C:30]([F:29])=[CH:35][CH:34]=2)[CH:41]=[CH:40][CH:39]=1)=[O:43]
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(N)cc3F)ccn2)cn1
Reactant: O=C(Cl)c1cccn(-c2ccc(F)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 180.2 %

Procedure:
A mixture of Example A2 (0.324, 1.073 mmol) and K2CO3 (0.178 g, 1.288 mmol) in EtOAc (1.4 mL) and H2O (2.15 mL) was stirred vigorously for 5 min, treated with a solution of Example A3 (0.108 g, 0.429 mmol) in EtOAc (1.4 mL) and stirred at RT for 2 h. The layers were separated, the aqueous layer extracted with DCM and the combined organics were dried over Na2SO4 and concentrated to dryness. The residue was combined with K2CO3 (0.265 g, 1.920 mmol) in DCM (1.4 mL) and H2O (2.1 mL), stirred vigorously for 5 min, treated with a solution of Example A3 (0.403 g, 1.60 mmol) in DCM (1.4 mL) and stirred at RT overnight. The layers were separated, the aqueous layer extracted with DCM and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (400 mg, 72%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 12.43 (s, 1H), 8.60 (dd, J=7.3, 2.2 Hz, 1H), 8.55 (dd, J=12.6, 7.2 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 8.15 (dd, J=6.6, 2.2 Hz, 1H), 7.97 (s, 1H), 7.62-7.56 (m, 3H), 7.41 (m, 2H), 7.25 (d, J=2.4 Hz, 1H), 6.76-6.71 (m, 2H), 3.84 (s, 3H); MS (ESI) m/z: 518.1 (M+H+).
Reaction SMILES: O([C:8]([NH:10][C:11]1[CH:23]=[CH:22][C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:12]=1)=[O:9])C1C=CC=CC=1.[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C.O>CN(C)C=O>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([NH:24][C:8](=[O:9])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:22][CH:23]=2)[CH:26]=1
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(NC(=O)Nc2cccnc2)cc1
Yield: 61.4 %

Procedure:
A solution of ethyl 4-(phenoxycarbonylamino)cinnamate (500 mg), 3-aminopyridine (154 mg) and triethylamine (325 mg) in N,N-dimethylformamide (5 ml) was stirred for 2 hours at 80° C. Water was added thereto, and the resulting precipitate was collected by filtration to give ethyl 4-[3-(3-pyridyl)ureido]cinnamate (307 mg) as a colorless powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][NH2:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C1COCC1.C(O)(=O)C>[O:1]1[CH:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]2[CH:3]=[C:2]1[CH2:10][NH:13][CH3:12]
Reactant: O=Cc1cc2ccccc2o1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CNCC1=CC2C=CC=CC2O1
Yield: 64 %

Procedure:
To a stirred solution of benzofuran-2-carboxaldehyde (1.50 g) and 4 Å molecular sieves in dichloroethane (50 ml) under an atmosphere of nitrogen was added methylamine in THF (2.0M, 10.3 ml) and acetic acid (1.23 g). Stirring was continued for 2 h before sodium triacetoxyborohydride (2.18 g) was added and stirring as continued overnight. The mixture was filtered, absorbed onto silica gel and chromatographed eluting with dichloromethane/methanol (9:1) to yield the title compound (1.05 g, 64%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl.C1C(O)=CC=CC=1C.[CH3:19][NH:20][C:21]#[N:22].[OH-].[Na+]>CCOCC>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:21]([NH:20][CH3:19])=[NH:22]
Reactant: CNC#N
Reactant: Cc1cccc(C)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1cccc(O)c1
Product: CNC(=N)Nc1c(C)cccc1C

Procedure:
To 40.5 g. (0.315 mole) of 2,6-dimethylaniline is added 0.4 moles of ethereal HCl and 200 ml. of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 17.7 g. (0.315 mole) of methyl cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml. of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2 × 1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 1-(2,6-dimethylphenyl)-3-methylguanidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17].[CH2:23]([NH:25][C:26]#[N:27])[CH3:24].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:26]([NH:25][CH2:23][CH3:24])=[N:27][C:15]([CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])=[N:14]1
Reactant: CCNC#N
Reactant: CC(C(Cl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNc1nc(C(C)C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 3 h
Yield: 68.9 %

Procedure:
7.8 g (0.02 mol) of 2-trifluoromethylpropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 1.5 g (0.022 mol) of ethyl cyanamide were dissolved in 50 ml of tetrahydrofuran, and 2.5 g (0.025 mol) of triethylamine was dropwise added thereto under stirring and cooling with ice. After completion of the dropwise addition, the stirring was continued at room temperature for 3 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in hexane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, hexane was distilled off under reduced pressure. Further, the residue was subjected to distillation under reduced pressure. The fraction having a boiling point of 110°-120° C./0.1-0.2 mmHg was subjected to recrystallization from hexane to obtain 5.8 g (yield: 69%) of the desired compound having a melting point of from 82° to 83° C. as slightly yellow prismatic crystals.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[O:7]1CC[CH2:9][CH2:8]1.[Na].C1OC1>O>[CH2:1]([O:6][CH2:9][CH2:8][OH:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: C1CCOC1
Reactant: CCCCCO
Agent: [Na]
Solvent: O
Solvent: C1CO1
Product: CCCCCOCCO
Reaction time: 24 h

Procedure:
To 14.0 ml. of anhydrous 1-pentanol in 100 ml. tetrahydrofuran is added 0.25 g. sodium. After the sodium has reacted, gaseous ethylene oxide (0.34 g.) is added at a rate such that the temperature is maintained between 35° and 40°. The flask is sealed and allowed to stand for one day. The reaction mixture is poured into water and then extracted with ether, dried over sodium sulfate, the solvent removed and the residue distilled and fractionated to yield 2-pentyloxy-1-ethanol.