Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[C:6]([N:14]2[CH2:18][CH2:17][C@H:16]([N:19]([CH3:21])[CH3:20])[CH2:15]2)[C:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:4][C:3]=1[C:28]#[N:29].C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(#N)C.CC#N.CC#N.Cl[Pd]Cl>[C:10]([C:9]1[NH:1][C:2]2[C:7]([CH:8]=1)=[C:6]([N:14]1[CH2:18][CH2:17][C@H:16]([N:19]([CH3:21])[CH3:20])[CH2:15]1)[C:5]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:4][C:3]=2[C:28]#[N:29])([CH3:13])([CH3:11])[CH3:12]
Reactant: CN(C)[C@H]1CCN(c2c(-c3ccccc3)cc(C#N)c(N)c2C#CC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CN(C)[C@H]1CCN(c2c(-c3ccccc3)cc(C#N)c3[nH]c(C(C)(C)C)cc23)C1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
4-Amino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(3,3-dimethylbutyn-1-yl)biphenyl-3-carbonitrile (I-246) (54 mg, 0.14 mmol) was dissolved in acetonitrile (3 ml), and at room temperature, bis(acetonitrile)palladium(II) dichloride (7.3 mg, 0.28 mmol) was added, followed by heating under reflux for 3 hours. After cooling to room temperature, the reaction liquid was fractionated with chloroform and an aqueous saturated sodium hydrogencarbonate solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=95:5) to obtain a crude product of the entitled compound (32 mg, 60%) as a pale brown gel. This was recrystallized from hexane/diethyl ether to obtain the entitled compound (15 mg) as a pale brown powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9](=[O:10])[C:8]4=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]4[C:6]3=[O:15])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(c2ccccc2)CC1
Reaction time: 4.5 h
Yield: 90 %

Procedure:
To the solution of N-(3-bromopropyl)phthalimide (15.6 g) in acetone (150 ml) were added 1-phenylpiperazine (10.4 g) and potassium carbonate (12.0 g). The resulting mixture was refluxed with stirring for 4.5 hours. The reaction mixture was cooled and then filtered. The filter cake was washed with acetone. The filtrate and washing were combined and evaporated under reduced pressure. The residue was recrystallized from ethanol to give an oil of N-[3-(4-phenyl-1-piperazinyl)propyl]phthalimide (18.3 g), mp 129° to 134° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:17])C=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.C(OCC)C>[CH:3]1([CH:1]([OH:17])[CH2:2][S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Sc1ccccc1
Reactant: C=CC1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: OC(CSc1ccccc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A room temperature solution of vinylcyclohexane (1.71 g, 15.5 mmol) in dichloromethane (20 mL) was treated with 70% mCPBA (4.90 g, 19.9 mmol), stirred for 3 hours, diluted with diethyl ether (100 mL), washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in 1,2-dichloroethane (20 mL), treated with thiophenol (1.8 g, 16.3 mmol), heated to 80° C., stirred for 5 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% ethyl acetate/hexanes to provide the desired product. MS (DCI/NH3) m/e 254 (M+NH4).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)=[N:12][N:11]=2)=[CH:6][CH:5]=1.[CH2:23](Cl)[O:24][CH3:25]>C1COCC1.CCOC(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:23][O:24][CH3:25])[C:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)=[N:12][N:11]=2)=[CH:6][CH:5]=1.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH2:23][O:24][CH3:25])[N:12]=[C:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[N:14]=2)=[CH:6][CH:5]=1
Reactant: Clc1cccc(Cc2nnc(-c3ccc(Br)cc3)[nH]2)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCn1c(Cc2cccc(Cl)c2)nnc1-c1ccc(Br)cc1
Product: COCn1nc(Cc2cccc(Cl)c2)nc1-c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 150 %

Procedure:
To a suspension of NaH (1.1 mmol in 60% mineral oil) in THF (3 mL) at 0° C. was added 3-(4-bromo-phenyl)-5-(3-chloro-benzyl)-4H-[1,2,4]triazole (1.0 mmol). After the mixture was stirred for 30 min, MOMCl (1.0 mmol) was added and the mixture was stirred from 0° C. to room temperature overnight. The reaction mixture was diluted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography to give 3-(4-bromo-phenyl)-5-(3-chloro-benzyl)-4-methoxymethyl-4H-[1,2,4]triazole and 5-(4-bromo-phenyl)-3-(3-chloro-benzyl)-1-methoxymethyl-1H-[1,2,4]triazole (0.75 mmol) as a mixture of two isomers (4:1).
Reaction SMILES: Cl[Si:2]1([CH3:6])[CH2:5][CH2:4][CH2:3]1.[C:7]([O:10][Si](C)(C)C)([CH3:9])=[CH2:8]>>[CH3:6][Si:2]1([O:10][C:7]([CH3:9])=[CH2:8])[CH2:5][CH2:4][CH2:3]1
Reactant: C[Si]1(Cl)CCC1
Reactant: C=C(C)O[Si](C)(C)C
Product: C=C(C)O[Si]1(C)CCC1

Procedure:
In accordance with the general procedure of Example 1, when 1-chloro-1-methylsilacyclobutane and isopropenoxytrimethylsilane are reacted it is predicted that the title compound is obtained.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[S:6][C:7]([CH2:10][NH:11][C:12](=[N:15][N+:16]([O-:18])=[O:17])SC)=[CH:8][N:9]=1>C(#N)C>[Cl:4][C:5]1[S:6][C:7]([CH2:10][NH:11][C:12]([N:2]([CH3:3])[CH3:1])=[N:15][N+:16]([O-:18])=[O:17])=[CH:8][N:9]=1
Reactant: CNC
Reactant: CSC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Solvent: CC#N
Product: CN(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
252 mg of a 50% aqueous dimethylamine solution was dropwise added to a mixture consisting of 600 mg N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitroisothiourea and 20 ml acetonitrile at room temperature. After stirring at room temperature for 2 hours the reaction mixture was concentrated and 20 ml of ethanol was added to the residue, followed by stirring thoroughly. The resultant crystals were collected by filtration and dried to afford 350 mg of N-(2-chloro-5-thiazolylmethyl)-N',N'-dimethyl-N"-nitroguanidine (compound No.17) as a white powder. The mothor liquor after the filtration was concentrated and 5 ml of ethanol was added, followed by stirring thoroughly, then the resultant crystals were collected by filtration and dried to give additional 120 mg of compound No.17 (mp 154-159° C.). Recrystallization of this product from acetonitrile afforded a product having a melting point of 164-166° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)=[CH:6][CH:5]=[C:4]([N+:20]([O-])=O)[N:3]=1>[Pd].CCOC(C)=O.CO>[NH2:20][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH:10]=2)=[CH:6][CH:5]=1
Reactant: CCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2C)ccn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1cc(Oc2ccc(N)nc2C)ccn1
Yield: 84.6 %

Procedure:
A solution of N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)propionamide (0.42 g, 1.389 mmol) in 2:1 EtOAc/MeOH (30 mL) was treated with palladium on carbon (50% wet, 0.165 g, 0.139 mmol) and hydrogenated (1 atm) for 2 days. The solids were removed via filtration through diatomaceous earth, washed well with MeOH and the filtrate was concentrated to dryness to afford N-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)propionamide (320 mg, 85%). 1H NMR (400 MHz, DMSO-d6): δ 10.41 (s, 1H), 8.12 (d, J=5.7 Hz, 1H), 7.56 (d, J=2.4 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 6.56 (dd, J=5.7, 2.4 Hz, 1H), 6.34 (d, J=8.7 Hz, 1H), 5.93 (s, 2H), 2.33 (q, J=7.5 Hz, 2H), 2.04 (s, 3H), 1.00 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 273.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:4][C:3]=1[CH:17]=[O:18].FC(F)(F)C1C=CC(C2C=C(C(O)=[O:33])SC=2)=CC=1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:11][CH:12]=2)[S:4][C:3]=1[C:17]([OH:33])=[O:18]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)cs1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O

Procedure:
The title compound was prepared using 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde (intermediate 74) by a method analogous to the preparation of 4-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylic acid (intermediate 38).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].N1C=CC=CC=1>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH:23]=[N:26][OH:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(CCC=O)cc2-c2ccc(Cl)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(-n2nc(CCC=NO)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of the aldehyde 11 (1.00 g, 2.93 mM) in EtOH (30 ml) was added hydroxylamine hydrochloride (0.31 g, 4.40 mM) and pyridine (0.47 g, 5.87 mM). After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo. The remaining residue was taken up in CH2Cl2, washed with H2O, dried (Na2SO4), filtered, and concentrated in vacuo. Crystallization from Et2O:hexane afforded 26, (0.67 g, 64%) as a white crystalline solid, mp=134°-135° C.
Reaction SMILES: [C:1]([N:9]([CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([CH3:31])[C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.Cl>O.CO>[CH3:31][CH:25]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:9]([CH3:10])[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:13]=2)=[CH:23][CH:22]=1)[C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)C(C)Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(Cc1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1)C(=O)O
Yield: 77.4 %

Procedure:
1.25 g (3 mmol) of ethyl 3-{3′-[(benzoyl-methylamino)methyl]biphenyl-4-yl}-2-methylpropionate, 3 ml of sodium hydroxide (10N), 32 ml of THF and 2 ml of methanol are introduced into a round-bottomed flask. The reaction medium is refluxed for 8 hours, poured into water, acidified to pH 4 with 1N hydrochloric acid and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluded with a mixture of heptane and ethyl acetate (60/40). 900 mg (90%) of 2-methyl-3-(3′-{[methyl-(1-phenylmethanoyl)-amino]methyl}biphenyl-4-yl)propionic acid, with a melting point of 60-61° C., are obtained.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]2[O:45][C:38]3([CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]3)[CH:37]=[CH:36][C:35]=2[CH:46]=1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([CH:42]3[CH2:43][C:38]4([CH:37]=[CH:36][C:35]5[CH:46]=[C:31]([NH2:30])[CH:32]=[CH:33][C:34]=5[O:45]4)[CH2:39][CH2:40][N:41]3[CH3:44])=[N:5]2)=[CH:10][CH:11]=1
Reactant: CN1CCC2(C=Cc3cc(N)ccc3O2)CC1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(C3CC4(C=Cc5cc(N)ccc5O4)CCN3C)nn12
Yield: 12.8 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (87.49 mg, 0.0003045 mol), N,N-Diisopropylethylamine (0.175 mL, 0.00100 mol) and 6-amino-1′-methyl-spiro(2H-1-benzopyran-2,4′-piperidine) (0.141 g, 0.000609 mol) were dissolved in 1-Methoxy-2-propanol (0.350 mL, 0.00358 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 17.67 mg of 7-(2-methoxy-phenyl)-pyrrolo(2,1-f)(1,2,4)triazin-2-yl-6-amino-1′-methyl-spiro(2H-1-benzopyran-2,4′-piperidine) as a lyophilized powder. (M+H)=456.1. 1H NMR (400 MHz, DMSO, d6) δ 9.19 (s, 1H), 8.91 (s, 1H), 7.81 (d, 1H, J=7.24 Hz), 7.57 (m, 1H), 7.45 (m, 1H), 7.34 (m, 1H), 7.21 (m, 1H), 7.11 (m, 1H), 6.90 (d, 2H, J=7.65 Hz), 6.70 (d, 1H, J=8.56 Hz), 3.79 (s, 3H), 3.33 (m, 2H), 3.18 (m, 2H), 2.83 (m, 3H), 2.62 (m, 2H), 1.92 (m, 2H), 1.79 (m, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:20]=[C:19](Cl)[N:18]=[CH:17][C:16]=3[N:22]=2)=[C:9]([F:23])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([C:36](B(O)O)=[CH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(Cl)Cl>O1CCOCC1.O>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[CH:20]=[C:19]([C:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH2:37])[N:18]=[CH:17][C:16]=3[N:22]=2)=[C:9]([F:23])[CH:8]=1
Reactant: C=C(B(O)O)c1ccccc1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2cnc(Cl)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: C=C(c1ccccc1)c1cc2sc(-c3ccc(C4OCCCO4)cc3F)nc2cn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-chlorothiazolo[4,5-c]pyridine (1.00 g, 2.85 mmol), (Amphos)2PdCl2 (0.0505 g, 0.0713 mmol), potassium carbonate (1.34 g, 9.69 mmol), 1-phenylvinylboronic acid (0.928 g, 6.27 mmol) in 12 mL dioxane and 3 mL water was heated to 60° C. overnight in a sealed tube. Additional (Amphos)2PdCl2 (0.0505 g, 0.0713 mmol) was added and the temperature raised to 90° C. After 3 h, the homogeneous reaction mixture was cooled and treated with water and DCM. The organic layer was extracted with DCM, and combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The solid was suspended in MTBE and filtered to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylvinyl)-thiazolo[4,5-c]pyridine as an off-white solid. MS (ESI) m/z: calculated: 418.1; Observed: 419.0 (M++1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:36])[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH2:22][C:21]([C:27]4[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=4)([C:23]([F:26])([F:25])[F:24])[O:20][N:19]=3)=[CH:14][C:13]=2[CH3:35])[CH:7]=[CH:6][CH:5]=1.[H][H].[C:39](Cl)(=[O:41])[CH3:40]>CN(C)C=O>[C:39]([N:10]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:3])[N:9]=1)[C:11](=[O:36])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:22][C:21]([C:27]3[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=3)([C:23]([F:25])([F:26])[F:24])[O:20][N:19]=2)=[CH:14][C:13]=1[CH3:35])(=[O:41])[CH3:40]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cccc(Cl)n1
Reactant: [H][H]
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1cccc(Cl)n1
Temperature: 0 °C
Yield: 34 %

Procedure:
In a suspension of 0.10 g of 55% oily sodium hydride suspended in 15 mL of N,N-dimethylformamide, a solution of 0.30 g of N-(6-chloro-2-pyridyl)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-yl]-2-methyl benzoic acid amide in 5 mL of N,N-dimethylformamide was added under cooling with ice and with stirring, and stirred at the same temperature for 10 minutes. After ceasing the generation of hydrogen gas, 0.30 g of acetyl chloride was added, ice bath was removed and continued to stir further for 5 minutes. After the completion of the reaction, the reaction mixture was poured in 20 mL of ice water, extracted with ethyl acetate (50 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.11 g of the aimed product as colorless resinous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([NH:8][C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=CN=2)[CH:7]=1.[CH2:20]([N:22](CC)CC)C.[CH3:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH3:27])=[CH:29][CH:30]=2)=[CH:7][C:6]=1[NH:8][C:9](=[O:18])[CH:10]=[CH:11][C:12]1[CH:20]=[N:22][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(N)cc1NC(=O)/C=C/c1ccccn1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(C)c(NC(=O)C=Cc3cccnc3)c2)cc1

Procedure:
To a solution of the product of step 3 (0.25 g) and triethylamine (0.2 ml) in dichloromethane (25 ml), a solution of 4-methylbenzoyl chloride (0.5 g) in dichloromethane (10 ml) was added dropwise slowly in an ice-bath with the temperature no more than 5° C. After addition, the reaction was carried out for to 30 min in an ice-bath, and then at room temperature overnight. The completion of reaction was indicated by TLC. After that potassium carbonate solution (10%) was added, and then a solid was precipitated, and filtered out. The filter cake was washed with water, and recrystallized from ethyl acetate to give a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.ClC(Cl)(O[C:14](=[O:20])[O:15][C:16](Cl)(Cl)Cl)Cl.[N-:22]=[C:23]=[O:24]>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:23]([NH:22][C:5]2[C:6]3[NH:7][C:14](=[O:20])[O:15][C:16]=3[CH:2]=[CH:3][CH:4]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccc(Cl)cc1
Reactant: [N-]=C=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)Nc1cccc2oc(=O)[nH]c12
Temperature: 80 °C
Yield: 14 %

Procedure:
Commercially available p-chlorobenzylamine (1.6 g, 11.4 mmol) was dissolved in 60 ml of AcOEt and at 0° C. triphosgene (3.38 g, 1 equiv.) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 30 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1b (1.7 g, 11.4 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 7/petroleum ether 3). The solvent was evaporated and the crude was dissolved in AcOEt (80 ml) and washed with water (1×50 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 500 mg of a white solid. Yield=14% 1HNMR (DMSO, 200 MHz) δ 4.57 (2H, d, J=5.8 Hz), 6.53 (2H, m), 7.04 (1H, m), 7.41 (4H, s), 9.88 (1H, t), 11.53 (1H, s), 11.80 (1H, bs); [M+1] 318.5 (C15H12ClN3O3 requires 317.73).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH:17]([O:20][NH:21][CH3:22])([CH3:19])[CH3:18].[OH-].[Na+]>O1CCOCC1.O>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:21]([CH3:22])[O:20][CH:17]([CH3:19])[CH3:18])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CNOC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCNc1nc(NCCC)nc(N(C)OC(C)C)n1
Temperature: 100 °C
Yield: 41.1 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (1.65 g, 16.61 mmol), O-isopropyl-N-methyl-hydroxylamine hydrochloride (LXIII, 2.09 g, 16.61 mmol) and NaOH (0.66 g, 16.61 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was heated at 100° C. for 16 h. The volatiles were then removed under reduced pressure. Saturated NaHCO3 solution (50 mL) was added to the residue and the mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV, 1.93 g, 95%). ESI-MS (m/z): 283 [M+H]+.
Reaction SMILES: [NH:1]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)=[O:10])[CH3:8])=[O:5])[CH3:3].CN1CCOCC1.[NH2:33][C@H:34]([C:38]([CH2:40][F:41])=[O:39])[CH:35]([CH3:37])[CH3:36].Cl.Cl>C1COCC1.CN(C=O)C>[NH:33]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:34]([C:38]([CH2:40][F:41])=[O:39])[CH:35]([CH3:37])[CH3:36].[NH:1]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([NH:33][C@H:34]([C:38]([CH2:40][F:41])=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:15])=[O:10])[CH3:8])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)[C@H](N)C(=O)CF
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)CF
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)CF
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To a solution of Boc-ValCH2F (0.48 g, 2.06 mmol) in ether (10 mL) was added a saturated solution of HCl in ether (25 mL). The mixture was stirred for 30 minutes at room temperature. The solvent was evaporated under reduced pressure at room temperature. The residue was quickly triturated with ether (2×30 mL) and then was pumped dry, giving 0.24 g of ValCH2F hydrochloride. Boc-Ala-Ala-ProOH (Enzyme Systems Products, 0.503 g, 1.41 mmol) was dissolved in THF (5 mL) and was cooled to -20° C. NMM (0.155 mL, 1.41 mmol) was added, followed by IBCF (0.183 mL, 1.41 mmol) After 5 minutes, this mixture was charged with a solution of ValCH2F hydrochloride (0.24 g, 1.41 mmol) in DMF (2 mL). A second equivalent of NMM (0.155 mL, 1.41 mmol) was added. The mixture was stirred at -15° C. for 15 minutes. 1 molar HCl (15 mL) was added. The product was extracted with ethyl acetate (2×15 mL). The combined extracts were washed with saturated aqueous NaHCO3 (15 mL), brine (15 mL), dried over MgSO4, filtered, and evaporated to dryness. The residue was slowly crystallized at -20° C. from CH2Cl2 /hexane, giving 0.47 g (47% from Boc-ValCH2F of Boc-Ala-Ala-Pro-ValCH2F.