Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11](Cl)[C:10]=2[F:16])[CH2:4][CH2:3]1.[C:17](=[NH:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:30]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:10]=2[F:16])[CH2:4][CH2:3]1
Reactant: CN1CCC(Nc2cccc(Cl)c2F)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CN1CCC(Nc2cccc(N=C(c3ccccc3)c3ccccc3)c2F)CC1
Yield: 53.3 %

Procedure:
Combine 1-methyl-4-(3-Chloro-2-fluorophenylamino)piperidine (Preparation 19) (0.439 g, 1.8 mmol), benzophenone imine (0.393 g), Pd2(dba)3 (4.1 mg), 2-(dicyclohexylphosphino)biphenyl (4.7 mg), and sodium t-butoxide (0.242 g) with toluene (5 mL) and heat at reflux overnight. Dissolve the reaction mixture in methanol and filter through a SCX column (10 g), wash with methanol, elute the product with 2M NH3 in methanol, evaporate the solvent, and further purify on a silica gel column (35 g, using a dichloromethane-2M NH3 in methanol gradient) to give crude 1-methyl-4-(3-benzhydrylideneamino-2-fluorophenylamino)piperidine (0.372 g). Add 1N HCl (2 mL) into a solution of the benzhydrylidenyl intermediate in THF (10 mL) and stir at room temperature for 30 minutes. Basicify with NH4OH, extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate and purify on a silica gel columnn (10 g), using a gradient of dichloromethane-2M NH3 in methanol to give the title intermediate (0.08 g): mass spectrum (ion spray): m/z=224 (M+1); 1H NMR (CDCl3): 6.75 (ddd, 1H), 6.12 (m, 2H), 3.70 (br d, 1H), 3.62 (br s, 2H), 3.25 (m, 1H), 2.80 (m, 2H), 2.29 (s, 3H), 2.10 (m, 4H), 1.53 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12](I)[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])#[CH:17].CCN(CC)CC>CN(C=O)C.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([C:17]#[C:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(I)ccn1
Reactant: C#Cc1ccccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1C#Cc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of (4-iodo-pyridin-2-yl)-carbamic acid tert-butyl ester (250.0 mg, 0.781 mmol), 1-ethynyl-2-methoxy-benzene (93.8 mg, 0.710 mmol), CuI (13 mg, 0.071 mmol), Pd(PPh3)2Cl2 (25 mg, 0.036 mmol), and Et3N (9 mL) in dry DMF (3 mL) is stirred at room temperature for 19 hours. The reaction is diluted with ethyl acetate (20 mL) and quenched with saturated aqueous NH4Cl (10 mL). The organic layer is washed with an additional portion of saturated aqueous NH4Cl (10 mL), dried over MgSO4, filtered and concentrated. The residue is purified on SiO2 (0-30% ethyl acetate in heptanes, gradient) to give the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([CH3:12])([CH3:11])[CH2:6][CH2:7][C:8](Cl)=[O:9])=[O:4].[CH2:13]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH3:16].CCN(C(C)C)C(C)C>C(OCC)(=O)C>[CH2:13]([N:17]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1)[C:8](=[O:9])[CH2:7][CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])([CH3:12])[CH3:11])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Reactant: COC(=O)C(C)(C)CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)CCC(C)(C)C(=O)OC
Reaction time: 1 h

Procedure:
The starting material can be prepared, for example, as follows: A solution of 3.3 g (17 mmol) of 4-methoxycarbonyl-4-methyl-pentanoic acid chloride in 20 ml of ethyl acetate is added dropwise at from 0° to 5° to a solution of 3.0 g (11.3 mmol) of N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 6.5 ml of Hunig base in 50 ml of ethyl acetate. The reaction mixture is stirred for 1 hour and then worked up analogously to Example 1 b) to yield 4-methoxycarbonyl-4-methyl-pentanoic acid N-butyl-N-(2'-cyano-biphenyl-4-ylmethyl)-amide in the form of an oil that has an Rf value of 0.27 [toluene/methanol (19:1)] and is further used in crude form.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:12][NH2:13]>C(O)C>[CH3:12][NH:13][CH:3]([C:2]([F:10])([F:11])[F:1])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: CN
Solvent: CCO
Product: CCOC(=O)CC(NC)C(F)(F)F

Procedure:
Gaseous methylamine was bubbled into absolute ethanol (50 ml.) at 0° C. until 8.5 g. (0.27 mole) was dissolved in the ethanol solvent. Ethyl 4,4,4-trifluorocrotonate (25.0 g., 0.15 mole) in ethanol was added to the methylamine solution at 0° C. The reaction mixture in ethanol was left overnight at 20° C. Thereafter, the solvent was driven off and the residue distilled to produce ethyl 3-(methylamino)-4,4,4-trifluorobutanoate in a yield of 22 g. This product was characterized by a boiling point, at a pressure of 12 mm. Hg., of 62° C. to 64° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:19]1([CH3:24])OCC[O:20]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:19](=[O:20])[CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:25]
Reactant: CCOC(=O)C(CN1C(=O)c2ccc(C)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2ccc(C)cc2C1=O)C(C)=O

Procedure:
Ethyl 2-(5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (93 mg, 35%) in the same manner as described in the above example 6 (20) from ethyl 3-(5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.38 g, 1.07 mmol) and p-toluenesulfonic acid monohydrate (30 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 104.7 %

Procedure:
To 4-bromo-1-ethyl-2-nitrobenzene (20.0 g, 87 mmol) in 1,2-dimethoxyethane (150 ml) is added, at room temperature, 4-chlorophenylboronic acid (14.98 g, 96 mmol) and tetrakis-(triphenylphosphine)palladium(0) (2.0 g, 1.74 mmol) and nitrogen gas is bubbled through the mixture. After stirring for 10 minutes at 20° C., a solution of sodium carbonate (73.8 g, 0.696 mol) in water (350 ml) is added and mixture is refluxed for 16 hours. The reaction mixture is cooled to room temperature, filtered through diatomaceous earth, washing with ethyl acetate (200 ml). The mixture is poured into a separating funnel and the two phases are separated. The aqueous phase is extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 4′-chloro-4-ethyl-3-nitrobiphenyl (23.84 g) as a brown oil used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(N)cn1
Product: COc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
prepared by reaction of 6-methoxy-pyridin-3-ylamine with 4-tert-butyl-benzenesulfonyl chloride
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH:25][CH2:26]C)[CH:20]=1>>[CH3:26][NH:25][C:21]1[CH:20]=[C:19]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:12][CH:13]=2)[N:24]=[CH:23][N:22]=1
Reactant: CN1CCN(CCOc2ccc(N)cc2)CC1
Reactant: CCNc1cc(Cl)ncn1
Product: CNc1cc(Nc2ccc(OCCN3CCN(C)CC3)cc2)ncn1
Temperature: 150 °C
Reaction time: 20 h

Procedure:
The title compound is prepared as described in Example 160A but using 4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenylamine (500 mg, 2.13 mmol, 1 eq.), (6-chloro-pyrimidin-4-yl)-ethyl-amine and stirring the reaction mixture at 150° C. for 20 h. Purification of the crude product by silica gel column chromatography (DCM/MeOH+1% NH3aq, 9:1) followed by trituration in diethyl ether affords 250 mg of the title compound as a white solid: ESI-MS: 343.2 [MH]+; tR=1.00 min (gradient J); TLC: Rf=0.23 (DCM/MeOH+1% NH3aq, 9:1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[N:10]=[CH:11][C:3]=12.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.C([O-])(O)=O.[Na+]>C1COCC1.O.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>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:9]1[C:4]2=[N:5][C:6]([NH2:8])=[N:7][C:2]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[C:3]2[CH:11]=[N:10]1
Reactant: OB(O)c1cccs1
Reactant: Nc1nc(Cl)c2cnn(Cc3ccccc3F)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(-c2cccs2)c2cnn(Cc3ccccc3F)c2n1
Yield: 19.7 %

Procedure:
A stirred solution of 4-chloro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-6-amine(139 mg, 0.5 mmol) in dry THF (10 mL) was treated with 2-thiopheneboronic acid (128 mg, 1.0 mmol), Pd(PPh3)4 (50 mg, 10 mol %) and saturated aqueous NaHCO3 solution (2 mL), refluxed for 30 min, diluted with H2O, extracted with EtOAc, dried MgSO4) and concentrated in vacuo. The resulting dark brown oil was purified by chromatography [SiO2; heptane:EtOAc (1:1) then (1:3)] to give the title compound (32 mg, 20%) as a cream solid.
Reaction SMILES: B.CSC.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=O)[CH:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]=[CH:22]2)[CH2:15][CH2:14]1.Cl>C1COCC1>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:21]2[CH:25]=[C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:23]=[CH:22]2)[CH2:15][CH2:14]1
Reactant: COc1ccccc1N1CCN(C(=O)C(c2ccccc2)n2cnc(-c3ccccc3)c2)CC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccccc1N1CCN(CC(c2ccccc2)n2cnc(-c3ccccc3)c2)CC1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
2.0 M Borane-methylsulphide in THF (45 ml) was added over 45 mins to a solution of 1-(2-methoxyphenyl)-4-[1-oxo-2-phenyl-2-(4-phenyl-1H-imid azol-1-yl) ethyl]piperazine (4.0 g, 0.009 m, prepared in an analogous manner to the method of Example 5a) in dry THF (30 ml) at ambient temperature, and the mixture was then refluxed 24 hrs. The cooled mixture was treated with conc. HCl (25 ml) dropwise over 30 mins and the resulting white suspension was then heated at 90° C. for 4 hrs. After further standing 48 hrs the mixture was filtered. The white solid was washed with 6N HCl and dried, then recrystallised from ethanol to yield the title compound as the trihydrochloride (1.425 g), m.p. 233°-36° C.(d).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH:12][C:11]=1[F:27])=[O:5])=[N-]>ClCCCl.C1(C)C=CC=CC=1>[F:27][C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:18])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=[CH:15][C:10]=1[C@H:9]1[C@H:3]2[C@@H:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: [N-]=[N+]=CC(=O)OC/C=C/c1ccc(NC(=O)OCc2ccccc2)cc1F
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccc([C@@H]2[C@H]3COC(=O)[C@H]32)c(F)c1)OCc1ccccc1

Procedure:
A solution of (2E)-3-(4-{[(benzyloxy)carbonyl]amino}-2-fluorophenyl)prop-2-enyl diazoacetate (13.9 g, 37.5 mmol) in 1,2-dichloroethane (150 mL) was added dropwise over 14 h to a refluxing solution of bis-(N-t-butylsalicylaldiminato)copper(II) (0.82 g, 1.9 mmol, prepared as described by R. G. Charles, J. Org. Chem. 1957, 22, 677) in 1.5 L of toluene. After the addition was complete, the reaction mixture was heated another hour at reflux, then cooled, filtered and concentrated. The crude oil was purified by column chromatography (0-50% ethyl acetate-hexanes) to provide the (racemic) title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][NH2:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][NH:39][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 66.8 %

Procedure:
4-({[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (155 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (150 mg), 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (100 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[C:16]=2[Cl:23])[C:7]=1[N:8](C(=O)C)[C:9](=[O:11])[CH3:10])#[N:2]>C(O)C.C(=O)(O)[O-].[Na+]>[C:9]([NH:8][C:7]1[N:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[C:16]=2[Cl:23])[N:5]=[CH:4][C:3]=1[C:1]#[N:2])(=[O:11])[CH3:10]
Reactant: CC(=O)N(C(C)=O)c1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Yield: 50.7 %

Procedure:
4-Cyano-5-diacetylamino-1-(2,3,4-trichlorophenyl)pyrazole (0.2 g) in ethanol (5 ml) containing saturated aqueous sodium bicarbonate solution (4 drops), was heated at reflux for 20 minutes. The reaction mixture was then evaporated to dryness under reduced pressure (20 mmHg) to give a fawn coloured powder which was crystallized from ethanol (2 ml), to give 5-acetamido-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (0.09 g), m.p. 222°-224° C., in the form of a colourless crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=2)(C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC1C=CC=CC=1C.CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)(c2cncc(Cl)n2)C1
Solvent: Cc1ccccc1C
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCCC(c2cncc(Cl)n2)C1
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A solution of 3-(6-chloro-pyrazin-2-yl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (46 g) in o-xylene (300 mL) and DMA (30 mL) was heated under reflux for 5 hrs. After cooling to room temperature, it was washed with brine (200 mL×2). The organic layer was then dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The residue obtained was then purified on a silica gel column eluting with EA:DCM:Hex=1:1:3 to give the title compound (18 g) as a white solid. MS: 298.7 (M+H+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1.Cl[CH2:19][C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:19][C:20]([NH2:22])=[O:21])[CH2:13][CH2:14]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=1
Reactant: NC(=O)CCl
Reactant: O=[N+]([O-])c1cc(Br)ccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: NC(=O)CN1CCN(c2ccc(Br)cc2[N+](=O)[O-])CC1
Yield: 40.3 %

Procedure:
Using the same reaction conditions as described in step-i of example-82A, 1-(4-bromo-2-nitrophenyl)piperazine hydrochloride (1.2 g 3.69 mmol) was alkylated using 2-chloroacetamide (517 mg, 5.53 mmol) and sodium carbonate (930 mg, 11.07 mmol) in toluene/ethanol (15/15 mL) to get 510 mg (40.3% yield) of the titled compound. MS: m/z=343.0 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:34]=[C:22]1[CH2:23][C:24]([C:26]2[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=2)[C:32]#[N:33])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[CH:10][C:9]=2[NH:21]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2nccs2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4nccs4)cc3NC(=O)C2)c1
Yield: 40.7 %

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-thiazol-2-ylethynyl-phenyl}-carbamic acid tert.-butyl ester (Example K11) (119 mg, 0.24 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (36 mg).
Reaction SMILES: CN(C=O)C.CO.S(Cl)([Cl:10])=O.[CH:12]1[C:17]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=[C:14]([N:24]([CH2:28][CH2:29][Cl:30])[CH2:25][CH2:26][Cl:27])[CH:13]=1>[Pd].C(Cl)Cl>[Cl:27][CH2:26][CH2:25][N:24]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH2:19][CH2:20][C:21]([Cl:10])=[O:22])=[CH:12][CH:13]=1)[CH2:28][CH2:29][Cl:30]
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Reactant: O=S(Cl)Cl
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCc1ccc(N(CCCl)CCCl)cc1
Reaction time: 7 h

Procedure:
0.33 g (0.83 mmol) of 1H-2-(3-nitrophenyl)benzimidazole-5-[N-(2-amidinoethyl)]carboxyamide hydrochloride was suspended in a mixed solvent of DMF and methanol, and catalytic hydrogenation was then carried out in the presence of 10% Pd/C as a catalyst to lead the above-mentioned compound to a corresponding amino compound. This DMF solution was stirred under ice cooling and under a nitrogen gas stream, and a methylene chloride solution of 4-[4-[N,N-bis(2-chloroethyl)amino]phenyl]butyryl chloride {which was prepared by adding 0.55 g (4.6 mmols, 5.0 eq.) of thionyl chloride to 0.28 g (0.92 mmol) of chlorambucil, removing thionyl chloride under reduced pressure after 5 minutes, and then carrying out azeotropic distillation with benzene twice} was added dropwise. The temperature of the suspension was returned to room temperature, followed by stirring for 7 hours. Next, the suspension was concentrated under reduced pressure, and the resulting residue was then purified through silica gel column chromatography (ethyl acetate/IPA/water=6/2/1), and then solidified with ethanol to obtain 0.23 g (0.36 mmols, 43.4%) of the desired compound in the state of light yellowish white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1.C([O:14][C:15](=[O:17])[CH3:16])(=O)C.[C:18](O)(=[O:20])[CH3:19]>>[CH3:19][C:18]([CH2:16][C:15]([OH:14])=[O:17])=[O:20].[CH3:1][C:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([CH3:10])=[CH2:9])[CH2:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Agent: C=C(C)[C@H]1CC=C(C)CC1
Product: CC(=O)CC(=O)O

Procedure:
This patent discloses a process in which the 1,2 epoxide of limonene is refluxed with acetic acid and acetic anhydride to yield the 1,2 diacetate of limonene and the excess of these esterification reagents is removed. The diester product of pyrolysed by heating at atmospheric pressure at an elevated temperature. The carvyl acetate is obtained by fractional distillation of the resulting mixture.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.[NH2:39][C@@H:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[C:41]([NH:43][CH3:44])=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][C@@H:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[C:41]([NH:43][CH3:44])=[O:42])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)[C@@H](NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1)C(C)(C)C
Reaction time: 8 h
Yield: 28.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), (S)-2-amino-N,3,3-trimethylbutanamide (6.69 mg, 0.046 mmol), and HATU (31.7 mg, 0.083 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (S)-2-((R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N,3,3-trimethylbutanamide (7.6 mg, 0.013 mmol, 29.1% yield): LCMS=558.0 [M+H]+; 1H NMR (Mixture of diastereomers, 400 MHz, methanol-d4) δ ppm 8.17 (4 H, dd, J=8.28, 6.53 Hz), 7.51-7.76 (14 H, m), 5.20 (1 H, s), 5.15 (1 H, s), 4.21 (2 H, d, J=4.02 Hz), 2.74 (3 H, s), 2.71 (3 H, s); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.6 min+2.7 min (mixture of diastereomers).