Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.IC1C=CC=CC=1.I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].C(#N)C>CN(C=O)C>[C:1]1([CH3:8])[C:6]([O:7][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1O
Reactant: Cc1ccccc1I
Solvent: Ic1ccccc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccccc1Oc1ccccc1C

Procedure:
Example 3.1 was repeated, replacing the phenol with 206 μl of o-cresol (2 mmoles) and the iodobenzene with 383 μl of 2-iodotoluene (3 mmoles), the acetonitrile with DMF, and with the nucleophile and the arylation agent being added at the same time as the solvent.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:23])[CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=3)[CH:9]=2)[N:4]=1.Cl>>[CH3:23][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)[CH:9]=[C:10]2[C:5]=1[NH:4][C:3](=[O:2])[CH:12]=[CH:11]2
Reactant: COC(=O)c1ccc(-c2cc(C)c3nc(OC)ccc3c2)cc1
Agent: Cl
Product: COC(=O)c1ccc(-c2cc(C)c3[nH]c(=O)ccc3c2)cc1

Procedure:
0.5H2O, m.p. 293°, was prepared similarly to Example 13(A) using 2-methoxy-8-methyl-6-(4-methoxycarbonylphenyl)quinoline and 5M HCl.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:11](Br)[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O-])(=[O:28])[CH3:27].[Tl+].C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCCCC)=C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:26]([C:11]1[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14](=[O:19])[C:13]2=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(C)C2=O
Agent: [Pd+2]
Agent: C=COCCCC
Agent: [Tl+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 8-(benzyloxy)-6-bromo-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (0.42 g, 1.03 mmol), palladium acetate (29 mg, 0.13 mmol), thallium acetate (0.34 g, 1.29 mmol), diisopropyl ethylamine (0.58 mL, 4.12 mmol), 1,3-bis(diphenylphosphino)propane (60 mg, 0.14 mol), n-butyl vinyl ether (0.67 mL, 5.2 mmol) in DMF (3 mL) was purged with nitrogen for 5 minutes. The mixture was sealed and heated at 100° C. overnight. The reaction mixture was concentrated under vacuum, and the residue was treated with 1 N aq HCl and stirred at room temperature for one hour. The reaction mixture was diluted with dichloromethane. The organic extract was dried over sodium sulfate, filtered and concentrated. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate to provide titled product.
Reaction SMILES: Cl[C:2]1[C:3]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH3:34])[CH:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([NH2:24])[C:12]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][C:14]=2[O:15][CH3:16])=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[C:69]([Zn]C#N)#[N:70].CC(N(C)C)=O>CCOC(C)=O.[Zn].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]>[NH2:24][C:11]1[C:12]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[C:2]([C:69]#[N:70])=[CH:7][N:6]=2)[CH:10]=1
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Reactant: N#C[Zn]C#N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2cn(C)c3ccccc23)n1
Reaction time: 2 h
Yield: 103.2 %

Procedure:
A mixture of N′-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 91, 344 mg, 0.72 mmol), zinc powder (4.71 mg, 0.07 mmol), tris(dibenzylideneacetone)dipalladium(0) (65.9 mg, 0.07 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (‘XPhos’, 68.6 mg, 0.14 mmol), and dicyanozinc (50.7 mg, 0.43 mmol) were placed in a reaction tube under N2 and then degassed DMA (1.91 mL) was added. The resulting suspension was shirred at 95° C. for 2 h. The mixture was then diluted with EtOAc and washed 5 times with water, and then with brine. The solution was then dried (MgSO4) and concentrated in vacuo. The residue was dissolved in CH3OH and allowed to pass through a stratospheres SPE cartridge PL-Thiol MP SPE (available from Polymer Laboratories) under gravity. The resulting solution was concentrated in vacuo and the resulting residue was triturated with diethyl ether. The resulting solid was collected by filtration and washed with diethyl ether to give the title compound (208 mg, 62%) as a yellow solid; 1H NMR: 2.28 (3H, s), 2.51-2.58 (4H, m), 2.89-2.95 (4H, m), 3.69 (3H, s), 3.91 (3H, s), 4.23 (2H, br s), 6.75 (1H, s), 7.08 (1H, s), 7.09-7.12 (1H, m), 7.26 (1H, ddd), 7.50 (1H, d), 8.31 (1H, d), 8.43 (1H, s), 8.61 (1H, s), 8.64 (1H, s); m/z: ES+ MH+ 469.33.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH2:15]O)[CH:3]=1.O=S(Cl)[Cl:19]>C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH2:15][Cl:19])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)COc1ccc(Br)cc1CO
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(Br)cc1CCl
Yield: 75.1 %

Procedure:
To ethyl [4-bromo-2-(hydroxymethyl)phenoxy]acetate (Example 7, 5.00 g, 17.4 mmol) in 150 mL CH2Cl2 under Ar, was added SOCl2 (4.13 g, 34.7 mmol) dropwise with stirring. The mixture was then heated to reflux for 4 hours, cooled, and the volatiles were removed under reduced pressure. The crude oil was then subjected to flash chromatography (15% EtOAc/hexanes) to provide 4.02 g (76%) of the desired product as a clear oil. 1H-NMR (acetone-d6, δ): 1.25 (t, 3H), 3.50 (ddd, 2H), 4.22 (q, 2H), 5.37 (dd, 1H), 6.77 (d, 1H), 7.29 (m, 1H), 7.37 (m, 1H); LRMS (GC/MS/EI) 270 [M]+.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([N+:20]([O-:22])=[O:21])=[C:12]([NH:16]C(=O)C)[CH:13]=2)[CH2:8]1)(=O)C.O.[CH]Cl>CO>[NH2:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[N+:20]([O-:22])=[O:21])[CH2:8][CH:7]([CH2:6][CH2:5][OH:4])[CH2:15]2
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CC(CCOC(C)=O)C2
Agent: [CH]Cl
Solvent: CO
Solvent: O
Product: Nc1cc2c(cc1[N+](=O)[O-])CC(CCO)C2
Temperature: 20 °C
Yield: 100.4 %

Procedure:
Acetamide 155 (24.0 g, 78 mmol) was suspended in MeOH (350 mL), H2O (180 mL) and cHCl (150 mL), and stirred at reflux temperature for 1 h. The resulting orange solution was cooled to 20° C. and the solvent evaporated to give nitroaniline 156 (17.4 g, 100%) as an orange solid: mp 89-91° C.; 1H NMR δ 7.90 (s, 1H, H-4), 6.62 (s, 1H, H-7), 6.02 (br s, 2H, NH2), 3.74 (t, J=6.6 Hz, 2H, CH2O), 2.96-3.04 (m, 2H, H-1, H-3), 2.49-2.60 (m, 3H, H-1, H-2, H-3), 1.77 (q, J=6.6 Hz, 2H, CH2), 1.40 (br s, 1H, OH); 13C NMR δ 153.4, 144.3, 133.0, 131.2, 120.9, 113.5, 61.7, 39.3, 38.2, 37.7, 37.2. Anal. calcd for C11H14N2O3: C, 59.5; H, 6.4; N, 12.6. Found: C, 59.7; H, 6.3; N, 12.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18]C)=[O:17])=[CH:11][CH:12]=2)[N:7]([CH3:20])[C:6]1=[O:21].[OH-].[Na+].Cl>CO>[C:16]([C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:15])[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=3[Cl:1])[C:6](=[O:21])[N:7]2[CH3:20])=[CH:12][CH:11]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3Cl)c(=O)n(C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(=O)n(Cc2ccc(Cl)cc2Cl)c(=O)c2ccc(C(=O)O)cc21
Yield: 97.5 %

Procedure:
3-(2,4-Dichlorobenzyl)-7-(methoxycarbonyl)-1-methyl-2,4-(1H,3H)-quinazolinedione (2.02 g) in a mixture of a 5% aqueous sodium hydroxide solution (10 g) and methanol (30 g) was heated under reflux for 1 hr. After cooling, concentrated hydrochloric acid (5.5 g) was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was washed with water (50 g) and methanol (50 g) and dried to give the objective compound (1.90 g) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]#[N:11])=[C:8](F)[C:7]([CH2:13][OH:14])=[CH:6][CH:5]=1)[CH3:2].[SH:15][CH2:16][C:17]([NH2:19])=[O:18].[O-]CC.[Na+]>CN(C=O)C.[OH-].[Na+]>[NH2:11][C:10]1[C:9]2[C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=[C:7]([CH2:13][OH:14])[C:8]=2[S:15][C:16]=1[C:17]([NH2:19])=[O:18]
Reactant: CCOc1ccc(CO)c(F)c1C#N
Reactant: NC(=O)CS
Agent: CC[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOc1ccc(CO)c2sc(C(N)=O)c(N)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a stirred solution of the above benzonitrile intermediate (500 mg, 2.56 mmol) in dry DMF (3 mL) was added 2-mercaptoacetamide (1.1 M in MeOH, 3.50 mL, 3.85 mmol) and sodium ethoxide (2.68 M in EtOH, 1.05 mL, 2.81 mmol). The reaction was stirred at 80° C. overnight, and then it was cooled to room temperature and diluted with 2 M sodium hydroxide solution (30 mL). The precipitate formed was collected by filtration, and dried in vacuo to give the title compound (0.455 g, 1.71 mmol, 88.9%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[OH-].[Na+].[CH3:13][C:14]([CH3:16])=[O:15]>O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1/[CH:4]=[CH:13]/[C:14](=[O:15])[CH3:16]
Reactant: CC(C)=O
Reactant: O=Cc1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 100ml reaction bottle equipped with magnetic stir bar was charged 5.0 g (35.2 mmole) of 2,6-difluorobenzaldehyde in 20 ml acetone and to this was added 3.4 g of 50% aqueous NaOH (42 mmole) in 60 ml water (exothermic) and stirred at room temperature. The reaction was monitored by GLC and after 2 hours the reaction was worked up. The reaction mixture was extracted with 50 ml CHCl3, washed with 50 ml H2O, dried over anhydrous MgSO4, filtered, and the solvent removed in vacuuo on a rotary evaporator to afford 5.7 g of trans-4-(2,6-difluorophenyl)-3-buten-2-one as a yellow oil in 81% purity by GC. and 89.5% isolated yield.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][O:8][CH3:9])[CH:6]=1.C([Mg]Cl)(C)C.[F:15][C:16]1([F:23])[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1.[Cl-].[NH4+]>C1COCC1>[F:15][C:16]1([F:23])[CH2:21][CH2:20][C:19]([C:2]2[CH:3]=[N:4][N:5]([CH2:7][O:8][CH3:9])[CH:6]=2)([OH:22])[CH2:18][CH2:17]1
Reactant: COCn1cc(I)cn1
Reactant: O=C1CCC(F)(F)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCn1cc(C2(O)CCC(F)(F)CC2)cn1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
To a solution of 4-iodo-1-(methoxymethyl)-1H-pyrazole (Organic Letters, 2007, 9, 4947-4950; 1.40 g, 5.88 mmol) in THF (15 mL), isopropyl magnesium chloride (2.0 M solution in THF; 3.8 mL, 7.64 mmol) was added with cooling on ice. The reaction solution was stirred for 30 minutes with cooling on ice. Then, 4,4-difluorocyclohexanone (2.30 g, 17.6 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, an aqueous ammonium chloride solution (50 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (0.95 g, 66%) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23]>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][NH:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Reactant: CC(C)(O)CN
Product: CC(C)(O)CNCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.3 g) was reacted with 1-amino-2-methylpropan-2-ol via General Procedure B to afford quantitative yield of 1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylamino)-2-methylpropan-2-ol.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([OH:25])[C:15]([O:17]CC1C=CC=CC=1)=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:27])([CH3:26])[C@@H:14]([OH:25])[C:15]([OH:17])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)O
Reaction time: 8 h
Yield: 21.5 %

Procedure:
Following the general procedure for the hydrogenolysis of benzyl ethers of Description 18, a mixture of phenylmethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-2-hydroxy-3,3-dimethylbutanoate (31) (40 mg, 0.1 mmol) and 30 mg of 10 wt-% palladium on activated carbon in 2 mL of ethanol (EtOH) was stirred overnight under a hydrogen atmosphere. After filtration through a 0.2 μM nylon syringe filter and evaporation of the solvents, 6.7 mg (23% yield) of the title compound (33) was obtained as a pale-yellow, viscous oil. 1H NMR (400 MHz, DMSO-d6): δ=0.90 (s, 3H), 0.91 (s, 3H), 1.80 (s, 3H), 1.76-1.85 (m, 2H), 3.09-3.16 (m, 2H), 3.28-3.35 (m, 2H, superimposed with residual water), 3.76-3.82 (br. m, 1H), 3.94 (d, J=8.8 Hz, 1H), 4.07 (d, J=8.8 Hz, 1H), 7.90 (br. t, J=5.2 Hz, 1H), 12.59 (br. s, 1H) ppm. MS (ESI) m/z: 312.0 (M+H)+, 334.0 (M+Na)+, 310.1 (M−H)−. The analytical data was consistent with the proposed structure.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11](Br)[CH:12]=[CH2:13].[BH4-].[Na+]>CC(C)=O.CO>[CH2:13]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[CH:12]=[CH2:11]
Reactant: c1cnc2ccncc2c1
Reactant: C=CCBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: C=CCN1CCc2ncccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,6-naphthyridine (6.5 g, 0.05 mol) and allyl bromide (9.1 g, 0.075 mol) in acetone (50 ml) was refluxed for 8 hours. The precipitated quatenary salt was separated by filtration, dissolved in technical grade methanol (300 ml) and sodium borohydride (18.9 g, 0.5 mol) was added portionwise under ice cooling. After stirring overnight at room temperature, the reaction mixture was evaporated in vacuo, water added and extracted with benzene. The benzene layer was dried over anhydrous potassium carbonate and evaporated in vacuo. The residue was purified by alumina column chromatography (eluted successively with n-hexane and benzene-chloroform (3:1)) and distilled, bp 98° C./1.0 mmHg, to afford the Compound No. 12 (5.70 g, 65.5%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:5][C:4]=1[C:23]([F:26])([F:25])[F:24])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:5][C:4]=1[C:23]([F:26])([F:24])[F:25])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C#N)c(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of tert-butyl 4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate (150 mg, 0.41 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 ml). The solution was stirred for 2 hours at room temperature and then concentrated under vacuum. The crude material was diluted with 100 ml of EtOAc and washed with sodium bicarbonate (saturated aqueous) and then brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude solids were recrystallized from EtOAc/PE to afford N-[4-cyano-3-(trifluoromethyl)phenyl]piperidin-4-amine as a yellow powder (93.1 mg, 85% yield); (ES, m/z): [M+H]+ 270.1; 1H NMR (300 MHz, CDCl3): δ 7.69 (d, J=8.7 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.03 (d, J=1.2 Hz, 1H), 6.85 (dd, J=2.1, 8.7 Hz, 1H), 3.42 (m, 1H), 2.94 (m, 2H), 2.53 (m, 2H), 1.82 (d, J=10.2 Hz, 2H), 1.27 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:20][CH2:21][CH:22]([Mg]Br)[CH2:23][CH3:24].CCOCC.[NH4+].[Cl-]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:14])[CH:22]([CH2:23][CH3:24])[CH2:21][CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(CC)[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CC)[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C

Procedure:
(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (0.8 g, 3.8 mmol;) and THF (8 mL, 90 mmol) were combined under nitrogen, and the resulting solution was cooled to −78° C. 2M 3-Pentylmagnesium bromide in ether (4.70 mL, 9.4 mmol) was then added dropwise over 1 hour. The mixture was allowed to warm to room temperature slowly overnight. Then aqueous saturated NH4Cl (5 mL) was added dropwise to quench the reaction. The resulting mixture was extracted with EtOAc (2×25 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 (25 mL) and saturated aqueous NaCl (25 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (5-25% EtOAc in Hexanes) to yield the following as clear oils:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14](=[O:29])[N:15]2[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>CS(C)=O>[Br:9][C:10]1[C:11]2[CH:12]3[CH2:4][CH:13]3[C:14](=[O:29])[N:15]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(Cn2c(=O)ccc3c(Br)cccc32)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN2C(=O)C3CC3c3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a suspension of sodium hydride (136 mg, 3.40 mmol) in DMSO (5 mL) at room temperature was added trimethylsulfoxonium iodide (661 mg, 3.00 mmol) slowly under nitrogen. The reaction mixture was stirred at room temperature for 1 h, and then 5-bromo-1-(4-methoxybenzyl)quinolin-2(1H)-one (689 mg, 2.00 mmol) in 1 mL DMSO was added. Upon completion of addition, the reaction mixture was stirred at room temperature for 2 h, and then heated to 90° C. for 2 d. After cooling to room temperature, the reaction mixture was quenched with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0 to 30% ethyl acetate:hexanes) to afford the title compound (330 mg, 45% yield) as a white powder. LCMS, [M+H]+=358.0. 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J=7.7 Hz, 1H), 7.08 (d, J=8.2 Hz, 2H), 6.91 (t, J=8.0 Hz, 1H), 6.85-6.75 (m, 3H), 4.97-5.25 (m, 2H), 3.75 (s, 3H), 2.90 (td, J=8.1, 5.2 Hz, 1H), 2.40 (ddd, J=9.6, 8.0, 4.9 Hz, 1H), 1.74 (td, J=9.1, 4.4 Hz, 1H), 0.69 (q, J=4.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[NH2:24][C:25]1([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:24][C:25]4([C:28]([OH:30])=[O:29])[CH2:27][CH2:26]4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: NC1(C(=O)O)CC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CC1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 1-aminocyclopropanecarboxylic acid using an analogous method to that described for the equivalent step in Example 1 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopropanecarboxylic acid; 1H NMR Spectrum: (DMSO d6) 0.90-1.00 (m, 2H); 1.10-1.20 (m, 2H); 3.93 (s, 2H); 3.96 (s, 3H); 7.14 (s, 1H); 7.28 (m, 1H); 7.40-7.55 (m, 2H); 8.29 (s, 1H); 8.40 (s, 1H); Mass Spectrum: (M+H)+ 417. 1-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopropanecarboxylic acid reacted with para-formaldehyde using an analogous method to that described for the equivalent step in Example 11 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]cyclopropanecarboxylic acid; 1H NMR Spectrum: (DMSO-d6) 1.08 (m, 2H); 1.21 (m, 2H); 2.43 (s, 3H); 3.94 (s, 3H); 4.08 (s, 2H); 7.17 (s, 1H); 7.28 (t, 1H); 7.52 (m, 2H); 8.21 (s, 1H); 8.42 (s, 1H); 9.73 (s, 1H); Mass Spectrum: (M+H)+ 431
Reaction SMILES: N1C=C[CH:3]=N1.[N:6]1([CH:11](C)[CH2:12][NH:13][C:14]([C:16]2[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[NH:18][N:17]=2)=[O:15])[CH2:10]CC[CH2:7]1>>[CH3:10][N:6]([CH3:7])[CH2:11][C@H:12]([NH:13][C:14]([C:16]1[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[NH:18][N:17]=1)=[O:15])[CH3:3]
Reactant: CC(CNC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br)N1CCCC1
Reactant: c1cn[nH]c1
Product: C[C@H](CN(C)C)NC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br

Procedure:
The pyrazole acid, prepared as described in Procedure 8, was coupled with (R)—N,N dimethyl-1,2-propanediamine (prepared as shown in Procedure 2) using the method of Procedure 3.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2F)([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[ClH:19]>CN(C)C=O.C1C=CC=CC=1.CCOCC>[ClH:19].[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:8]2)[CH2:4][CH2:3]1
Reactant: CN1CCC(O)(Cc2ccccc2F)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CN1CCC2(CC1)Cc1ccccc1O2
Temperature: 120 °C
Reaction time: 84 h

Procedure:
12.5 g of 1-methyl-4-(2-fluorobenzyl)-4-piperidinol dissolved in 50 ml of dimethylformamide and 20 ml of benzene are added to a stirred suspension at 120° C. of 2.3 g of a 57% oil dispersion of sodium hydride in 110 ml of dimethylformamide and 20 ml of benzene. The reaction mixture is stirred at 120° C. for 84 hours and then successively permitted to cool to ambient temperature, poured into 800 ml of ice-water and extracted with ether. The combined ether extracts were dried before the ether evaporated leaving a light yellow oil. The oil is dissolved in ether and converted to its hydrochloride salt with ethereal hydrogen chloride. The salt is recrystallized twice from an ethanol-ether mixture to provide the product, 2,3-dihydro-1'-methylspiro[benzofuran-2,4'-piperidine]hydrochloride, mp 248°-250° C.