Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]3[C:17]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:18][CH:19]=[C:13]3[CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.Cl[C:30]1N=C(Cl)C2OC=CC=2N=1.[H-].[Na+].CI.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]3[C:17]([CH2:20][N:21]([CH3:30])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[N:18][CH:19]=[C:13]3[CH2:12]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)NCc1ncc2n1CCN(c1nc(Cl)nc3ccoc13)C2
Reactant: Clc1nc(Cl)c2occc2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(Cc1ncc2n1CCN(c1nc(Cl)nc3ccoc13)C2)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of tert-butyl (7-(2-chlorofuro[3,2-d]pyrimidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)methylcarbamate (0.300 g, 0.741 mmol, prepared using A from 2,4-dichlorofuro[3,2-d]pyrimidine [Arkpharm] with Preparation #G.1) in THF (10 mL) was cooled to about 0° C. To the flask was added NaH (60 wt % dispersion in mineral oil, 0.036 g, 1.5 mmol) and the mixture was stirred for about 0.5 h at about 0° C. To the mixture was added MeI (0.21 g, 1.48 mmol) and the mixture was stirred for about 30 min. Saturated NH4Cl (15 mL) was added then the mixture was extracted with EtOAc (3×20 mL). The organic extracts were combined then dried over anhydrous Na2SO4 then filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (7-(2-chlorofuro[3,2-d]pyrimidin-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)methyl(methyl)carbamate (0.255 g, 82%): LC/MS (Table 2, Method h) Rt=1.93 min; MS m/z: 419 (M+H)+.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[CH2:32]([OH:35])[C:33]#[CH:34]>CN(C=O)C.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.[Cu](I)I>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[C:34]#[C:33][CH2:32][OH:35])=[CH:13][CH:14]=1
Reactant: C#CCO
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(C#CCO)n2Cc1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (300 mg, 0.588 mmol, intermediate 14) in anhydrous DMF (12 mL) was added prop-2-yn-1-ol (0.15 ml, 2.545 mmol), bis(triphenylphosphine)palladium(II) chloride (10 mg, 0.043 mmol), copper iodide (10 mg, 0.053 mmol) (45 mg, 0.402 mmol) and TEA (3 mL, 21.6 mmol). Then the mixture was degassed and refilled with nitrogen 3 times. The reaction was stirred at 85° C. overnight under nitrogen. The mixture was cooled, filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/ethyl acetate (3:1 to 1:1) to give 7-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (170 mg, 59.5% yield) as a light yellow solid. LCMS retention time 1.523 min; LCMS MH+ 487.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[N+:13]([O-])([OH:15])=[O:14].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2cccc(Cl)c2n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2c([N+](=O)[O-])ccc(Cl)c2n1
Temperature: 0 °C
Yield: 96.7 %

Procedure:
53.3 g (0.3 mole) of the resulting 8-chloroquinaldine was dissolved in 180.2 g of 98% sulfuric acid, and at 40° C., 40.2 g of nitric acid (specific gravity 1.50) was added dropwise over the course of 1 hour, followed by further reaction for 30 minutes. The reaction mixture was poured into ice water, and neutralized with an aqueous solution of sodium hydroxide. The product precipitated was collected by filtration, washed with water, and dried to afford 64.1 g (0.29 mole) of 8-chloro-5-nitroquinaldine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[CH:24]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1)([O-])=O>[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[CH:24]=4)=[CH:19][C:17]=3[N:18]=2)[C:7]([NH:10][CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1
Reactant: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc(Cl)c(C)c3)ccc2o1
Agent: [Zn]
Product: CCCNc1ccc(N)cc1-c1nc2cc(-c3ccc(Cl)c(C)c3)ccc2o1

Procedure:
Prepared by the method of Example 47b), from 2-(3-nitro-6-propylaminophenyl)-5-(3-methyl-4-chlorophenyl)benzoxazole (230 mg, 0.48 mmol) and zinc (314 mg, 4.8 mmol) the subtitle compound was obtained (187 mg, 100%). MS 392.3 m/z (M+H)+.
Reaction SMILES: O[CH:2]([C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][CH3:23])[CH:17]=[CH:16][N:15]=1)[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[SH:13].[OH-].[Na+]>>[CH2:22]([S:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([CH:2]2[S:13][C:5]3=[N:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]3[CH2:3]2)[C:19]=1[CH3:20])[CH3:23]
Reactant: CCSc1ccnc(C(O)Cn2c(S)nc3ccccc32)c1C
Agent: [Na+]
Agent: [OH-]
Product: CCSc1ccnc(C2Cn3c(nc4ccccc43)S2)c1C
Temperature: 100 °C

Procedure:
1-[2-Hydroxy-2-(4-ethylthio-3-methylpyrid-2-yl)ethyl]-2-mercaptobenzimidazole (0.01 mole) is dissolved in polyphosphoric acid (10 g) and the mixture heated at 100° C. for 2 hours with stirring. The mixture is then neutralised with sodium hydroxide solution and the product extracted with chloroform. Purification by column chromatography on silica gives the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20](OCC)=[O:21])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1COCC1.[CH3:30][NH2:31]>O>[CH3:30][NH:31][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][N:5]1[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=[C:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)NC
Temperature: 70 °C

Procedure:
A mixture of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanoate (2.0 g, 6.1 mmol), THF (10 mL), and methylamine (available as a 40% solution in water, 4 mL, 52 mmol) was sealed in a high-pressure vessel and heated at 70° C. overnight. An analysis by TLC indicated the presence of starting material, and the reaction was sealed and heated at 80° C. for nine hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane (100 mL). The resulting solution was washed with 5% aqueous sodium hydroxide (2×25 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 1.83 g of N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butanamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([OH:21])=O)[N:13]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[NH:26]([C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)[NH2:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][C:5]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([NH:27][NH:26][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)=[O:21])[N:13]=2)=[CH:4][C:3]=1[C:22]([F:24])([F:25])[F:23]
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c2)n1
Reactant: NNc1cnccn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c2)n1)NNc1cnccn1
Temperature: -70 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
In a 50-mL, 3-necked, round-bottomed flask charged with a solution of (Z)-3-(3-(4-chloro-3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.8 g) in 1:1 EtOAc:THF (20 mL). The solution was cooled to −70° C. and treated sequentially with 2-hydrazinopyrazine (0.275 g, 1.2 eq.), T3P (50% in EtOAc; 2.5 mL, 2.0 eq.) and DIPEA (1.44 mL, 4.0 eq.), added dropwise. The clear reaction mixture was stirred at −60° C. for 1 h before being concentrated under reduced pressure (25° C., 20 mm Hg) to afford crude compound. Purification by column chromatography using (60/120 mesh SiO2, elution with 3-4% MeOH in CH2Cl2) afforded 0.30 g (yield: 30%) (Z)-3-(3-(4-chloro-3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyrazin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) 8=10.53 (s, 1H), 9.58 (s, 1H), 9.11 (s, 1H), 8.47 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.97 (s, 1H), 7.52-7.55 (d, J=10.4 Hz, 1H), 6.08-6.11 (d, J=10.4 Hz, 1H); LCMS for C17H11ClF6N7O [M+H]+ 478.76 found 478.1 (RT 2.64 min, purity: 100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].C(N(C(C)C)CC)(C)C.[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27](=[O:28])[NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(=O)c1ccsc1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccsc1NC(=O)OCc1ccccc1
Reaction time: 60 h

Procedure:
To a stirred solution of 2-aminothiophene-3-carboxamide (5 g, 35.2 mmol) in tetrahydrofuran (200 mL) under argon was added diisopropylethylamine (9.52 ml, 54.5 mmol) and benzyloxycarbonyl chloride (7.53 mL, 52.8 mmol). After stirring for 60 hours, more diisopropylethylamine (9.52 mL, 54.5 mmol) and benzyloxycarbonyl chloride (7.53 mL, 52.8 mmol) were added. After an additional 24 hours, the suspension was filtered and the resulting solution was concentrated to ˜30 mL and diluted with ethyl acetate (100 mL) The organic layer was washed sequentially with saturated aqueous sodium bicarbonate (3×40 mL), a 3:1 mixture of saturated aqueous sodium bicarbonate and water (40 mL), and brine (40 mL), dried with sodium sulfate, filtered, and concentrated. The resulting mixture of white solid and brown oil was triturated with a mixture of ethyl acetate (10 mL) and hexanes (10 mL), and then the solid was collected by filtration. Drying under vacuum afforded the title compound as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:29]5[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[CH:3]=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)c1
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2cc(C)cc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)n2)cn1
Yield: 60 %

Procedure:
To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (200 mg, 0.61 mmol) in 1,2-dimethoxyethane (3 mL) was added 6-methoxypyridin-3-ylboronic acid (110 mg, 0.73 mmol), tetrakis(triphenylphosphine)-palladium (0) (70 mg, 0.061 mmol), and 2 M Na2CO3 (910 μL, 1.8 mmol). The reaction mixture was irradiated in the microwave at 120° C. for 20 minutes. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography eluting with (0-20% ethyl acetate/hexanes) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(6′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (147 mg, 60%). ESI-MS m/z calc. 401.2. found 402.3 (M+1)+. Retention time 1.90 minutes.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([C:16]([F:19])([F:18])[F:17])=[CH:5][C:3]=1[NH2:4].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[C:24]([Cl:34])=[CH:23][N:22]=1.Cl.C([O-])(O)=O.[Na+]>CC(O)C>[Cl:34][C:24]1[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)=[N:26][C:21]([NH:4][C:3]2[CH:5]=[C:6]([C:16]([F:17])([F:18])[F:19])[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)=[CH:8][C:2]=2[F:1])=[N:22][CH:23]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: CN1CCN(c2cc(F)c(N)cc2C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C(F)(F)F)c(N4CCN(C)CC4)cc3F)ncc2Cl)n[nH]1
Temperature: 130 °C

Procedure:
To a mixture of 2-fluoro-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)aniline (37 mg, 0.133 mmol) and 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (36 mg, 0.147 mmol) in iPrOH (1 mL) was added HCl (100 uL, 4N in dioxane). The reaction vessel was then sealed and heated to 130° C. for 4 hr. After cooling to room temperature, the mixture was treated with saturated NaHCO3 aqueous solution (5 mL) and extracted with EtOAc (3×5 mL). The organic layers were combined and concentrated. The residue was purified by preparative thin layer chromatography (silica gel, 8% MeOH/CH2Cl2), to provide 5-chloro-N2-(2-fluoro-4-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine. ESMS m/z 485.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:12]=2[O:11][CH2:10][C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([N:8]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:12]=2[O:11][CH2:10][C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(c1)OCC(=O)N2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)OCC(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 95.5 %

Procedure:
20.0 g of N-benzyl-7-methoxycarbonyl-4H-benz[1,4]oxazin-3-one are initially charged in 750 ml of MeOH. At room temperature, 35 ml of 2N aqueous sodium hydroxide solution are added dropwise, and the mixture is stirred at 40–55° C. for 30 h. The reaction solution is cooled to room temperature and poured into a mixture of 200 ml of 1N HCl and 1 kg of ice. The crude product is filtered off with suction, washed with water and dried. This gives 18.2 g (yield 95.5% of theory) of N-benzyl-7-hydroxycarbonyl-4H-benz[1,4]oxazin-3-one of melting point 230° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25][C:24]=2[CH:32]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25][C:24]=4[CH:32]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Reactant: COc1ccc(Nc2nc(Cl)ncc2F)cc1Cl
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC)c(Cl)c4)n3)ccc2O1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to produce N4-(3-chloro-4-methoxyphenyl)-5-fluoro-N2-[2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.31 (bs, 1H), 10.04 (bs, 1H), 8.21 (d, 1H, J=4.8 Hz), 7.75 (t, 1H, J=3.0 Hz), 7.54 (td, 1H, J=3.0 and 9.0 Hz), 7.34 (s, 1H), 7.20–7.15 (m, 2H), 6.80 (d, 1H, J=8.1 Hz), 5.38–5.31 (m, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 3.49 (dd, 1H, J=11.1 and 16.5 Hz); LCMS: purity: 99%; MS (m/e): 446(MH+).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[N:14]([CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:13]=[C:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7]
Reactant: ClCCN1CCCC1
Reactant: Cc1ccccc1C1=CNC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1C1=CN(CCN2CCCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=580.1 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-4-o-tolyl-2,8-diaza-spiro[4.5]dec-3-en-1-one and 1-(2-chloroethyl)-pyrrolidine.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2.CN(C)CCC=C1C2C=CC=CC=2C=CC2C=CC=CC1=2>>[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2
Reactant: CN(C)CCCC1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21
Agent: CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Product: CNCCCC1c2ccccc2C=Cc2ccc(S(C)(=O)=O)cc21

Procedure:
By substituting 5-(3-dimethylaminopropyl)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene for the 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene of Example 6, Step A., and following substantially the same procedure described in Example 6, Steps A and B., there is obtained 5-(3-methylaminopropyl)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene as an oily residue. The base is converted to the hydrogen oxalate salt by treating an ethanolic solution of the base with a 10% excess of oxalic acid in ethanol. Dilution with absolute ether precipitates 5-(3-methylaminopropyl)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene hydrogen oxalate as a white crystalline solid, m.p. 114°-119° C. dec. An analytical sample melts at 114°-115° C. dec. after two recrystallizations from mixtures of absolute ethanol and absolute ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH2:8][CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(Cl)ccc1O
Yield: 97.4 %

Procedure:
To a stirred solution of 1.7 g (9.96 mmol) of 1-(5-chloro-2-hydroxyphenyl)ethanone in 20 mL of CH2Cl2 and 11.34 g (99.47 mmol) of trifluoroacetic acid, slowly add 3.46 g of (29.82 mmol) of triethylsilane. Stir resulting solution at room temperature for 18 hours, and remove volatiles and excess reagents under reduced pressure to give 1.52 g (97.4%) of 4-chloro-2-ethylphenol as an oil. 1H NMR (500 MHz, CDCl3) δ 7.09 (d, J=2.6 Hz, 1H), 7.03-7.01 (m, 1H), 6.65 (d, J=8.5 Hz, 1H), 4.82 (s, 1H), 2.58 (q, J=7.6 Hz, 2H) and 1.21 (t, J=7.6 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 151.85, 131.82, 129.62, 126.62, 125.60, 116.28, 22.81 and 13.60. MS m/e 157. The 4-chloro-2-ethylphenol can be used in Preparation 13b.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11]([C@@H:13]3[C@@H:15]([CH2:16][CH2:17][CH2:18][CH3:19])[O:14]3)=[O:12])=[CH:4][C:3]=2[O:2]1.[N-:20]=[N+:21]=[N-:22].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:12])[C@@H:13]([OH:14])[C@@H:15]([N:20]=[N+:21]=[N-:22])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][C:3]=2[O:2]1
Reactant: CCCC[C@H]1O[C@@H]1C(=O)Nc1ccc2c(c1)OCO2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CO
Product: CCCC[C@H](N=[N+]=[N-])[C@H](O)C(=O)Nc1ccc2c(c1)OCO2
Yield: 70.1 %

Procedure:
30 ml of a methanol suspension containing 484 mg (1.84 mmol) of (2S-trans)-N-[(3,4-methylenedioxy)phenyl]-3-butyloxiranecarboxamide, 239 mg (3.68 mmol) of sodium azide and 228 mg (1.89 mmol) of anhydrous magnesium sulfate was refluxed for 5 hours. After the temperature of the reaction mixture was returned to room temperature, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with water, and then, with a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 395 mg (Yield: 70%) of the title compound.
Reaction SMILES: COCCOC.[Cl:7][C:8]1[CH:9]=[CH:10][C:11](I)=[C:12]([C:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[O:15])[CH:13]=1.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1[C:35](B(O)O)=[CH:36][C:37]([Cl:40])=[N:38][CH:39]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][C:34]1[CH:39]=[N:38][C:37]([Cl:40])=[CH:36][C:35]=1[C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][C:12]=1[C:14](=[O:15])[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCc1cnc(Cl)cc1B(O)O
Reactant: O=C(c1cc(Cl)ccc1I)c1c(F)cccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cnc(Cl)cc1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.9 %

Procedure:
Into a 50-mL single-necked round-bottom flask was added 1,2-dimethoxy-ethane (10 mL). The solvent was purged with nitrogen, then tetrakis(triphenylphosphine)-palladium(0) (80.7 mg, 0.07 mmol) and (5-chloro-2-iodo-phenyl)-(2,6-difluoro-phenyl)-methanone (528 mg, 1.40 mmol) were added. The mixture was stirred under an atmosphere of nitrogen for 15 minutes, then (5-{[(tert-butoxycarbonyl)amino]methyl}-2-chloropyridin-4-yl)boronic acid (600.0 mg, 2.09 mmol) and 2.00 M sodium carbonate in water (1.40 mL) were added and the mixture was heated to reflux and allowed to stir 5 hours. The reaction was then cooled to room temperature and allowed to sit overnight. The reaction was diluted with methylene chloride (30 mL) and then transferred to a separatory funnel and was washed with water (2×30 mL). The organic portion was dried over sodium sulfate, filtered, and concentrated to provide the crude product as an orange oil. The crude product was purified by column chromatography on silica gel (elution gradient from dichloromethane to 15% ethyl acetate/dichloromethane) to yield 165 mg (24%) tert-butyl({6-chloro-4-[4-chloro-2-(2,6-difluorobenzoyl)phenyl]pyridin-3-yl}methyl)carbamate as an amber glass/solid. The product structure was confirmed by NMR and MS.