Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([PH:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)Cl.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[C:29]=1[C:30](Cl)=[O:31]>O1CCCC1>[CH2:1]([P:8](=[O:13])([CH2:9][CH2:10][CH2:11][CH3:12])[C:30](=[O:31])[C:29]1[C:28]([O:27][CH3:26])=[CH:36][CH:35]=[CH:34][C:33]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[PH](=O)Cc1ccccc1
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCP(=O)(Cc1ccccc1)C(=O)c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 13.2 g (0.067 mol) of benzyl-butylphosphin oxide and 12.7 ml (0.101 mol) of trimethylchlorosilane in 100 ml of tetrahydrofuran are added 18.7 ml (0.134 mol) of triethylamine under a nitrogen atmosphere at 0°-5° C. in the course of 15 minutes. After 2 hours of stirring at 0°-5° C., 13.5 g (0.067 mol) of 2,6-dimethoxybenzoyl chloride, diluted in 50 ml of tetrahydrofuran, are added during the course of 20 min. the stirring at 0°-5° C. is continued for 2 h, then the solution is allowed to warm to room temperature and filtered over silicea gel. The solution is concentrated in vacuo and the residue recrystallized from a hexan/acetic acid ester mixture. 3.8 g (15.8% of theory) of the title compound with a melting point of 56°-57° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:29][CH2:30]C)[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[C:19]=1[O:27][CH3:28])S(C1C=CC(C)=CC=1)(=O)=O)C.O.[OH-].[Na+].[CH2:35](Cl)Cl>>[CH3:30][O:29][CH:4]([O:3][CH3:1])[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[C:19]=1[O:27][CH3:28])[CH3:35]
Reactant: ClCCl
Reactant: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(CN(C)CC(OC)OC)ccc2c1OCO2
Yield: 99.7 %

Procedure:
17.8 g (74.3 mmol) of the compound (2) thus obtained was added to 50 ml of water, to which 100 ml of methylene chloride was added. This solution was made basic with 25% aqueous solution of sodium hydroxide under water-cooling. The solution was separated and the aqueous layer was extracted with 20 ml of methylene chloride. The obtained methylene chloride layers were combined, washed with 30 ml of water, dried over anhydrous magnesium sulfate and then concentrated under vacuum to obtain 15.06 g of 8-methoxy-6,7-methylenedioxyisoquinoline (3) (yield 99.7%). The product thus obtained was recrystallized from ethylacetate-n-hexane, m.p. 144°-5° C. IR and NMR spectra of the resultant product are listed below. ##STR48##
Reaction SMILES: [N:1]1[NH:2][C:3](=[S:15])[N:4]2[CH:10]=[CH:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][C:5]=12.[CH3:16][O-].[Na+].CO.CI>CO>[CH3:16][S:15][C:3]1[N:4]2[C:5]([CH2:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10]2)=[N:1][N:2]=1
Reactant: S=c1[nH]nc2n1C=Cc1ccccc1C2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nnc2n1C=Cc1ccccc1C2
Reaction time: 0.33 h

Procedure:
To 3 ml of methanol was added 0.215 g of 2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepine-3-thione and, under stirring, 0.6 ml of 2N-sodium methoxide/methanol was added. Then, 0.07 ml of methyl iodide was added dropwise. After 20 minutes, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over Na2SO4. The solvent was then evaporated off and the residue was treated with ether. In this manner, 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine were obtained as crystals. Recrystallization from methanol yielded colorless needles melting at 168°-169° C. This was identical with the products obtained in Examples 1 and 2.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([C:22]([NH:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2sc3ccccc3c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc2sc3ccccc3c2c1
Yield: 65.3 %

Procedure:
2-Aminodibenzthiophene (Bull. Soc. Chim. Fr. (1996), 133 (6), 597-610; 2.0 g, 10 mmol) and triethylamine (1.11 g, 11 mmol) were dissolved in DCM (50 ml) and cooled in an ice bath. A solution of pivaloyl chloride (1.21 g, 10 mmol) in DCM (10 ml) was added slowly and the resultant solution was stirred at ambient temperature for 16 hours then evaporated in vacuo. The residue was triturated with methanol to leave the product as a colourless solid (1.85 g). NMR: 9.40 (s, 1H), 8.59 (s, 1H), 8.17 (m, 1H), 7.98 (d, 1H), 7.90 (d, 1H), 7.73 (dd, 1H), 7.46 (m, 2H), 1.15 (s, 9H); m/z 284.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16]N[CH2:14][CH2:13]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1.FC1C(F)=CC2C3C([C:39](=[O:48])N(C4C=CC=CC=4)N=3)=CNC=2C=1.OC1CCNCC1>>[F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH:39]([OH:48])[CH2:14][CH2:13]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Agent: OC1CCNCC1
Product: O=c1c2c[nH]c3cc(N4CCC(O)CC4)c(F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and 4-hydroxypiperidine. 1H-NMR (DMSO-d6) δ (ppm): 1.54 (2H, brm), 1.87 (2H, brm), 2.85 (2H, brm), 3.20 (1H, m), 3.64 (1H, brm), 4.74 (1H, brd, J=3.84 Hz), 7.10 (1H, m), 7.22 (1H, d, J=7.97 Hz), 7.40 (2H, m), 7.76 (1H, d, J=2.90 Hz), 8.20 (2H, m), 8.64 (1H, s). m/z 379.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]3[C:16](=O)[NH:15][C:14]([CH2:18][O:19][CH3:20])=[N:13][C:12]=3[N:21]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:32]>C(Cl)(Cl)Cl>[Cl:32][C:16]1[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[N:21][C:12]=2[N:13]=[C:14]([CH2:18][O:19][CH3:20])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1nc2nc(-c3ncccc3Cl)ccc2c(=O)[nH]1
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: COCc1nc(Cl)c2ccc(-c3ncccc3Cl)nc2n1

Procedure:
Reflux a mixture of 7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-3H-pyrido[2,3-d]pyrimidin-4-one (0.25 g), 2,6-lutidine (0.44 g), and POCl3 (0.51 g) in CHCl3 (5 mL) for 20 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (Na2SO4) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4-chloro-7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-pyrido[2,3-d]pyrimidine.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:9][O:10]/[C:11](=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:42])[C:30](OC3C=CC([N+]([O-])=O)=CC=3)=[O:31])[CH:24]=2)=[CH:19][CH:18]=1)/[C:12]([O:14][CH3:15])=[O:13].O>CN(C)C=O>[CH2:1]([NH:8][C:30](=[O:31])[N:29]([C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17](/[CH:16]=[C:11](\[O:10][CH3:9])/[C:12]([O:14][CH3:15])=[O:13])=[CH:18][CH:19]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:42])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OC
Reactant: CCCCCCCN
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
0.6 mL (3.9 mmol) of heptylamine is added to a solution of 1.7 g (3.2 mmol) of methyl (Z)-2-methoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate (prepared according to Example 11e) in 10 mL of dimethylformamide and the reaction medium is then placed in a bath preheated to 80° C. After stirring at 80° C. for 3 hours, water is added and the reaction medium is extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 and then 6/4 heptane/ethyl acetate mixture. 1.1 g (80%) of methyl (Z)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate are obtained in the form of a white solid with a melting point of 93° C.
Reaction SMILES: [CH:1]1([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:23]CCCC>CCOCC.CCCCCC>[C:11]1([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:1]2([Li:23])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C1=CC(P(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]C1(P(c2ccccc2)c2ccccc2)C=Cc2ccccc21
Reaction time: 8 h
Yield: 87.3 %

Procedure:
(1H-Inden-1-yl)diphenylphosphine (5.00 g, 16.65 mmol) was dissolved in a mixture of 60 mL of ether and 60 mL of hexane. n-BuLi (7.35 mL, 18.31 mmol) was added to the mixture within 10 minutes. After stirring overnight no precipitate appeared. Solvent was removed under reduced pressure leaving a waxy yellow residue. This residue was triturated with 120 mL of hexane for 15 minutes The hexane solution was decanted and the residue was dried under reduced pressure to give 4.45 g of off-white solid. Yield 87 percent.
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]([NH2:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O>>[Cl:12][CH2:13][C:14]1[N:11]=[C:9](/[CH:8]=[CH:7]/[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:10][CH:16]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=CC1CCCCC1
Product: ClCc1coc(/C=C/C2CCCCC2)n1
Yield: 4.5 %

Procedure:
In substantially the same manner as in Reference Example 47, 3-cyclohexylpropeneamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-[(E)-2-cyclohexylethenyl]oxazole. The yield was 4.5%. Oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[S:32]>O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:31](=[S:32])[N:30]([CH3:34])[CH3:29])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:16])[CH:11]=2)[CH:6]=1
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)Cc1cc(O)c2cc(F)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cc(OC(=S)N(C)C)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.4 %

Procedure:
A mixture of (6-fluoro-4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (500 mg, 2.14 mmol), finely ground potassium carbonate (591 mg, 4.28 mmol), and N,N-dimethylformamide (10 mL) was stirred at room temperature for 20 minutes. Dimethylthiocarbamoyl chloride (290 mg, 2.35 mmol) was added in one portion. After being stirred for 2 hours, the resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with water (15 mL) and brine (20 mL), then dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 0-30% ethyl acetate in hexanes) to afford (4-dimethylthiocarbamoyloxy-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (491 mg, 71.5%) as a yellow oil.
Reaction SMILES: N(C(C)C)(C(C)C)CC.[Cl:10][C:11]1[C:12]([CH:17]([NH2:34])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][C:24](C4C=CC=CC=4)=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1.[CH:35]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:10][C:11]1[C:12]([CH:17]([NH:34][C:39]([CH:35]2[CH2:38][CH2:37][CH2:36]2)=[O:40])[C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: O=C(Cl)C1CCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC(c1ccc2cccnc2c1)c1nccnc1Cl)C1CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of NEt(iPr)2 (520 μL, 386 mg, 2.99 mmol), DMAP (12 mg, 0.098 mmol), and C-(3-chloropyrazin-2-yl)-C-quinolin-7-ylmethylamine (compound of Formula IV where Q1=quinolin-7-yl) (608 mg, 1.97 mmol) in dry CH2Cl2 (10 mL), cooled by ice/water, was added cyclobutanecarbonyl chloride (250 μL, 260 mg, 2.19 mmol), then the cooling bath was removed, and the reaction mixture was stirred at ambient temperature for 2.5 h. Water was added, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with dilute HCl (pH=2), water, saturated NaHCO3 solution, and brine and dried over MgSO4. The crude material is chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 1:1 (1-21)-1:3 (22-44)→EtOAc (45-56)], yielding the title compound as an orange foam; 1H NMR (CDCl3, 400 MHz) δ 1.81-1.91 (m, 1H), 1.91-2.03 (m, 1H), 2.11-2.23 (m, 2H), 2.23-2.35 (m, 2H), 3.12 (quint, J=8.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.39 (dd, J=4.0, 8.0 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.83 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 8.37 (d, J=2.2 Hz, 1H), 8.56 (d, J=2.2 Hz, 1H), 8.87 (dd, J=1.6, 4.0 Hz, 1H); MS (ES+): m/z 353.1/355.0 (100/39) [MH+].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[C:12]2[N:13]=[C:14]([CH3:24])[N:15]=[C:16]([N:17]3[CH2:22][C@@H:21]4[CH2:23][C@H:18]3[CH2:19][NH:20]4)[N:11]2[N:10]=1.C(N(C(C)C)CC)(C)C.[CH2:42]([S:44](Cl)(=[O:46])=[O:45])[CH3:43]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:25]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)=[C:12]2[N:13]=[C:14]([CH3:24])[N:15]=[C:16]([N:17]3[CH2:22][C@@H:21]4[CH2:23][C@H:18]3[CH2:19][N:20]4[S:44]([CH2:42][CH3:43])(=[O:46])=[O:45])[N:11]2[N:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1nc(N2C[C@@H]3C[C@H]2CN3)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)N1C[C@@H]2C[C@H]1CN2c1nc(C)nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reaction time: 8 h

Procedure:
To a suspension of (1S,4S)-7-(2-chlorophenyl)-8-(4-chlorophenyl)-4-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-methylpyrazolo[1,5-a][1,3,5]triazine, hydrochloride salt (9A-1; 24.3 mg, 0.0463 mmol) in methylene chloride (1 ml) was added diisopropylethylamine (0.028 ml, 0.16 mmol), followed by a 0.56 M solution of ethanesulfonyl chloride in methylene chloride (0.1 ml, 0.056 mmol). After stirring overnight, the reaction directly loaded and then purified on a Biotage™ Flash 12S column using 0-20% methanol in methylene chloride as eluant to afford 10A-1 (18 mg, 72%) as a solid: +ESI MS (M+1) 543.3; 1H NMR (400 MHz, CD3OD) δ 7.50-7.36 (m, 4H), 7.32 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 4.58 (br s, 1H), 3.62 (s, 2H), 3.11 (q, J=7.5 Hz, 2H), 2.46 (s, 3H), 2.18-2.21 (br m, 2H), 1.30 (t, J=7.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:30]=1[CH2:31][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:31][C:30]5[C:29]([F:28])=[CH:36][CH:35]=[CH:34][C:33]=5[F:37])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reactant: Fc1cccc(F)c1C[Zn+]
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5c(F)cccc5F)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,6-difluoro-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 9): tR=0.91 min; Mass spectrum (ESI+): m/z=491 [M+Na]+.
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([I:11])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:6]2[N:7]=[CH:2][C:3]3[S:10][C:9]([I:11])=[CH:8][C:4]=3[N:5]=2)[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Clc1ncnc2cc(I)sc12
Solvent: ClCCCl
Product: Ic1cc2nc(N3CCN(Cc4ccccc4)CC3)ncc2s1
Yield: 88.2 %

Procedure:
To a solution of 4-chloro-6-iodothieno[3,2-d]pyrimidine (0.5 g, 1.7 mmol) in DCE (5 mL)/TEA (1 mL) was added 1-Benzyl-piperazine (0.3 g, 1.69 mmol). The mixture was refluxed for 1 hour. The solvent was removed and the residue was subject to chromatography on silica gel to afford (4-Benzyl-piperazin-1-yl)-6-iodothieno[3,2-d]pyrimidine (0.65 g, 88%). 1H NMR (CDCl3, 400 Hz) δ 8.47 (s, 1H) 7.60 (s, 1H), 7.35-7.23 (m, 5H), 3.95-3.92 (m, 4H), 3.51 (s, 2H), 2.59-2.54 (m, 4H). MS (ESI+) [M+H]+ 437.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:3]1=[O:20].[I:21]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.O>[I:21][C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:20])[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:5]=1[CH3:9]
Reactant: Cc1cc(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(I)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of 3,6-dimethyl-1-(3-trifluoromethylphenyl)-pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 20) (800.0 mg) in acetic acid (13.0 ml) was added in water bath N-iodosuccinimide (784.5 mg) and the resulting mixture was stirred at room temperature for five hours. To the reaction mixture was added water (20 ml) and the resulting mixture was stirred for thirty minutes, and thereto was added sodium thiosulfate solution (20 ml) and the resulting mixture was stirred for thirty minutes. The precipitated solids were collected by filtration and washed with water to afford 5-iodo-3,6-dimethyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (819.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]3[CH:13]=[N:14][C:15]([CH3:18])=[C:16]([OH:17])[C:11]=3[CH2:10][O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:21](=O)([O:37]C(Cl)C)[O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1/[N+:29](/[O-:36])=[N:30]/[O:31][CH2:32][CH2:33][CH2:34][CH3:35]>CN(C=O)C>[C:21](=[O:37])([O:17][C:16]1[C:11]2[CH2:10][O:9][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]=[N:14][C:15]=1[CH3:18])[O:22][CH2:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1/[N+:29](/[O-:36])=[N:30]\[O:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: Cc1ncc2c(c1O)CO[C@H]2c1ccc(Cl)cc1
Reactant: CCCCO/N=[N+](\[O-])N1CCC[C@H]1COC(=O)OC(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCO/N=[N+](/[O-])N1CCC[C@H]1COC(=O)Oc1c(C)ncc2c1CO[C@H]2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (3S)-3-(4-chlorophenyl)-6-methyl-1,3-dihydrofuro[3,4-c]pyridine-7-ol (900 mg, 3.44 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (206 mg, 5.16 mmol) and, in 10 minutes, followed by addition of {(2S)-1-[(Z)-butoxy-NNO-azoxy]pyrrolidin-2-yl}methyl 1-chloroethyl carbonate (1.3 g, 4.02 mmol). After stirring at rt for 3 h, the mixture was partitioned between Et2O (50 mL) and water (50 mL). The organic layer was washed with brine (3×50 mL), dried over MgSO4, and concentrated. The residue was purified by flash chromatography (Biotage 25+M) using 30-50% EtOAc/hexane gradient, affording the title compound: 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.37-7.27 (m, 4H), 6.21 (s, 1H), 5.29-5.13 (m, 2H), 4.49 (m, 1H), 4.40 (m, 1H), 4.35 (m, 1H), 4.20 (m, 2H), 3.65 (m, 1H), 3.57 (m, 1H), 2.52 (s, 3H), 2.20 (m, 1H), 2.05 (m, 2H), 1.90 (m, 1H), 1.75 (m, 2H), 1.42 (m, 2H), 0.94 (m, 3H).
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][N:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1>>[CH3:10][N:11]1[CH2:15][CH2:14][CH:13]([O:16][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:12]1
Reactant: CN1CCC(O)C1
Reactant: N#Cc1cccnc1F
Product: CN1CCC(Oc2ncccc2C#N)C1

Procedure:
2-Fluoro-nicotinonitrile was reacted with 1-methyl-pyrrolidin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 204 (M+1)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[CH:19][C:20]4[CH:25]=[C:24]([CH:26]=O)[N:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:21]=4[N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:33]([NH2:39])[C:34]1[O:38][CH:37]=[CH:36][CH:35]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1COCC1>[CH2:29]([CH:28]([N:23]1[C:21]2[N:22]=[C:17]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]4)=[CH:15][CH:14]=3)[N:18]=[CH:19][C:20]=2[CH:25]=[C:24]1[CH2:26][NH:39][CH2:33][C:34]1[O:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH3:32])[CH3:30]
Reactant: CCC(CC)n1c(C=O)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Reactant: NCc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(CC)n1c(CNCc2ccco2)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (30 mg, 0.07 mmol) in THF (1 mL) is added furfurylamine (0.03 mL, 0.35 mmol), NaBH(OAc)3 (45 mg, 0.21 mmol), and acetic acid (1 mL). The reaction mixture is stirred for 16 h and concentrated in vacuo. The residue is purified by preparative HPLC to give 20 mg of 1-{4-[4-(7-(1-ethyl-propyl)-6-{[(furan-2-ylmethyl)-amino]-methyl}-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazin-1-yl}-ethanone as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:4]2[N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].O>CN1C(=O)CCC1>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[C:5]3=[CH:12][CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:4]3[N:3]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)c1cccc2c1nc(Cl)c1ccncc12
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Yield: 45.3 %

Procedure:
Methyl 5-chlorobenzo[c][2,6]naphthyridine-7-carboxylate (1.0 eq, 48 mg, 0.176 mmol) and 3-chloroaniline (3.0 eq, 60 ul, 0.56 mmol) were stirred under microwave heating at 120° C. in NMP (0.3 ml) for 10 minutes. Water was added and the solid isolated by filtration. Trituration in methanol and filtration afforded methyl 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxylate as a solid (29 mg, 45% yield). LCMS (ES): >85% pure, m/z 364 [M+1]+.