Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([NH2:18])[CH:12]=2)=[S:10])=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Nc1cccc(N)c1
Solvent: ClC(Cl)Cl
Product: Nc1cccc(NC(=S)Nc2ccc(Cl)cc2)c1
Reaction time: 1 h

Procedure:
A solution of p-chlorophenyl isothiocyanate (39.6 g.) in chloroform (100 ml.) is added dropwise with stirring to a solution of m-phenylene diamine (25.2 g.) in chloroform (200 ml.) at room temperature. The mixture is stirred for 1 hour after the addition is complete, and the precipitated solid is filtered off, washed with chloroform and dried to give 1-(p-chlorophenyl)-3-(m-aminophenyl)thiourea, m.p. 132°-133.5° C. This product (20 g.) is dissolved in ethanol saturated with ammonia gas (300 ml.), yellow mercuric oxide (17.2 g.) is added and the mixture is stirred for 24 hours at room temperature. The black precipitate is filtered off and washed thoroughly with boiling ethanol, and the filtrate is evaporated to dryness. The residue is dissolved in chloroform, the solution is filtered and an excess of ethereal hydrochloric acid is added to the filtrate, followed by a large volume of ether. The oily precipitate is allowed to solidify, is triturated with fresh dry ether, and is filtered off and dried, to give 1-(p-chlorophenyl)-3-(m-aminophenyl)guanidine dihydrochloride, m.p. 236°-238° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19](O)[CH3:20])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>ClCCCl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]([Cl:24])[CH3:20])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(Cl)c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1

Procedure:
A mixture of 4-tert-butyl-2-[5-(1-hydroxyethyl)-benzofuran-2-yl]thiazole (1.5 g) and thionyl chloride (0.44 ml) in 1,2 dichloroethane (35 ml) was stirred under reflux for 2 hours. After cooling, the resulting mixture was adjusted to pH 7 with aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 4-tert-butyl-2-[5-(1-chloroethyl)-benzofuran-2-yl]thiazole (1.31 g).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][S:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl>[Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][S:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH:8][CH:27]1[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1SCc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2SCc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-bromobenzyl)thioaniline (7.55 g) and 1-tert-butyloxycarbonylpiperidin-4-one (6.68 g) in 2-dichloroethane (100 ml) were added acetic acid (30 ml) and sodium triacetoxyborohydride (7.1 g), and the mixture was stirred at a room temperature for 2 hours. Additional amount of sodium triacetoxyborohydride (500 mg) was added, and the mixture was further stirred at a room temperature for 2 hours. The reaction was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water, a saturated aqueous sodium hydrogen carbonate solution, and water, dried over magnesium sulfate, and the solvent was removed. The residue thus obtained was purified by chromatography on a silica gel column (250 g) to give the title compound as a resinous product (11.2 g, 91%) from the fraction eluted with n-hexane:ethyl acetate=5:1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C@@H:14]([OH:15])[CH2:13][C@@H:12]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C@@H:11]1/[CH:24]=[CH:25]/[C@@H:26]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:27][CH2:28][C:29]1[S:30][C:31]([CH3:35])=[C:32]([Br:34])[CH:33]=1.C[N+]1([O-])CCOCC1>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:1][O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@H:10]1[C:14](=[O:15])[CH2:13][C@@H:12]([O:16][Si:17]([C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:18])[CH3:19])[C@@H:11]1/[CH:24]=[CH:25]/[C@@H:26]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:39])[CH2:27][CH2:28][C:29]1[S:30][C:31]([CH3:35])=[C:32]([Br:34])[CH:33]=1
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2cc(Br)c(C)s2)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COC(=O)CCC/C=C\C[C@H]1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@H](CCc1cc(Br)c(C)s1)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
A mixture of alcohol 4 (3.591 g, 4.9 mmol), 4 A molecular sieves (2.5 g), and NMO (867 mg, 7.4 mmol) in dichloromethane (10 mL) was treated with TPAP (117 mg, 0.33 mmol). After 1 h, the mixture was filtered through celite and the filtrate evaporated in vacuo. Purification by flash chromatography (5% ethyl acetate/hexanes→7.5%) gave 5 (2.984 g, 4.1 mmol, 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](Br)=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>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.CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1cccc(Br)c1OCc1ccccc1
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: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2c(-c3cccnc3)cccc2-c2cccnc2)cc1
Temperature: 85 °C
Reaction time: 48 h
Yield: 40.8 %

Procedure:
2,6-Dibromophenyl benzyl ether (25.61 g, 74.88 mmol), 3-pyridylboronicacid (20.25 g, 164.7 mmol), aqueous potassium carbonate (233 mL 2 M), and DMF (370 mL) were put together in a 1 liter flask. Oxygen was removed by several vacuum-argon cycles. Then Pd(PPh3)4 (5.38 g, 4.65 mmol) was added and the mixture was heated to 85° C. under an argon atmosphere. After 48 hr, the reaction mixture was cooled to rt, and poured into an ice/water mixture (1 L). This was extracted with diisopropylether (3 times 300 mL), and the combined organic layers were dried over MgSO4, filtered, and the solvent was removed in vacuo, yielding a yellow crystalline solid. Recrystallisation from diethyl ether yielded the product as a white crystalline solid (10.34 g, 41%). The residue was further purified by column chromatography (silicagel, EtOAc/n-pentane=3:2), yielding another 2.60 g (10%) of the product (total yield 51%). 1H-NMR(CDCl3):δ=8.80 (s, 2H), 8.59 (d, 2H), 7.93 (dd, 2H), 7.65 (d, 2H), 7.34 (m, 3H), 7.19 (t, 1H), 7.10 (t, 2H), 6.64 (d, 2H), 4.15 (s, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-])=O.C(O)(=O)C>O.[Fe]>[NH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(O)ccc1Cl
Temperature: 100 °C
Yield: 88.2 %

Procedure:
A 100-mL round bottomed flask equipped with a magnetic stir bar was charged with 4-chloro-3-nitrophenol (6.0 g, 34.6 mmol) and acetic acid (60 mL). Iron powder (325 mesh) (19.31 g, 346 mmol) was added, and the mixture was heated at 100° C. for 30 min. The mixture was cooled to room temperature and diluted with water (40 mL). The mixture was then filtered through a pad of Celite and rinsed with water. The filtrate was then extracted with ethyl acetate, and the combined extracts were concentrated under reduced pressure. Heptane (ca. 100 mL) was added to the filtrate and then removed under reduced pressure in order to remove residual acetic acid and water. This was repeated. The residue was dissolved in acetonitrile and concentrated under reduced pressure. The resulting solid was suspended in heptane and concentrated under reduced pressure to afford 3-amino-4-chlorophenol (4.38 g, 88%) as a pale purple/amber solid. MS (ESI, pos. ion) m/z 144 [M+1].
Reaction SMILES: [NH2:1][CH:2]([CH:8]=[C:9]=[CH2:10])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[ClH:11].[CH2:12](O)[CH3:13]>>[ClH:11].[NH2:1][CH:2]([CH:8]=[C:9]=[CH2:10])[CH2:3][CH2:4][C:5]([O:7][CH2:12][CH3:13])=[O:6]
Reactant: C=C=CC(N)CCC(=O)O
Reactant: CCO
Agent: Cl
Product: C=C=CC(N)CCC(=O)OCC
Reaction time: 8 h

Procedure:
To 4-amino-5,6-heptadienoic acid in anhydrous ethanol at 0° C. was added gaseous HCl. The reaction was left overnight at room temperature and then evacuated to a residue. This was taken in ethyl acetate, decolorized with charcoal, and then crystallization accomplished from ethyl acetate-ether to give the title compound. mp. 81°-83° C.; IR (KBr): 1952, 1710 cm-1. 'H NMR (δD2O): 1.3 (t, 3H, J=6.9 Hz, CH3), 1.9-2.8 (m, 4H, CH2CH2), 3.95 (m, 1H, CHN), 4.2 (q, 2H, J=6.9 Hz, OCH2), 5.0-5.4 (m, 3H H2C=C=CH). Anal. Calcd. for C9H16ClNO2 : C, 52.56, H, 7.84, N, 6.87; Found: C, 52.45, H, 7.95, N, 6.98.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[NH2:22]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1)[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Cc1cc(N)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1cc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-methyl-5-(trifluoromethyl)aniline (51 mg, 0.290 mmol) similar to Example 117 and isolated as a yellow solid (60 mg, 78%). 1H NMR (DMSO-d6): 10.60 (s, 1H), 9.45-9.44 (m, 1H), 8.77-8.75 (m, 1H), 8.60-8.56 (m, 1H), 8.30 (s, 1H), 7.68 (s, 1H), 7.62-7.58 (m, 1H), 7.32 (s, 1H), 7.16 (s, 1H), 2.45 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[NH:29][C:28]2[CH:30]=[CH:31][C:32]([C:34]([F:37])([F:36])[F:35])=[CH:33][C:27]=2[N:26]=1>CN(C=O)C>[F:37][C:34]([F:35])([F:36])[C:32]1[CH:31]=[CH:30][C:28]2[NH:29][C:25]([NH:2][C:3]3[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=3)[CH2:6][NH:7][C:8]3[C:17]4[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][N:9]=3)=[N:26][C:27]=2[CH:33]=1
Reactant: FC(F)(F)c1ccc2[nH]c(Cl)nc2c1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4nc5cc(C(F)(F)F)ccc5[nH]4)c3)ncnc12
Temperature: 100 °C
Reaction time: 15 h

Procedure:
33 mg (0.11 mmol) 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 24 mg (0.11 mmol) 2-Chloro-5-trifluoromethyl-1H-benzoimidazole were dissolved in 500 μl DMF and stirred at 100° C. for 15 h. The reaction mixture was directly purified using preparative HPLC. The product was treated with HCl in methanol and concentrated in the SpeedVac.
Reaction SMILES: [CH3:1][CH:2]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:8](Br)[CH2:7][C:6]=2[CH2:5][C:4](=[O:17])[NH:3]1.[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(O)C>[CH3:1][CH:2]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]=3[N:8]([NH:21][CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]=2[CH2:5][C:4](=[O:17])[NH:3]1
Reactant: CC1NC(=O)CC2=C1c1cccnc1N(Br)C2
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)NN1CC2=C(c3cccnc31)C(C)NC(=O)C2
Yield: 87 %

Procedure:
3.6 g (0.012 mol) of 1-methyl-6-bromo-1,2-dihydropyrido[4,3-c][1,8]naphthyridin-3(4H)-one, 30 ml of absolute ethanol and 10 ml of isopropylamine are stirred for 6 hours at 160° C. in an autoclave. After cooling, the crystalline precipitate is filtered off under suction and recrystallized from methanol. 2.82 g (87% of theory) of 1-methyl-6-isopropylamino-1,2-dihydropyrido-[4,3-c][1,8]naphthyridin-3(4H)-one are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:21][CH2:22][C:23](OC)(OC)OC>>[Cl:21][CH2:22][C:23]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[CH:10][C:9]([C:11]3[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:8][CH:7]=2)[N:1]=1
Reactant: COC(CCl)(OC)OC
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Product: O=c1[nH]c(CCl)nc2cc(-c3ncccc3C(F)(F)F)ccc12

Procedure:
Heat a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (100 mg, 0.356 mmol) in 2-chloro-1,1,1-trimethoxyethane (bp 138° C.) at 130° C. for 4 hours. Concentrate the mixture under reduced pressure to give 2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-quinazolin-4-one as an oil which crystallizes on standing.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10](OC(OCC)CBr)[CH3:11].Br.C([O-])(O)=O.[Na+]>CCO.CCOC(C)=O>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(Br)cn2ccnc12
Temperature: 23 °C
Yield: 71.5 %

Procedure:
To a solution of commercially available 2-amino-5-bromo-3-picoline (21.48 g, 115 mmol) and bromoacetaldehyde diethyl acetal (90%, 39.6 mL, 230 mmol) in EtOH (110 mL) was added 48% aq. HBr (11 mL) and the mixture was refluxed for 11 h. Cooled to 23° C., diluted with EtOAc, poured into sat. NaHCO3-sol., separated phases, washed with the organic layer with brine, dried over Na2SO4. Removal of the solvent in vacuum (not over 40° C. bath temperature) left an orange liquid, which was directly coated on silica gel for chromatography. Silica gel column filtration with heptane/EtOAc 50:50→0:100 gave the title compound as a light brown solid (17.36 g, 72%).MS (ISP) 211.0 [(M+H)+], 231.1 [(M+2+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[N-:14]=[N+]=[N-].[Na+].[I-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][N:14]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Agent: [I-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Brc1ccc(C2=NCCC2)cc1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A mixture of 4′-bromo-4-chlorobutyrophenone (20.0 g, 76.5 mmol), sodium azide (7.46 g, 115 mmol) and sodium iodide (344 mg, 2.29 mmol) is stirred overnight at 55° C. The reaction mixture is poured on water and extracted with DCM. The organic phases are dried over MgSO4 and concentrated in vacuo. The residue is dissolved in 150 mL cyclohexane, triphenylphosphine (20.1 g, 76.5 mmol) is added and the reaction mixture is stirred overnight at RT. The reaction mixture is filtered and the solids are washed with cold diethyl ether. The filtrate is concentrated in vacuo, water is added and the mixture is extracted with DCM. The combined organic phases are washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue is treated with a mixture diethyl ether/cyclohexane (1/1, v/v), filtered and the filtrate is concentrated in vacuo. Yield: 15.6 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[C:11]([CH2:13][Br:23])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Cc1ccc(CBr)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 38.3 %

Procedure:
2-Tert-butoxycarbonylmethyl-5-methyl benzoic acid tert-butyl ester (4.751, 15.5 mmol) was dissolved in 75 ml of CCl4. To the solution was added N-bromosuccinimide (2.90 g, 16.3 mmol, 1.05 equivalents) and benzoyl peroxide (180 mg). The reaction mixture was refluxed under an argon atmosphere overnight; the reaction mixture was then cooled to room temperature, and the solid precipitate was filtered off, and washed with hexanes, the combined organic was taken to dryness and the residue was purified by chromatography to obtain 2-tert-butoxycarbonylmethyl-5-bromomethyl benzoic acid tert-butyl ester 2.286 g (38.3% yield) as an oil. 1H NMR (CDCl3): 7.920 (1H, d, J=2.2 Hz), 7.460 (1H, dd, J=1.95, 7.81 Hz), 7.193 (1H, d, J=7.81 Hz), 4.500 (2H, s), 3.953 (2H, s), 1.590 (9H, s), 1.444 (9H, s). FABMS (+Ve), m/z 387 [MH+, 81Br], 385 [MH+, 79Br], 331 [MH+−C4H8, 81Br], 329 [MH+−C4H8, 79Br], 275 [MH+−2C4H8, 81Br], 273 [MH+−2C4H8, 79Br]. Anal. calcd. for C18H25BrO4: C, 56.1; H, 6.5; Br, 20.7. Found: C, 56.27; H, 6.60; Br, 20.75.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: N#Cc1ccnc(F)c1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2cc(C#N)ccn2)cc1
Temperature: 130 °C

Procedure:
Compound 18 was prepared as outlined in Scheme 4. Accordingly, potassium t-butoxide (6.1 g) was added slowly to a stirred solution of tert-butylnitrite (5.5 mL) and 2-fluoro-4-methylpyridine (compound 1001, 4.0 g) in 75 mL of THF at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the crude product extracted with ethyl acetate (4×50 mL). The resulting solid was washed with hexanes to yield (2-fluoropyridin-4-yl)methan-N-hydroxyimine (compound 1002; 4.0 g; ESMS: M+H+=141). Thionyl chloride (2.6 mL) was added slowly to a stirred solution of compound 1002 (4.0 g in 40 mL of THF) at 0° C. After stirring for 1 hour at room temperature, the volatiles were removed in vacuo. The residue was taken up in ethyl acetate (50 mL) and the organics were washed with water and brine. The organics were concentrated in vacuo to give 2-fluoropyridine-4-carbonitrile (compound 1003) as a white solid (3.0 g; ESMS: M+H+=123). Compound 1003 (1.0 g) and 4-methoxybenzylamine were combined and heated at 130° C. for 1 hour. The crude product was partitioned between water and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate and the combined organics dried over Na2SO4, concentrated, and recrystallized from ethyl acetate/hexanes to provide 2-(4-methoxybenzylamino)pyridine-4-carbonitrile (compound 1004; 1.7 g; ESMS: M+H+=238) as pale yellow solid. Compound 1004 (1.6 g) was dissolved in 50 mL of anhydrous ether and 9 mL of 3M methyl magnesium bromide in ether was added. The reaction mixture was stirred at room temperature for 16 hours and poured over ice (c. 50 g), which was subsequently acidified with 6M HCl, followed by basicification with 1M ammonium hydroxide. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organics were concentrated in vacuo and purified by silica gel chromatography to provide 1-(2-(4-methoxybenzylamino)pyridin-4-yl)ethanone (Compound 1005; 1.2 g; ESMS: M+H+=257) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([OH:8])[CH:7]=1.[C:18]1([N:24]2[CH2:27][CH:26](O)[CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([CH:7]=1)[O:8][CH:26]1[CH2:27][N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25]1
Reactant: OC1CN(c2ccccc2)C1
Reactant: Oc1cc(Br)ccc1OCc1cccc(F)c1
Product: Fc1cccc(COc2ccc(Br)cc2OC2CN(c3ccccc3)C2)c1

Procedure:
Prepared by the procedure of Example 163 using 5-bromo-2-(3-fluoro-benzyloxy)-phenol and 1-phenyl-azetidin-3-ol. MS (ESI): mass calcd. for C22H19BrFNO2, 427.1; m/z found, 428.2 [M+H]+. 1H NMR (CDCl3): 7.34-6.47 (m, 12H), 5.11-5.03 (m, 3H), 4.36-4.28 (m, 2H), 3.98-3.91 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:15])[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=1.Cl.[CH3:17][CH:18]1[CH2:24][O:23][CH2:22][CH2:21][NH:20][CH2:19]1.C(N(CC)CC)C>O1CCCC1>[CH3:15][N:3]1[C:4](=[O:14])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)[N:7]=[C:2]1[N:20]1[CH2:19][CH:18]([CH3:17])[CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: CC1CNCCOC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1COCCN(c2nc(-c3ccncn3)cc(=O)n2C)C1
Reaction time: 15 h
Yield: 60.3 %

Procedure:
To a slurry of 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (113 mg, 0.507 mmol) and 6-methyl-[1,4]oxazepane hydrochloride (100 mg, 0.660 mmol) in tetrahydrofuran (1.1 mL) was added triethylamine (154 mg, 1.52 mmol) at room temperature. The mixture was stirred for 15 hours and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was washed with ether and dried under reduced pressure to afford 1-methyl-2-(6-methyl-[1,4]oxazepan-4-yl)-1H-[4,4′]bipyrimidinyl-6-one (A087) as white solid (92.2 mg, 60%).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[NH2:25][C:26]1[C:34]2[O:33][C:32]([F:36])([F:35])[O:31][C:30]=2[CH:29]=[CH:28][CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:25][C:26]3[C:34]4[O:33][C:32]([F:36])([F:35])[O:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: Nc1cccc2c1OC(F)(F)O2
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2cccc3c2OC(F)(F)O3)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 150 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 815 mg, 2.19 mmol), 4-amino-2,2-difluoro-1,3-benzodioxole (950 mg, 5.49 mmol), p-toluenesulfonic acid monohydrate (416 mg, 2.19 mmol) and xylene (3.0 mL) was stirred at 150° C. for 2 hr. The mixture was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound as a colorless powder (900 mg, 1.77 mmol, 81%).