Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:15]2[C:10]3=[C:11]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[C:13](B(O)O)[CH:14]=2.Cl[C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]=[C:29]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCOCC1>[C:39]1([C:29]2[N:30]=[C:31]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:32]=[C:27]([C:5]3[CH:4]=[C:3]4[C:8]5=[C:7]([C:23]6[CH:22]=[CH:21][CH:20]=[CH:19][C:24]=6[N:9]5[C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=5[C:2]4([CH3:25])[CH3:1])[CH:6]=3)[N:28]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC1(C)c2ccccc2-n2c3ccccc3c3cc(B(O)O)cc1c32
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC1(C)c2ccccc2-n2c3ccccc3c3cc(-c4nc(-c5ccccc5)nc(-c5ccccc5)n4)cc1c32

Procedure:
36 g (110.0 mmol) of 8,8-dimethyl-8H-indolo[3,2,1-de]acridine-6-boronic acid, 29.5 g (110.0 mmol) of 2-chloro-4,6-diphenyl-1,3,5-triazine and 44.6 g (210.0 mmol) of tripotassium phosphate are suspended in 500 ml of toluene, 500 ml of dioxane and 500 ml of water. 913 mg (3.0 mmol) of tri-o-tolylphosphine and then 112 mg (0.5 mmol) of palladium (II) acetate are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness. The residue is recrystallised from toluene and from dichloromethane/isopropanol and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 46 g (89 mmol), corresponding to 83% of theory.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:22]=[C:21]([C:23](=[O:28])N(OC)C)[S:20][C:19]=2[CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[F:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:22]=[C:21]([C:23]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=3)=[O:28])[S:20][C:19]=2[CH:29]=1
Reactant: CON(C)C(=O)c1cc2ccc(F)cc2s1
Reactant: Brc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1cccc(Br)c1)c1cc2ccc(F)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A solution of 1,3-dibromobenzene (493 mg) in tetrahydrofuran (10 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 0.86 ml). The reaction mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of the above 6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene (500 mg) in tetrahydrofuran (3 ml). The mixture was warmed to room temperature, and added thereto was a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-85:15) to give 3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone (479 mg) as a pale yellow solid. APCI-Mass m/Z 335/337 (M+NH4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[CH:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1.C(Cl)(=O)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.SC[C@H]([C@@H](CS)O)O>CN(C)C=O.CN(C)C=O.CO>[C:12]1([C:15]2[S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccccc1S
Reactant: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(Cl)c1ccccc1
Product: c1ccc(-c2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1 g of 2-chlorotrytyl chloride resin (1.66 mmol/g, 1 eq) was allowed to swell in methylene chloride for 3-5 min, 1.162 mmol of N,N-diisopropylethylaminem (0.202 ml, 0.7 eq) and 1.66 mmol of aminothiophenol (0.178 ml, 1 eq) were added thereto, and the mixture was gently stirred for 3 hr at room temperature. Then, the resin was filtered and washed with a mixture of methylene chloride, methanol and N,N-diisopropylethylamine (85:10:5 v/v/v) to obtain 2-chlorotrityl resin loaded with 0.332 mmol/g of 2-aminobenzenethiol. The loaded 2-chlorotrityl resin 200 mg was suspended in 5-6 ml of N,N-dimethylformamide, 0.996 mmol of benzoyl chloride (0.116 ml, 3 eq) and the mmol of N,N-diisopropylethylamine (0.173 ml, 3 eq) were added thereto, and the mixture was shaken for 3 hr at room temperature. Then, the resin was filtered and washed with 5×10 ml N,N-dimethylformamide and 5×10 ml methylene chloride. The resin still remaining on the filter was then treated with 20 ml portions of 65% trifluoroacetic acid/methylene chloride and 5% triethylsilane/methylene chloride. The obtained filtrates were concentrated in a vacuum to obtain an oily residue, which was dissolved in 10 ml of N,N-dimethylformamide/methanol (9:1 v/v) containing 0.2 mmol of dithiothreitol (0.031 g). After 3 hr of standing at room temperature, the mixture was extracted with ether, washed with water, dried and concentrated in a vacuum to obtain the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](OC)=[O:9])=[C:6]([O:12][CH3:13])[C:5]([O:14][CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.C(O)(=O)C.[CH:22](N)=[NH:23]>COCCO>[CH3:13][O:12][C:6]1[C:5]([O:14][CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=[C:2]2[C:7]=1[C:8](=[O:9])[N:23]=[CH:22][NH:1]2
Reactant: N=CN
Reactant: COC(=O)c1c(N)cc(OC)c(OC)c1OC
Solvent: COCCO
Solvent: CC(=O)O
Product: COc1cc2[nH]cnc(=O)c2c(OC)c1OC
Yield: 35.6 %

Procedure:
A solution of methyl 6-amino-2,3,4-tris(methyloxy)benzoate (2.87 g, 11.90 mmol) and formamidine acetate (3.72 g, 35.7 mmol) in 2-methoxyethanol (25 mL) was stirred at 125° C. for 2 hrs before being concentrated. The residue was suspended in water and the solid was collected by filtration, washed with water, and dried under vacuum (45° C.) to give 5,6,7-tris(methyloxy)-4(1H)-quinazolinone (1 g, 34%) as a light brown solid. MS (m/z) 237.1 (M+H+).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH3:17])[CH:8]=1)=O.Cl.[N+:20]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([NH2:32])=[NH:31])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]>>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:32]=[C:30]([NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=3)[N:31]=2)=[CH:8]1)[CH3:17]
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Reactant: N=C(N)Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CCn1cc(-c2ccnc(Nc3cccc([N+](=O)[O-])c3)n2)c2cccnc21

Procedure:
Prepared by treatment of (E)-3-(dimethylamino)-1-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one and 1-(3-nitrophenyl)guanidine hydrochloride. 1H-NMR (DMSO-d6) δ: 1.49 (t, 3H, J=7.2 Hz, CH3), 4.37 (q, 2H, J=7.6 Hz, CH2), 7.26 (m, 1H, Ar—H), 7.39 (d, 1H, J=5.2 Hz, Pyrimidin-H), 7.61 (t, 1H, J=8.0 Hz, Ph-H), 7.83 (m, 1H, Ar—H), 8.12 (d, 1H, J=8.0 Hz, Ph-H), 8.38 (m, 1H, Ar—H), 8.49 (d, 1H, J=5.2 Hz, Pyrimidin-H), 8.62 (s, 1H, Ph-H), 8.92 (d, 1H, J=8.0 Hz, Ph-H), 9.01 (s, 1H, Ar—H). MS (ESI+) m/z 361.1308 (M+H)+.
Reaction SMILES: CNCCNC.I[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:15]=2)[N:10]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:9]=1.[C:39]([NH2:47])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[CH:26]([S:23]([C:20]1[CH:21]=[CH:22][C:17]([C:14]2[N:15]=[C:16]3[C:8]([NH:47][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:9][N:10]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)(=[O:31])=[O:30])[C:11]3=[N:12][CH:13]=2)=[CH:18][CH:19]=1)(=[O:24])=[O:25])([CH3:27])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Reactant: NC(=O)c1ccccc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(NC(=O)c3ccccc3)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Temperature: 95 °C
Yield: 37.4 %

Procedure:
CuI (95 mg, 0.4988 mmol), and N,N′-dimethylethane-1,2-diamine (176 mg, 1.997 mmol) in dioxane (5 mL) was heated for 5 minutes at 100° C. in a microwave. 1 mL of this solution was added to a mixture of 7-iodo-2-(4-isopropylsulfonylphenyl)-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine (100 mg, 0.1720 mmol), benzamide (104.2 mg, 0.8600 mmol) and K3PO4 (73.02 mg, 0.344 mmol) in dioxane (1 mL) and the solution was heated at 95° C. for 1 hour. The reaction mixture is concentrated in vacuo. The residue was partitioned between DCM and water. Combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo yielding an oil which was purified by prep HPLC to give the sub-title product (37 mg, 37%). MS (ES+) 575.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:8]=3[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[C:4]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[C:5]2[O:10][C:9]3[CH:11]=[CH:12][C:13]([Cl:15])=[CH:14][C:8]=3[C:6]=2[N:7]=1
Reactant: Clc1ccc2oc3c(Cl)nc(Cl)nc3c2c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CN1CCN(c2nc(Cl)nc3c2oc2ccc(Cl)cc23)CC1
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of 2,4,8-trichloro-benzo[4,5]furo[3,2-d]pyrimidine (1.0 g, 4.8 mmol) in ethanol (15 mL) was added K2CO3 (1.3 g, 9.6 mmol) followed by N-methylpiperazine (0.532 mL, 4.8 mmol). After 2 h, the reaction mixture was diluted with 1 N NaOH (30 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with 1 N NaOH (20 mL), dried, and concentrated to afford the desired product (1.03 g, 77%). 1H NMR (CDCl3): 8.10 (s, 1H), 7.55-7.49 (m, 2H), 4.13-4.11 (m, 4H), 2.59-2.56 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[CH:13]=[C:12]2[CH3:22])[CH:18]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:25]N(C)C=O.CC(C)([O-])C.[K+].S(OC)(OC)(=O)=O>O>[F:5][C:4]([F:7])([F:6])[C:3]([C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]3[C:14](=[O:21])[CH:13]=[C:12]2[CH3:22])[CH:18]=1)([O:8][CH3:25])[C:2]([F:1])([F:23])[F:24]
Reactant: CN(C)C=O
Reactant: Cc1cc(=O)n2c3c(cc(C(O)(C(F)(F)F)C(F)(F)F)cc13)CC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC(c1cc2c3c(c1)c(C)cc(=O)n3CC2)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Yield: 49 %

Procedure:
To a stirred mixture of 3.5 g of 1,2-dihydro-8-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one and 20 ml of dry dimethylformamide is added 1.3 g (0.012 mole) of potassium tert-butoxide in a dry nitrogen atmosphere. The mixture is heated gently to 100° and is allowed to cool. Then 1 ml (1.35 g, 0.011 mole) of dimethyl sulfate is added, and the mixture is warmed gently to 100°. The mixture is allowed to cool to room temperature and is poured into 100-200 ml of water. The precipitate is filtered off and then is triturated with 10% sodium hydroxide solution. The insoluble material is filtered off, washed with water, and dried. Recrystallization from alcohol gives 1.8 g (49%) of 1,2-dihydro-8-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)-ethyl]-6-methyl-4H-pyrrolo[3,2,1-ij]quinolin-4-one, m.p. 242°-243°.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](SC)=[N:19][C:18]2=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[NH2:25][NH:26][C:27]([NH2:29])=[S:28]>C(O)C>[CH3:13][C:12]([C:9]1[CH:8]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=[N:25][NH:26][C:27](=[S:28])[NH2:29])[NH:19][C:18]2=[O:24])[CH:6]=[C:5]([C:2]([CH3:3])([CH3:4])[CH3:1])[C:10]=1[OH:11])([CH3:14])[CH3:15]
Reactant: NNC(N)=S
Reactant: CSC1=NC(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)S1
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2SC(=NNC(N)=S)NC2=O)cc(C(C)(C)C)c1O
Reaction time: 7 h
Yield: 84.1 %

Procedure:
A mixture of 5-[(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-(methylthio)-4(5H)-thiazolone (6.13 g, 0.0169 mole) and thiosemicarbazide (1.53 g, 0.0169 mole) in ethanol (300 mL) is refluxed with stirring for 7 hours. After standing overnight at room temperature, the product is separated by filtration, washed with ethanol to give 5.78 g of a solid. It is recrystallized from DMF-methanol to give 3.4 g (47%) of pure 2-[5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4-oxo-2-thiazolidinylidene]hydrazinecarbothiamide, (Z)-, mp 200°-202° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:27])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[C:17]([F:26])=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:25])=[CH:19]2)=O)C.CC(C[AlH]CC(C)C)C.C(O)C>C(Cl)Cl>[F:26][C:17]1[C:16]([O:15][C:9]2[C:8]3=[C:7]([CH3:27])[C:6]([CH2:4][OH:3])=[CH:14][N:13]3[N:12]=[CH:11][N:10]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:25])[NH:21]2
Reactant: CCOC(=O)c1cn2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2c1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc2c(F)c(Oc3ncnn4cc(CO)c(C)c34)ccc2[nH]1
Temperature: -15 °C
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
To a solution of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (68 mg 0.19 mmol) in anhydrous methylene chloride (2.0 mL) at −78° C. under argon was added DIBAL (0.48 mmol, 0.48 mL, 1.0M, 2.5 eq.) dropwise. After 5 minutes, the mixture was warmed to −15° C. and allowed to stir for an additional 15 minutes. A drop of ethanol was added to quench the reaction followed by 1N sodium hydroxide (0.2 mL) and 1.0 mL of ethyl acetate and 1.0 mL of THF. After 30 minutes, the mixture was filtered to remove the resulting solid. The filtrate was dried, concentrated in vacuo, and chromatographed using silica gel eluting with 40-75% ethyl acetate in hexanes (gradient). Concentration of the desired fractions afforded the title compound (39 mg, 63%) as a clear oil. LC/MS; (M+H)+=327.3
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.O=[C:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]#[N:28].[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[C:27]#[N:28])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: N#CC1CCCC1=O
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCCC3C#N)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-2-oxo-cyclopentanecarbonitrile using decaborane yielded a mixture of epimers of the title compound as a white solid. MS (ESI): m/z=372.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: BrCc1ccccc1
Product: COc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1ccccc1
Yield: 90.7 %

Procedure:
2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole (5005, Example 46) (2.02 g, 7.77 mmol) was reacted with benzyl bromide (1.20 mL, 10.1 mmol, 130 M %). The crude product was purified by flash chromatography eluting with 2% MeOH/ CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-benzyl-2-(2.6-difluorophenyl)-4-methoxylbenzimidazole (2.47 g, 7.05 mmol, 90% yield). M.p. 139-141° C. 1H-NMR (200 MHz, CD2Cl2) δ 7.48 (m, 1H, H4′), 7.25-6.96 (m, 8H), 6.86 (dd, J=0.8, 8.3 Hz, 1H, H5), 6.72 (dd, J=8.0, 0.8 Hz, 1H, H7), 5.24 (s, 2H, CH2Ph), 4.01 (s, 3H, OCH3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(C)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(C)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 356 g of 4-nitro-3-(4-methylphenyl)-butanoic acid methyl ester, 138 g of methyl acrylate and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(4-methylphenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=2)[CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[NH2:15])[CH:3]=1
Reactant: Cc1ccnc(Oc2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccnc(Oc2cccc(N)c2)c1
Yield: 98.6 %

Procedure:
A suspension of 3-(4-methylpyridin-2-yloxy)nitrobenzene (0.5 g) in ethanol (5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 100 mg) under a hydrogen atmosphere for 4 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(4-methylpyridin-2-yloxy)aniline (429 mg).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[O:18]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=1[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(F)(F)F)ccc1Oc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(C(F)(F)F)ccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
A −78° C. solution of the crude 2-phenoxy-5-trifluoromethyl-anisole (3.79 g, 14.1 mmol) in CH2Cl2 (38 mL) is treated with BBr3 (14.04 g, 56.1 mmol) and then warmed to 0° C. The mixture is stirred for 1.5 h under N2, poured into ice water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude material that is absorbed on silica gel and columned with 6/1 hexanes/ethyl acetate to afford 1.29 g (18%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES−+) m/z mass calculated for C13H9O2F3 254, found 253 (M+1, 100%).
Reaction SMILES: Br[C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[CH:6]=1.[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>>[N:10]1[CH:15]=[CH:14][C:13]([C:2]2[O:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(O)c1coc(Br)c1
Product: O=C(O)c1coc(-c2ccncc2)c1

Procedure:
Using the procedure outlined in Description 29, the title compound was prepared from 2-bromo-furan-4-carboxylic acid (S. W. En, M. C. Yuen, H. N. C. Wong, Tetrahedron, 1996, 52(37), 12137) and 4-pyridylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12](SC)[N:11]=[C:10]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.ClC1N=C(N2CCOC[C@@H]2C)C=C(C2C=NC=C(F)C=2)N=1.[CH:44]1([NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][C:54](B3OC(C)(C)C(C)(C)O3)=[C:53]([F:66])[CH:52]=2)=[O:49])[CH2:46][CH2:45]1>>[CH:44]1([NH:47][C:48]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([C:12]3[N:13]=[C:8]([C:4]4[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)[CH:9]=[C:10]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]4[CH3:22])[N:11]=3)=[C:53]([F:66])[CH:52]=2)=[O:49])[CH2:46][CH2:45]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Reactant: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Agent: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(Cl)n1
Product: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(-c2ccc(NC(=O)NC3CC3)cc2F)n1

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(5-fluoropyridin-3-yl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 7) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 11). Material was purified by prep HPLC twice (low pH) followed by purification using a TsOH cartridge (100 mg) to afford a yellow solid, (4.5 mg, 15%)
Reaction SMILES: C(OC([N:8]([O:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([O:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[S:41]([N:44]([CH2:51][CH2:52][C:53]#[N:54])[CH2:45][C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)(=[O:43])=[O:42])(=[O:34])=[O:33])[CH:25]=1)[C:9]([NH:11]C(OC(C)(C)C)=O)=[NH:10])=O)(C)(C)C.C(NCCC#N)C1OC=CC=1>>[CH3:30][C:28]1[CH:27]=[C:26]([O:31][S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[S:41]([N:44]([CH2:51][CH2:52][C:53]#[N:54])[CH2:45][C:46]2[O:47][CH:48]=[CH:49][CH:50]=2)(=[O:42])=[O:43])(=[O:33])=[O:34])[CH:25]=[C:24]([CH:29]=1)[O:23][CH2:22][CH2:21][CH2:20][O:19][NH:8][C:9]([NH2:11])=[NH:10]
Reactant: Cc1cc(OCCCON(C(=N)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(CCC#N)Cc2ccco2)c1
Agent: N#CCCNCc1ccco1
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(CCC#N)Cc2ccco2)c1
Yield: 49 %

Procedure:
N,N′-Bis-(tert-butoxycarbony)-3-[5-methyl-3-(2-(N-(2-cyanoethyl)-N-(2-furanylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine: The title compound was prepared in 49% yield from 3-(furfurylamino)propionitrile, in a manner analogous to step h of Example 20. 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.29 (dd, 1H, J=7.9, 1.4 Hz), 8.16 (dd, 1H, J=7.8, 1.5 Hz), 7.79 (m, 1H), 7.70 (m, 2H), 7.33 (t, 1H, J=1.3 Hz), 6.60 (m, 1H), 6.57 (m, 1H), 6.52 (t, 1H, J=2.1 Hz), 6.32 (m, 2H), 4.65 (s, 2H), 4.18 (t, 2H, J=6.2 Hz), 3.94 (t, 2H, J=6.2 Hz), 3.65 (m, 2H), 2.55 (m, 2H), 2.24 (s, 3H), 2.10 (pentet, 2H, J=6.2 Hz), 1.49 (s, 18H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:18]#[N:19])[S:5][C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[CH:9][CH:8]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([CH3:30])[CH:22]=1.[F-].[K+]>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]>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]([C:18]#[N:19])[S:5][C:6]=2[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:17])=[CH:9][CH:8]=2)=[C:23]([CH3:30])[CH:22]=1
Reactant: Cc1ccc(-c2sc(C#N)cc2Br)c2ccccc12
Reactant: Cc1cc(Cl)ccc1B(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: Cc1cc(Cl)ccc1-c1cc(C#N)sc1-c1ccc(C)c2ccccc12
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A round-bottomed flask was charged with 4-bromo-5-(4-methylnaphthalen-1-yl)thiophene-2-carbonitrile (203 mg, 0.62 mmol), 4-chloro-2-methylphenylboronic acid (119 mg, 0.70 mmol), Pd2(dba)3 (9.2 mg, 0.010 mmol) and KF (126 mg, 2.17). After degassed, dioxane (2.0 mL) and P(Bu-t)3 (0.15 mL, 0.2M, 0.03 mmol) was added. The reaction mixture was stirred at rt until complete. 20 mL of water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:CH2Cl2=3:1). 0.21 g (90.6%) of product was obtained as a white solid.