Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]=O)=[C:10]([O:17][CH3:18])[CH:9]=2)[CH:4]=[N:3]1.CS(C1[N:24]=[CH:25][C:26]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=2[N:28]=1)(=O)=O>>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:24]=[CH:25][C:26]4[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:27]=4[N:28]=3)=[C:10]([O:17][CH3:18])[CH:9]=2)[CH:4]=[N:3]1
Reactant: COc1cc(-c2cnn(C)c2C)ccc1NC=O
Reactant: CC(C)(C)CNc1nccc2cnc(S(C)(=O)=O)nc12
Product: COc1cc(-c2cnn(C)c2C)ccc1Nc1ncc2ccnc(NCC(C)(C)C)c2n1
Yield: 8 %

Procedure:
The title compound was prepared according to Example 40 using N-(4-(1,5-dimethy-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide (Preparation 77) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47). The residue was purified by silica gel column chromatography eluting with 50-100% EtOAc in cyclohexane followed by a second chromatography eluting with, 50-90% EtOAc in cyclohexane. The residue was passed through a SCX-2 cartridge eluting with 100% MeOH-1M NH3 in MeOH to give the title compound (5 mg, 8%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1.C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:33]([C:30]4[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=4)(=[O:35])=[O:34])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2cccc(N)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1nc(-c2cccc(NS(=O)(=O)c3ccc(C)cc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 5-amino-2-methylthio-4-(3-aminophenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 9e, 100 mg) was dissolved in dry pyridine (5 ml). p-Toluenesulfonyl chloride (70 mg) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with 0.1M aq. HCl. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/EtOAc=3/2 (v/v) as eluent.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].[O:14]1[C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1>>[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1[S:9][C:10]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH2:20]2)=[CH:11][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)OC(=O)Nc1nccs1
Product: CC(C)(C)OC(=O)Nc1ncc(C2(O)CCC3(CC2)OCCO3)s1

Procedure:
The title compound was prepared as a white solid from thiazol-2-yl-carbamic acid tert-butyl ester (prepared according to Das, B. et al. Tetrahedron Lett. 2006, 47, 7551-7556) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 33.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[CH2:10][C:9]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)(C=O)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[C:42]3[C:38]=2[CH:39]=[CH:40][NH:41]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(#N)C.ClCCl.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>[CH:20]1([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C:9]3[S:8][C:6]4[N:7]=[C:2]([C:37]5[CH:45]=[C:44]([C:46]#[N:47])[CH:43]=[C:42]6[C:38]=5[CH:39]=[CH:40][NH:41]6)[N:3]=[C:4]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)[C:5]=4[CH:10]=3)[CH2:19][CH2:18]2)[CH2:22][CH2:21]1
Reactant: O=CC1(CN2CCN(C3CC3)CC2)Cc2c(nc(Cl)nc2N2CCOCC2)S1
Reactant: CC1(C)OB(c2cc(C#N)cc3[nH]ccc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(-c2nc(N3CCOCC3)c3cc(CN4CCN(C5CC5)CC4)sc3n2)c2cc[nH]c2c1
Temperature: 140 °C

Procedure:
A mixture of 2-chloro-6-(4-cyclopropyl-piperazin-1ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carbaldehyde (217 mg), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-H-indole-6-carbonitrile (256 mg), bis(triphenylphosphine)palladium chloride (19 mg), and sodium carbonate (175 mg) in water (1.7 mL) and acetonitrile (6 mL) was heated in a microwave reactor at 140° C. for 1 hour. The reaction mixture was cooled, diluted with dichloromethane (20 mL), washed with water, dried (MgSO4) and the solvents removed in vacuo to give, after purification using flash chromatography, the title compound (59 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=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.C1(C)C=CC=CC=1>[C:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:18]1[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
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: Cc1ccccc1
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1-c1ccncc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (8.6 g, 33.3 mmol) and toluene (70 mL) in a 150 mL round bottom flask, 4-pyridylboronic acid (4.5 g, 36.6 mmol), Pd(PPh3)4 (3.8 g, 3.3 mmol) and K2CO3 (13.8 g, 99.9 mmol) were added. The solution was stirred for 24 h at 80° C. before cooling to RT. The solution was filtered through a pad of Celite® and purified by silica flash chromatography (30% EtOAc/Hexanes). This afforded the desired compound as a yellow solid. MS (ES+): 257.2 (M+H)+; (ES−): 255.2 (M−H)−. Calc'd for C15H16N2O2: 256.12.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[N:12]1[CH:17]=[CH:16]C=[CH:14][CH:13]=1.O1CCCC1.C(NCC)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([N:12]([CH2:17][CH3:16])[CH2:13][CH3:14])=[O:8]
Reactant: O=C(Cl)c1cc(Cl)ccc1I
Reactant: c1ccncc1
Solvent: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1cc(Cl)ccc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
In a 100 mL round bottomed flask was placed the 5-chloro-2-iodobenzoyl chloride prepared above. Pyridine (50 mL, 600 mmol) and tetrahydrofuran (10 mL, 100 mmol) were then added. To the reaction mixture was added diethylamine (3 mL, 30 mmol) and the mixture was stirred for 3 hr at rt. The mixture was stirred for an additional 3 hr at 50° C. The mixture was allowed to cool to rt and then concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and then washed with 1N HCl (50 mL×2), 1N NaOH (50 mL), brine (50 mL), and dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (1.96 g, 61%) as a light yellow syrup. LCMS: (FA) ES+ 338, 340; 1H NMR (300 MHz, d6-DMSO) δ ppm 7.86 (d, 1H), 7.38 (d, 1H), 7.21 (dd, 1H), 3.61-3.68 (m, 1H), 2.91-3.29 (m, 3H), 1.17 (t, 3H), 1.01 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](/[CH:14]=[C:15]1/[C:16](=[O:36])[N:17]([C@@H:20]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]4[O:30][C:31](=[O:35])[O:32][C:33]=4[CH3:34])=[O:26])[CH2:21]3)[CH2:18][CH2:19]/1)=[C:7]2[C:11]([OH:13])=[O:12].O.[C:38]1(C)[CH:43]=[CH:42][C:41](S(O)(=O)=O)=[CH:40][CH:39]=1>CO>[NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6](/[CH:14]=[C:15]1/[C:16](=[O:36])[N:17]([C@@H:20]3[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]4[O:30][C:31](=[O:35])[O:32][C:33]=4[CH3:34])=[O:26])[CH2:21]3)[CH2:18][CH2:19]/1)=[C:7]2[C:11]([O-:13])=[O:12].[CH:7]1([NH2+:8][CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)[CH2:6][CH2:14][CH2:15][CH2:19][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](N)[C@H]4SC3)C2=O)C1
Solvent: CO
Solvent: O
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: Cc1oc(=O)oc1COC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](N)[C@H]4SC3)C2=O)C1

Procedure:
200 mg of (6R,7R)-7-amino-3[E-(R)-1′-(5-methyl-2-oxo-[1,3]-dioxol-4-ylmethoxycarbonyl)-2-oxo-[1,3′]bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid were dissolved in 3 ml of methanol with addition of 95 mg of p-toluenesulfonic acid monohydrate and precipitated by the addition of 12 ml of isopropanol.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[S:44]1[CH:48]=[C:47]([CH2:49][N:50]2[C:58]3[C:53](=[CH:54][C:55]([NH2:59])=[CH:56][CH:57]=3)[CH:52]=[N:51]2)[N:46]=[CH:45]1>ClCCCl>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:59][C:55]1[CH:54]=[C:53]3[C:58](=[CH:57][CH:56]=1)[N:50]([CH2:49][C:47]1[N:46]=[CH:45][S:44][CH:48]=1)[N:51]=[CH:52]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: Nc1ccc2c(cnn2Cc2cscn2)c1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A mixture of (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (200 mg, 0.77 mmol), triphenylphosphine (603 mg, 2.3 mmol) and carbon tetrachloride (2.2 ml, 23 mmol) in 1,2-dichloroethane (5 ml) was stirred at 45° C. for 2 hours. 1-(1,3-Thiazol-4-ylmethyl)-1H-indazol-5-amine (184 mg, 0.8 mmol) was added and the solvents were evaporated under vacuum. Acetonitrile (5 ml) was added. The mixture was stirred at 75° C. for 2 hours. After cooling, the solvents were evaporated under vacuum. The residue was diluted in 6N methanolic ammonia and the solvents were evaporated under vacuum. The residue was purified by chromatography on silica gel (eluant: 3% to 5% methanol in DCM) to give the title compound as a beige foam (215 mg, 60%); NMR Spectrum (CDCl3) 1.73 (d, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 5.43 (q, 1H), 5.80 (s, 2H), 6.81 (d, 1H), 6.93 (s, 1H), 7.48 (m, 2H), 7.60 (t, 1H), 7.84 (dd, 1H), 8.08 (s, 1H), 8.43 (s, 1H), 8.62 (s, 1H), 8.78 (s, 1H); Mass spectrum 474.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:46].[Li+]>O1CCCC1>[Br:46][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=1
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2ccccc2CO)c1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2ccccc2CBr)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.1 %

Procedure:
To a solution of 4 g of N-[2-(hydroxymethyl)phenyl]-3-(tetradecyloxy)benzeneacetamide in 75 ml of tetrahydrofuran is added 1.19 g of triethylamine and 1.34 q of methanesulfonyl chloride, followed by stirring at room temperature for 1.5 hours. Added 7.66 g of lithium bromide with stirring continued for an additional 2.5 hours. The solvent is evaporated and the residue partitioned between chloroform and saturated sodium bicarbonate. The organic layer is dried and evaporated to a residue which is crystallized from hexane to give 2.6 g of the desired product as a white solid, m.p. 103°-106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][N:18]([CH2:20][CH2:21]O)[CH3:19]>>[CH3:17][N:18]([CH2:20][CH2:21][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:19]
Reactant: CN(C)CCO
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCCN(C)C

Procedure:
Following General Procedure C′ above, and using N-(3-chlorophenylacetyl)alanine (from Example D′ above) and 2-(N,N-dimethyl amino) ethanol (Aldrich), the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 0.1:2:0.79 NH4OH:EtOH:CHCl3 as the eluant.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:26]=O>C(O)C>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH2:26][N:23]2[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])[CH2:21][CH2:22]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1COc2cc(O)c(Cl)cc21
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
A solution of 5-chloro-6-hydroxybenzofuran-3(2H)-one (0.185 g, 1.00 mmol) in ethanol (20 mL) was added with 1-tert-butoxycarbonylpiperazine (0.186 g, 1.00 mmol), and 37% aqueous formaldehyde (0.0812 g, 1.00 mmol) at room temperature. The mixture was stirred overnight at room temperature, and then the precipitates formed were collected by filtration, and then washed with ethyl acetate to obtain tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.216 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH2:11]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:11][CH3:10])=[CH:4][N:3]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CN
Solvent: CC#N
Product: CNCc1ccc(Cl)nc1
Yield: 60.3 %

Procedure:
A mixture of 15.05 g of 2-chloro-5-(chloromethyl) pyridine and 50 ml of acetonitrile was dropwise added to a mixture of 36 g of 40% methylamine aqueous solution and 200 ml of acetonitrile during an hour at room temperature and stirred for an hour and a half. The reaction mixture was concentrated. The resulting residue to which 100 ml of water was added, was neutralized by sodium hydrogen carbonate, saturated with sodium chloride and extracted with dichloromethane (200 ml ×2). The organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by a column chromatography [developing solvent: dichloromethane-methanol (4:1)] to afford 8.77 g of 2-chloro-5-(methylaminomethyl)pyridine as a yellowish brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:12].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CCOC(C)=O.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>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1c(Cl)cc(Br)cc1Cl
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)cc(-c2ccccc2)cc1Cl
Yield: 104.7 %

Procedure:
To a solution of 2,6-dichloro-4-bromobenzoic acid methyl ester (0.55 g) in THF (10 mL) was added benzeneboronic acid (1.30 g), Pd(PPh3)4 (0.16 g) and 2M Na2CO3 (5 mL). The mixture was refluxed for 4 h under N2. After cooling, the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (silica gel; eluent: hexane to EtOAc/hexane 1/1) to yield crude 2,6-dichloro-4-phenylbenzoic acid methyl ester (0.57 g). ESMS: m/z 281 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:18][C:19]2[C:20](=[O:37])[N:21]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=3[CH3:36])[C:29]([O:31][CH3:32])=[O:30])[CH:22]=[C:23](Br)[N:24]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1.C([O-])=O.[NH4+].ClCCl.O>C(O)C.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:18][C:19]2[C:20](=[O:37])[N:21]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=3[CH3:36])[C:29]([O:31][CH3:32])=[O:30])[CH:22]=[CH:23][N:24]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Br)nc(NC3(c4ccccc4OCc4ccccc4)CC3)c2=O)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Temperature: 75 °C

Procedure:
To Methyl 3-(3-(1-(2-(benzyloxy)phenyl)cyclopropylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 167b, 543 mg) in ethanol (15 mL) was added ammonium formate (855 mg) and 10% Pd/C (103 mg) and the reaction was heated at 75° C. for 1 h. The mixture was filtered through celite and the solids washed with ethanol. The filtrate was collected and the volatiles removed in vacuo to give a pale yellow solid. Dichloromethane and water were added and the organic layer separated. The aqueous layer was further extracted with dichloromethane and ethyl acetate. The combined organic extracts were dried (Na2SO4) and the solvent removed in vacuo to give the subtitle product an off white foam (331 mg).
Reaction SMILES: [OH-].[CH2:2]([N+:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1C=[C:35]2[C:37]([O:39]C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)[C:34]2=CC=1)=[O:38].C(O)(=O)C=C>CO>[C:37]([O-:39])(=[O:38])[CH:35]=[CH2:34].[CH2:24]([N+:9]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: C=CC(=O)O
Agent: CCCCCCC[N+](CCCCCCC)(CCCCCCC)CCCCCCC
Agent: [OH-]
Solvent: CO
Product: C=CC(=O)[O-]

Procedure:
The AgOH is resuspended in 400 ml of methanol. Purified tetraalkylammonium iodide (0.1 moles or 53.77 g) (Aldrich Chemical Co., Milwaukee, Wis.) is dissolved separately in 100 ml. of methanol and is added to the AgOH suspension. Almost immediately, the AgOH develops a greenish cast. The mixture is stirred for an hour and then filtered through a sintered-glass funnel. The filtrate now contains 0.1 moles of tetraheptylammonium hydroxide. A small amount of phenophthalein is added, turning the solution red indicating that the solution is basic. Acrylic acid is added until the red color disappears. The methanol is removed by evaporation in a rotary flash evaporator leaving tetraheptylammonium acrylate. The resulting tetraheptylammonium acrylate was found to be electrically conductive.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)cncc1-c1ccc(O)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(-c3cncc(Cl)c3C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 68 %

Procedure:
A mixture of 3-chloro-5-(4-hydroxyphenyl)isonicotinonitrile (50 mg, 0.217 mmol), 4-methoxyphenylboronic acid (132 mg, 0.867 mmol), copper(II) acetate (47.2 mg, 0.260 mmol), pyridine (0.140 mL, 1.734 mmol) and 4 A molecular sieves (300 mg) in dichloromethane (6 mL) was stirred under air at room temperature for 4 days. The mixture was filtered through a CELITE® pad to remove molecular sieves (rinsed with dichloromethane), quenched with saturated ammonium chloride (20 mL) and ammonium hydroxide (2 mL) and extracted with dichloromethane (3×10 mL). The combined extracts were dried (MgSO4) and concentrated. Silica gel chromatography, loading with toluene and eluting with 5-30% ethyl acetate in hexanes, gave 3-chloro-5-(4-(4-methoxyphenoxy)phenyl)isonicotinonitrile as a white solid (49.7 mg, 67% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.72 (1H, s), 8.68 (1H, s), 7.45-7.59 (2H, m), 6.99-7.14 (4H, m), 6.88-6.99 (2H, m), 3.83 (3H, s); MS (ES+) m/z: 337 (M+H); LC retention time: 4.321 min (analytical HPLC Method A).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1.[H-].[Na+].I[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8](=[O:10])[N:7]([CH3:11])[C:6]=2[CH:12]=1
Reactant: CC(C)(C)CI
Reactant: Cn1c(=O)[nH]c2ccc(Br)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(Br)cc21
Reaction time: 0.33 h

Procedure:
A solution of 6-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-4, 500 mg, 2.20 mmol) in DMF (10 ml) was treated with Sodium hydride (176 mg, 4.40 mmol, 2.0 eq) followed by the 1-Iodo-2,2-Dimethylpropane (585 pt, 4.40 mmol, 2.0 eq). The reaction was irradiated at 175 deg C. for 20 min in a microwave. The reaction was complete by LC/MS, so it was partitioned between EtOAc (2×125 ml) and water (150 ml). The combined organic layers were dried over Na2SO4 and concentrated. The crude maroon-orange oil was purified via flash column chromatography (SiO2: 100% Hex to 60:40 Hex:EtOAc), affording the title compound, 5-bromo-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-5), as a yellow solid with >95% purity. 1H NMR (600 MHz, CDCl3) δ 7.18 (dd, 1H, J=Hz), 7.10 (s, 1H), 6.88 (d, 1H, J=Hz), 3.63 (s, 2H), 3.40 (s, 3H), 1.02 (s, 9H). LRMS m/z: Calc'd for C7H7BrN2O2 (M+H) 232.1, found 232.8.