Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH3:2].[C:12]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:39])=[C:25]([NH:27][C:28](=[O:38])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[NH2:37])[CH:26]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:39])=[C:25]([N:27]2[C:28](=[O:38])[C:29]3[C:30](=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[N:37]=[C:1]2[CH3:2])[CH:26]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccccc3)ccc2Cl)c(N)c1
Reactant: CCOC(C)(OCC)OCC
Product: COc1ccc2c(=O)n(-c3cc(NC(=O)c4ccccc4)ccc3Cl)c(C)nc2c1
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 1, triethyl orthoacetate was reacted with N-(5-benzamido-2-chlorophenyl)-2-amino-4-methoxybenzamide. The material so obtained was purified by column chromatography on an isolute SCX ion exchange column using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound in 27% yield; NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 3.91 (s, 3H), 7.09–7.14 (m, 2H), 7.46–7.6 (m, 3H), 7.71 (d, 1H), 7.87–8.06 (m, 5H), 10.57 (s, 1H); Mass Spectrum: M+H+420 and 422.
Reaction SMILES: [O:1]([CH2:9][CH:10]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][C:13]#N)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.C[OH:29].Cl>C1(C)C=CC=CC=1.CCOCC>[O:1]([CH2:9][CH:10]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][CH:13]=[O:29])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CCCC(CCC#N)CO[Si](C)(C)C(C)(C)C
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCC(CCC=O)CO[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 3.25 h
Yield: 81.4 %

Procedure:
To a solution of 12.15 g (47.6 mmol) of 4-(t-butyldimethylsiloxymethyl)heptanenitrile in 120 mL of toluene at -70° C., under argon, was added 35.3 mL (53.0 mmol) of a 1.5 M solution of diisobutylaluminum hydride in toluene. After stirring at -70° C. for 3.25 hr, 36.5 mL of methanol was added and the mixture was poured into a mixture of ca. 200 mL of ether, ca. 100 g of ice and 214 mL of 3N hydrogen chloride solution. The aquenous layer was separated and extracted with 3×200 mL of ether. The combined organic layers were washed with 120 mL of saturated sodium bicarbonate solution and 120 mL of saturated brine (a gelatinous precipitate, which resulted on washing with saturated brine, was removed by filtration through celite prior to separation of the aqueous layer), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel to give 10.01 g (81.4%) of crude 4-(t-butyldimethylsiloxymethyl)heptanal; TLC (SiO2, 1:9 ethyl acetate:hexane) Rf 0.55 (PMA); IR (chloroform): μmax 1719 (adehyde C=O) cm-1.
Reaction SMILES: C([O:4][C:5]1[C:6]([S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][C:5]1[C:6]([S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)CSc1ncccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)CSc1ncccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
A mixture of 0.48 g of 3-acetoxy-2-(methoxycarbonyl)methylthiopyridine, 0.15 g of potassium carbonate, and 3 ml of methanol was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.26 g of 3-hydroxy-2-(methoxycarbonyl)methylthiopyridine.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:27]=[C:28]=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28](=[O:29])[O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]2([CH3:19])[CH3:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC1(C)CN(Cc2ccccc2)c2ccc(O)cc21
Product: CC1(C)CN(Cc2ccccc2)c2ccc(OC(=O)NCc3ccccc3)cc21

Procedure:
The title compound was synthesized from 1-benzyl-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with benzylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (10.3 mg, 36%) having the following characteristics.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)(=O)C.[Cl-].[Na+]>C1COCC1>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]([CH:10]=1)[NH:4][CH2:1][CH3:2]
Reactant: CC(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNc1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 40.6 %

Procedure:
Under ice cooling, the solution of N-acetyl-5-chloro-2-nitroaniline (3 g) in THF (30 ml) was added dropwise to the suspension of LiAlH4 (0.53 g) in THF (50 ml) over 30 minutes. The mixture was stirred under ice cooling for 1 hour. Into the resulting reaction solution was added ice with caution, followed by addition of ethyl acetate and saturated sodium chloride solution, and then insoluble materials was filtered off. The ethyl acetate layer was separated, washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified by chromatography on a silica gel column (hexane:ethyl acetate =19:1), to give the title compound (1.14 g; 41%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].[Br:27]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@:14]2([Br:27])[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@]2(Br)C(C)=O)C1

Procedure:
3α-Acetoxy-5α-pregnan-20-one (3 g, 360.5 g/m, 8.3 mmol), N-bromosuccinimide (2.7 g, 178 g/m, 15 mmol), and benzoyl peroxide (200 mg, 242 g/m, 0.83 mmol) dissolved in 50 ml of carbon tetrachloride were refluxed overnight (ca. 16h). The reaction mixture was cooled, filtered, and washed with sodium bisulfite, water, and brine, and then concentrated to give a crude reddish oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([OH:10])(=[O:9])=[O:8])=[C:5](Cl)[N:4]=[CH:3]1.[H][H]>O.[Pd]>[CH3:1][N:2]1[C:6]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:5][N:4]=[CH:3]1
Reactant: [H][H]
Reactant: Cn1cnc(Cl)c1S(=O)(=O)O
Agent: [Pd]
Solvent: O
Product: Cn1cncc1S(=O)(=O)O

Procedure:
A solution of 3.1 g (17 mmol) of 1-methyl-4-chloro-5-imidazolesulfonic acid from Example 5 in 100 ml of water is hydrogenated to constant pressure at 25° C. in the presence of 0.5 g of Pd/C catalyst with shaking at an initial pressure of 3.45 bar of hydrogen. The crystalline residue remaining after filtering off the catalyst and evaporating the water in vacuo is recrystallized from ethanol in order to give the title compound of melting point 286°-287° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:14](=[O:15])[NH:13][C:12]([CH3:16])=[N:11][C:10]=2[CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][C:3]=1[C:20]1[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=1.[CH:28]([O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:30])[CH3:29].N1C=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:14](=[O:15])[N:13]([C:35]3[CH:36]=[CH:37][C:32]([O:31][CH:28]([CH3:30])[CH3:29])=[CH:33][CH:34]=3)[C:12]([CH3:16])=[N:11][C:10]=2[CH2:17][CH2:18][CH3:19])[CH:5]=[CH:4][C:3]=1[C:20]1[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)c(F)c1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1nc(C)n(-c2ccc(OC(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
A mixture of 2′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g), (4-isopropoxyphenyl)boronic acid (0.51 g), copper acetate (0.5 g), pyridine (1.1 mL), triethylamine (1.9 mL), molecular sieves 4 A (2.0 g) and methylene chloride (10 mL) was stirred at room temperature for 24 hr. Ethyl acetate was added to the reaction mixture, and the insoluble solid was filtered off. The solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.94 g, 69%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([C:17]#[C:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Br:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[C:6]2[CH:17]=[C:18]([C:19]([CH3:22])([CH3:21])[CH3:20])[O:16][C:7]=2[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][C:14]=1[Br:15])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Br)c(NC(C)=O)c(C#CC(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)c(NC(C)=O)c2cc(C(C)(C)C)oc12
Temperature: 25 °C
Yield: 81.5 %

Procedure:
Methyl 4-acetylamino-5-bromo-3-(3,3-dimethyl-1-butynyl)salicylate (I-250) (202 mg, 0.55 mmol) was dissolved in a mixed liquid of triethylamine (4 ml) and toluene (10 ml), and stirred with heating under reflux for 2 hours. After cooling to room temperature, the reaction liquid was concentrated under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane/ethyl acetate (2:1) gave the entitled compound (165 mg, 82%) as a white solid.
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)=[O:45])=[CH:40][C:39]=1[N+:58]([O-])=O>>[NH2:58][C:39]1[CH:40]=[C:41]([S:44]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)=[O:45])[CH:42]=[CH:43][C:38]=1[NH2:37]
Reactant: Nc1ccc(S(=O)c2ccc(-c3ccccc3)cc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1ccc(S(=O)c2ccc(-c3ccccc3)cc2)cc1N
Yield: 95 %

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of 4-(4-amino-3-nitrophenylsulfinyl)-biphenyl, the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:16]=[CH2:17].O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[CH2:8][C:9](=[O:10])[CH2:17][CH2:16]2
Reactant: C=C
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C1CCc2cc(F)ccc2C1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
p-Fluorophenylacetyl chloride (17.25 g) in dichloromethane (100 ml) was added dropwise to aluminium chloride (26.7 g) suspended in dichloromethane (400 ml) maintained at -10° C. by cooling in a solid carbon dioxide/acetone bath. Ethylene gas was then passed through the mixture for 15 minutes while maintaining the temperature at -10° C. The mixture was then allowed to warm to room temperature and stirred for 3 hours. The mixture was then cooled to 5°-10° C. and ice and water (160 ml) added cautiously with stirring over a period of 45 minutes. The dichloromethane was then separated and washed successively with dilute hydrochloric acid, (150 ml×2), sodium bicarbonate solution (150 ml×2) and brine. The dichloromethane was then dried and evaporated. The residue was distilled to give 6-fluoro-2-tetralone (12.81 g) with a boiling range of 68°-76° C./0.05 Torr. The distillatte crystallised on standing.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCCC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 56.3 %

Procedure:
Beginning with 0.30 gm (1.3 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.165 mL (1.56 mMol) butyryl chloride, 0.22 gm of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. This residue was crystallized from ethanol:water to provide material for analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[C:22]([CH:23]=CC)=[CH:21][CH:20]=[C:19]([Cl:26])[C:18]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH:14]=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:14]=[CH:23][C:22]3[C:17](=[C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[C:19]([Cl:26])=[CH:20][CH:21]=3)[O:16]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1c(C=CC)ccc(Cl)c1-c1ccccc1Cl
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccc(Cl)c(-c4ccccc4Cl)c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a solution of (2R)-2-(2′,6-dichloro-3-(prop-1-enyl)biphenyl-2-yloxy)but-3-enyl 4-methylbenzenesulfonate (3.0 g, 5.96 mmol) in 1,2-dichloroethane (60 mL) was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (1.5 g, 1.82 mmol) and the resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 2.15 g (78%) of ((2R)-7-chloro-8-(2-chlorophenyl)-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate as an off-white solid. MS (ESI) m/z 460.9 ([M+H]+); m/z 477.9 ([M+NH4]+).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:23]1[NH:24][N:25]=[N:26][C:22]=1[C:20]1[CH:19]=[CH:18][C:17]2[N:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[N:7]=[C:3]([S:2][CH3:1])[S:4][C:5]=4[CH:11]=3)[CH:14]=[N:15][C:16]=2[CH:21]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(C#N)ccc43)cc2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cc(-c5nn[nH]n5)ccc43)cc2s1
Temperature: 125 °C
Yield: 99.9 %

Procedure:
A suspension of 1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (694 mg, 2.1 mmol), sodium azide (403 mg, 6.3 mmol), and ammonium chloride (331 mg, 6.3 mmol) in DMF (3 mL) was heated in a sealed tube at 125° C. for 15 h. The mixture was cooled to rt and a precipitate formed. The solid was collected by filtration to afford 6-((5-(2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (796 mg, 100%) as a yellow solid that did not require further purification. 1H NMR (500 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.19 (s, 1H), 8.02 (s, 1H), 7.88 (dd, J=1.0, 8.4 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.45 (dd, J=1.4, 8.5 Hz, 1H), 7.15-7.30 (br s, 2H), 5.60 (s, 2H), 2.76 (s, 3H); LCMS (ESI) m/z 380 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23].C(OC(O)C)C>N1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(N)cc1OC
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Solvent: c1ccncc1
Product: COc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)cc1OC
Yield: 65.3 %

Procedure:
A mixture of 1.0 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 1.22 g of 3,4-dimethoxyaniline, 0.32 ml of pyridine, and 12 ml of ethoxyethanol was stirred, under nitrogen, at reflux temperature for 5 h. The mixture was cooled and partitioned with dichloromethane and aqueous sodium bicarbonate. The organic layer was washed with water, dried and evaporated. The residue was recrystalized from ethyl acetate to give 0.96 g of 4-[(3,4-dimethoxyphenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile as a solid, mp 230-240° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>CS(C)=O.[Cu]>[F:16][C:10]([F:17])([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Fc1ccc(Br)nc1
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)c1ccc(F)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
To a mixture of 2-bromo-5-fluoropyridine (2 g, 11.36 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.6 mL, 12.5 mmol) in DMSO (4 mL) was added copper powder (1.6 g, 24.98 mmol) and the mixture was stirred at 50° C. overnight in a sealed flask. The mixture was diluted with DMSO (10 mL) and filtered through Celite. Then water and EtOAc were added and the mixture was shaken and again filtered through Celite. The organic layer was washed with water (1×) and brine (1×) and dried over sodium sulfate, and concentrated to afford ethyl 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate as a yellow oil (1.5 g, 60%). 1H NMR (300 MHz, CDCl3) δ 1.34 (t, 3H), 4.38 (q, 2H), 7.56 (dt, 1H), 7.77 (dd, 1H), 8.50 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.C(=[NH:30])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl>C1(C)C=CC=CC=1.O1CCCC1.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]>[NH2:30][C:2]1[CH:3]=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)cc2c1OCC2(C)C

Procedure:
Following general procedure D and using 5-bromo-7-t-butyl-3,3-dimethyl-2,3-dihydro-benzofuran (Compound 10, see J. Med. Chem. 1998, 41, 1124-1137; 2.0 g, 5.5 mmol), benzophenone imine (1.2 g, 6.64 mmol), sodium-tert-butoxide (0.74 g, 7.75 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.025 g, 0.026 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.050 g, 0.078 mmol) in 10 mL of anhydrous toluene, followed by hydrolysis of the intermediary imine with 2M hydrochloric acid in tetrahydrofuran, the title compound was obtained as an oil (0.95 g, 72%). 1H NMR (300 MHz, CDCl3): δ 6.49 (d, 1H, J=2.4 Hz), 6.39 (d, 1H, J=2.4 Hz), 4.17 (s, 2H), 3.38 (br s, 2H), 1.37 (s, 9H), 1.32 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18](O)=O.ClCCl.[OH-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:18]([CH2:17][O:16][C:15]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:14]=3[Cl:13])=[N:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2[nH]c(COc3ccc(Cl)cc3Cl)nc2c1
Temperature: 160 °C
Yield: 76.6 %

Procedure:
A mixture of 3,4-diamino-benzoic acid methyl ester (105.24 mg, 0.63 mmol) and 2,4-dichlorophenoxy acetic acid (100 mg, 0.45 mmol) in PPSE (1.5 mL) was heated at 160° C. for 4 h. At the end of the reaction period, the mixture was taken to 3 mL dichloromethane and neutralized with 4.5 mL 1 N NaOH solution. The organic layer was separated and the aqueous solution extracted with 3×3 mL portions of dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (EtOAc:Hexanes=1:1) to afford 2-(2,4-dichloro-phenoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester as a colorless powder (0.121 g, 52% yield).
Reaction SMILES: Br[C:2]1[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]2[CH:5]=[C:6]([Cl:16])[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]=2[C:10]=1[CH3:11].[CH3:20][N:21]([CH2:23][B-](F)(F)F)[CH3:22].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.CCOC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:16][C:6]1[CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:10]([CH3:11])=[C:2]([CH2:20][N:21]([CH3:23])[CH3:22])[N:3]([CH:17]([CH3:19])[CH3:18])[C:4]=2[CH:5]=1
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)c(Br)n2C(C)C
Reactant: CN(C)C[B-](F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)cc2c1c(C)c(CN(C)C)n2C(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 48.1 %

Procedure:
To a stirred mixture of methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (1.0 g, 2.90 mmol), potassium ((dimethylamino)methyl)trifluoroborate (0.5 g, 3.03 mmol) and Potassium phosphate (1.9 g, 8.95 mmol) (purged with N2)) in dioxane (3 mL) and water (3 mL) was added palladium(II) acetate (25 mg, 0.111 mmol) and sPhos (90 mg, 0.219 mmol). The reaction was heated to 100° C. and stirred for 18 hr under N2. LCMS showed that the reaction was complete. The reaction was diluted with EtOAc and water, and filtered to remove insolubles. The EtOAc phase was removed, dried (Na2SO4), filtered, and concentrated under vacuum. The crude was purified by silica gel chromatography (Analogix, SF25-40 g, 0 to 2% (5% NH4OH/MeOH) in CH2Cl2). The product fractions were combined, evaporated to dryness under vacuum to give the product methyl 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylate (0.45 g, 1.394 mmol, 48.0% yield) as a light yellow oil (Only 84% pure by LCMS). This was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ=7.82 (d, J=1.8 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 4.96 (dt, J=7.1, 14.1 Hz, 1H), 3.88 (s, 3H), 3.52 (s, 2H), 2.17 (s, 3H), 2.16 (s, 6H), 1.53 (d, J=7.1 Hz, 6H). MS (ES)+m/e 323.2 [M+H]+, 278.1 [M+H]+ −45 (HNMe2).