Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][CH3:9])=[O:7].Cl[C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:16]=1[C:22]#[N:23]>C1COCC1.CCOC(C)=O>[Cl:21][C:19]1[CH:20]=[C:15]([NH:3][C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]([NH:8][CH3:9])=[O:7])[C:16]([C:22]#[N:23])=[CH:17][N:18]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: N#Cc1cnc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.3 %

Procedure:
Sodium hydride (2.345 g, 58.64 mmol) was added portionwise to a mixture of 2-amino-N-methylbenzamide (2.201 g, 14.66 mmol), in THF (40 mL) at room temperature under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 30 minutes and then 4,6-dichloropyridine-3-carbonitrile (2.536 g, 14.66 mmol) was added portionwise (caution—exotherm and effervescence); the mixture was then heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (200 mL). The mixture was washed sequentially with water (200 mL), water (150 mL), and finally with a saturated solution of NaCl (200 mL). The organic layer was filtered and the residue washed with water followed by EtOAc and then allowed to dry to leave 2-[(2-chloro-5-cyanopyridin-4-yl)amino]-N-methylbenzamide (0.687 g, 16% yield). The filtrate was dried over MgSO4 and then evaporated to leave a solid. The solid was crystallised from MeOH/Et2O to afford a second crop of 2-[(2-chloro-5-cyanopyridin-4-yl)amino]-N-methylbenzamide (2.471 g, 59% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.76 (3H, t), 7.10 (1H, d), 7.26-7.32 (1H, m), 7.57 (2H, dd), 7.72-7.74 (1H, m), 8.56 (1H, s), 8.68 (1H, d), 10.63 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=286.98 and 288.94.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.N1C=CC=CC=1.[NH2:32][C:33]1[CH:34]=[C:35]([CH:40]([CH:49]2[CH2:51][CH2:50]2)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[CH:37][C:38]=1[Cl:39]>ClCCl>[Cl:39][C:38]1[CH:37]=[CH:36][C:35]([CH:40]([CH:49]2[CH2:51][CH2:50]2)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])=[CH:34][C:33]=1[NH:32][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(c1ccc(Cl)c(N)c1)C1CC1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]([C@H](C(=O)Nc1cc(C(CC(=O)OC(C)(C)C)C2CC2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
45 mg (0.17 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 1 ml of dichloromethane, 36 mg (0.27 mmol) of 1-chloro-N,N,2-trimethylprop-1-ene-1-amine were added and the mixture was stirred at room temperature for 30 min. 411 (0.51 mmol) of pyridine and 50 mg (0.17 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)-3-cyclopropylpropanoate (enantiomer 1; Example 30A), dissolved in 1 ml of dichloromethane, were then added, and the reaction mixture was stirred for another 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product obtained was directly purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 78 mg of the target compound (85% of theory).
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.[C:8]([C:10]1[CH:25]=[CH:24][C:13]([CH:14]=[C:15]([C:21](=O)[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1)#[N:9].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:8]([C:10]1[CH:25]=[CH:24][C:13]([CH:14]2[N:4]3[N:5]=[N:6][N:7]=[C:3]3[NH:2][C:21]([CH3:22])=[C:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1)#[N:9]
Reactant: CCOC(=O)C(=Cc1ccc(C#N)cc1)C(C)=O
Reactant: Nc1nnn[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2nnnn2C1c1ccc(C#N)cc1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, 5-amino-1,2,3,4-tetrazole hydrate (1.0 g, 9.7 mmol) and ethyl 2-(4-cyanobenzylidene)-3-oxobutanoate (2.6 g, 10.7 mmol, 1.1 eq.) were dissolved in DMF (50 ml), and solid sodium bicarbonate (4.1 g, 48.5 mmol, 5 eq.) was added. The mixture was stirred at 55° C. for 12 h. The mixture was then filtered and the DMF from the filtrate was distilled off under reduced pressure. The residue was suspended in ethanol and stirred overnight. The product was filtered off and dried under high vacuum. This gave 950 mg (32% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]#[CH:25])[CH:21]=[CH:22][CH:23]=1>CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:25]#[C:24][C:20]2[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=2)[NH2:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Br)cc1F
Reactant: C#Cc1cccc(N)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Nc1cccc(C#Cc2ccc(F)c(F)c2)c1
Temperature: 65 °C
Yield: 38.5 %

Procedure:
A multinecked flask as described in Example 1 was charged with 5.0 g (0.026 mol) of 3,4-difluorobromobenzene, 50 ml of dried, degassed triethylamine, 3.0 g (0.026 mol) of 3-aminophenylacetylene, 0.07 g (0.1 mmol) of bis(triphenylphosphine) palladium II chloride, 0.1 g (0.38 mmol) of triphenylphosphine, and 0.02 g (0.1 mmol) of cuprous iodide. The reaction mixture was heated at 65° C. for 36 hours at which point gas chromatography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 50 ml of ether. Filtration of the insoluble triethylamine hydrobromide salt by-product followed by concentration of the filtrate gave the crude product (4.2 g, 78% yield) as a off-white solid. Short path distillation of the crude product under reduced pressure gave 2.38 g (0.01 mol, 38% yield) of the purified product as a colorless liquid which crystallized on standing.
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([CH:10]=[N+:11]=[N-:12])([CH3:9])[CH3:8].[CH:13](=[C:20](C#C)[C:21]#[N:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.C(OCC)(=O)C>[C:14]1([C:13]2[C:20]([C:21]#[N:22])=[N:12][NH:11][C:10]=2[Si:7]([CH3:9])([CH3:8])[CH3:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CC(C#N)=Cc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1[nH]nc(C#N)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
n-Butyl lithium (2.7 M solution in heptane) (3.3 ml, 9 mmol) was added drop wise to a stirred solution of trimethylsilyl diazomethane (2 M solution in diethyl ether) (4.5 ml, 9 mmol) in anhydrous THF (10 ml) at −78° C. under a nitrogen atmosphere, then stirred for a further 30 minutes. To this was added drop wise a solution of 2-benzylidene-but-3-yne nitrile (920 mg; 6 mmol) in anhydrous THF (5 ml), the mixture stirred for 30 minutes at −78° C. then gradually allowed to warm to room temperature overnight. The reaction mixture was diluted with ethyl acetate (30 ml) then washed with saturated ammonium chloride solution followed by brine. The ethyl acetate layer was separated, dried (MgSO4), filtered and evaporated. The crude product was purified by flash column chromatography eluting with 1:8 then 1:4 ethyl acetate/hexane and the product containing fractions combined and evaporated to give 1.0 g of 4-phenyl-5-trimethylsilanyl-1H-pyrazole-3-carbonitrile.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:11](=[O:12])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]4)=[CH:15][CH:14]=3)=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:8][C:7]=12.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1>>[O:12]=[C:11]1[C:6]2[C:7](=[C:2]([C:39]3[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=3)[N:3]=[CH:4][CH:5]=2)[O:8][C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:10]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Cl)nccc4c3=O)cc2)CCC1
Reactant: OB(O)c1cccnc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5cccnc5)nccc4c3=O)cc2)CCC1
Yield: 37 %

Procedure:
Following the procedure used to prepare tert-butyl 1-(4-(8-(1-isobutyl-1H-pyrazol-4-yl)-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutyl carbamate, tert-butyl 1-(4-(8-chloro-4-oxo-2-phenyl-4H-pyrano[2,3-c]pyridin-3-yl)phenyl)cyclobutylcarbamate was reacted with pyridine-3-boronic acid to give the title compound (20 mg, 37%). LCMS (Method I): RT=7.45 min, [M+H]+=546.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:26][C:25]2[C:20]([O:19][CH3:18])=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1ncccc1N
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1Nc1cc(Cl)ncn1
Temperature: 90 °C
Yield: 31.5 %

Procedure:
To a solution of 4,6-dichloropyrimidine (660.04 mg, 4.43 mmol) in 1-butanol (10 mL) was added DIPEA (0.67 ml, 4.03 mmol) followed by 2-methoxypyridin-3-amine (500 mg, 4.03 mmol). The reaction mixture was then heated to 90° C. for 2 hr. The reaction mixture was then concentrated in vacuo and partitioned between DCM and water. A precipitate was removed by filtration and the organics extracted (2×20 ml DCM). The combined organic extracts were then washed with 0.5M HCl (5 ml) and then dried (Na2SO4), filtered and concentrated in vacuo to give the title intermediate (300 mg, LC-MS purity=83%); LC-MS: m/z=+236.95/238.90 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(Cl)cc1F)C(=O)OC
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1F
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.80 g), 2-(4-chloro-2-fluorobenzyl)-3-oxopentanoic acid methyl ester (1.4 g), polyphosphoric acid (5 g) and dioxane (10 mL) was heated at 120° C. for 23 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3:7 to 7:10 by volume) to afford title compound, 0.20 g.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10])(=O)C.[H-].[OH-].[Li+]>O1CCCC1.O>[OH:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:6]=1[O:7][CH2:8][CH2:9][OH:10]
Reactant: CC(=O)Oc1cc(F)ccc1OCCO
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OCCOc1ccc(F)cc1O
Temperature: 90 °C

Procedure:
2-(2-Acetoxy-4-fluorophenoxy)ethanol 1.53 g was dissolved in a mixed solvent of tetrahydrofuran 10 ml and water 5 ml, then lithium hydroxide monohydride 294 mg was added thereto, and the mixture was stirred at 90° C. After stirred for 10 hours, the reaction mixture was cooled and partitioned by adding water and ethyl acetate. The organic layer was washed with water and then with brine, dried over magnesium sulfate anhydride and evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), whereby the title compound (1.07 g, 80%) was obtained as a colorless oil.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:2].[Na+].[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:16]1.C(O)(=O)C.C(=O)C>CN(C)C=O>[CH2:1]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([O:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]3)[CH2:16]1)[CH3:2]
Reactant: O=c1[nH]ccc2cc(OC3CCCNC3)ccc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCN1CCCC(Oc2ccc3c(=O)[nH]ccc3c2)C1
Reaction time: 17 h

Procedure:
Sodium triacetoxyborohydride (45 mg, 1.8 mol) was added to a solution of 6-(piperidin-3-yloxy)-2H-isoquinolin-1-one (30 mg, 0.12 mmol), acetic acid (100 μl) and acetaldehyde (50 μl or 50 mg) in N, N-dimethylformamide (500 μl) and shaken for 17 hours. The reaction was quenched with water and methanol and passed down an SCX cartridge. The product was purified by preparative HPLC under basic conditions. The clean products were isolated by evaporation under reduced pressure to give 6-(1-ethyl-piperidin-3-yloxy)-2H-isoquinolin-1-one: El-MS: m/z=273.5[M+H]+.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44]>O1CCCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: NCCCCCc1ccccn1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCCCc2ccccn2)c2ccc(OC)cc2)cc1
Yield: 252.7 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl) -2,4-pentadienoic acid 4-nitrophenyl ester (1.72 g) and 2-pyridinepentanamine (0.657 g) in tetrahydrofuran (25 mL) was stirred for 17 hours at room temperature and was worked up in the usual manner. The crude product was purified by HPLC (ethyl acetate) and then was crystallized from ethyl acetate to provide 4.6 g of (E)-5,5-bis(4-methoxyphenyl)-N-[5-(2-pyridinyl) pentyl]-2,4-pentadienamide, mp 99°-100° C.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][S:17][CH2:16][CH2:15]3)[S:11][C:10]=2[CH2:20][CH3:21])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:24])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([CH:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[S:11][C:10]=1[CH2:20][CH3:21]
Reactant: O=S(Cl)Cl
Reactant: CCc1sc(C2CCSCC2)cc1C(O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1sc(C2CCSCC2)cc1C(Cl)C1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of cyclohexyl[2-ethyl-5-(tetrahydro-2H-thiopyran-4-yl)thiophen-3-yl]methanol (1.91 g) synthesized above in toluene (20 mL) was added thionyl chloride (516 μL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.91 g, 95%) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C.[CH:16](OCC)(OCC)[O:17][CH2:18][CH3:19]>O>[CH2:18]([O:17][C:16]1[NH:11][C:10]2[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=2[N:1]=1)[CH3:19]
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCOc1nc2c(C(=O)O)cccc2[nH]1
Reaction time: 2 h
Yield: 89 %

Procedure:
1.0 g of 2,3-diaminobenzoic acid is dissolved into 20 ml of glacial acetic acid. Triethyl orthoformate (2.1 eq.) is added into the above mixture at temperature of 0° C.; and to stir it for 2 hours at temperature of 0˜5° C.; and 150 ml of water is added into it, and then to isolate and filter to produce 2-ethoxy-1H-benzimidazole-4-formic acid. The yield is about 89%. 2-ethoxy-1H-benzimidzzole-4-formic acid is added into 15 ml of thionyl chloride, and to react for 60 minutes, and after end of the reaction completely, and (L)-2-amino-1-p-nitrophenyl-1,3-propylene glycol (1.1 eq) is added into the reaction mixture under stirring for 2 hours at the room temperature, and then to filter the inorganic salt, and evaporate the solvent to dry, to obtain the final product of (L)-2-ethoxy-1H-benzimidazole-4-[N-(1-hydroxymethyl-2-p-nitrophenylhydroxyethyl)amide. The yield is about 91%. Using the same process to prepare the compounds in Table 3.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].[Cl:10][C:11]1[C:16]([C:17]2[C:22]([F:23])=[CH:21][C:20](F)=[CH:19][C:18]=2[F:25])=[C:15]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:14]=[C:13]([N:32]([CH3:35])[C:33]#[N:34])[N:12]=1>CS(C)=O.C(OCC)(=O)C>[Cl:10][C:11]1[C:16]([C:17]2[C:18]([F:25])=[CH:19][C:20]([O:8][CH2:7][CH2:6][CH2:5][N:4]([CH3:9])[CH3:3])=[CH:21][C:22]=2[F:23])=[C:15]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:14]=[C:13]([N:32]([CH3:35])[C:33]#[N:34])[N:12]=1
Reactant: CN(C)CCCO
Reactant: CN(C#N)c1nc(Cl)c(-c2c(F)cc(F)cc2F)c(NCC(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)CCCOc1cc(F)c(-c2c(Cl)nc(N(C)C#N)nc2NCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of sodium hydride (60% in mineral oil, 12 mg, 0.30 mmol) in 2 mL of dimethylsulfoxide is added 3-dimethylamino-1-propanol (27 μL, 0.23 mmol). The mixture is then stirred at room temperature for 1 h. 4-Chloro-6-[(2,2,2-trifluoroethyl)amino]-5-(2,4,6-trifluorophenyl)pyrimidin-2-yl(methyl)cyanamide (60 mg, 0.152 mmol) is then added, and the reaction mixture is heated at 60° C. for 4 h, and diluted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 50% methyl alcohol in ethyl acetate to methyl alcohol. Concentration provides 4-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl(methyl)cyanamide as a light yellow semisolid solid (20 mg). MS: m/z 479.3(M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[C:10](=O)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:19]([F:30])[CH:18]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[Br:14])[CH:10]([NH:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[C:19]([F:30])[CH:18]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc2c(cc1Br)C(=O)CC2
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1F
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: CC(=O)Nc1cc2c(cc1Br)C(Nc1ccc(C(=O)OC(C)(C)C)c(F)c1)CC2
Temperature: 25 °C
Reaction time: 11 h

Procedure:
To a solution of 5-acetamido-6-bromoindan-1-one (0.370 g, 1.38 mmol) in anhydrous methanol (32 ml) was added tert-butyl 4-amino-2-fluorobenzoate (V. Bavetsias et al, J. Med. Chem. 1996, 39, 73-85; 0.322 g, 1.52 mmol) followed by decaborane (0.030 g). The reaction mixture was stirred at room temperature for 11 hours then more decaborane (0.005 g) was added and stirring was continued for a longer 12 hours under argon. The solvent was removed in vacuo, and the residue was purified by column chromatography eluting with a gradient of ethyl acetate in hexane (30 to 40%). The desired compound was obtained as a white solid: 0.455 g (71%) m.p.>70° C. (softens); 1H-NMR (250 MHz, CDCl3, TMS) 1.57 (s, 9H, C(CH3)3), 2.24 (s, 3H, COCH3), 1.98, 2.56 (2×m, 2H, indanyl 2-H), 2.94 (m, 2H, indanyl 3-H), 4.33(d, J=7.90 Hz, 1H, N—H), 4.99 (q, J=7.06 Hz, 1H, indanyl 1-H), 6.37 (m, 2H, 3,5-H), 7.48, 8.25, 7.60 (3×s, each 1H, indanyl 4-H, 7-H, CONH), 7.72 (t, J=8.75 Hz, 6-H); MS (ESI, mz) 485, 487 {(M+Na)+, bromine isotopic pattern}.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][Si](C)(C)C)[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Li+].[OH-].Cl>CO.O>[CH3:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(O[Si](C)(C)C)ccc1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(O)ccc1C(=O)O
Temperature: 0 °C

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 5.7 g methyl. 2-methyl-4-trimethylsilyloxybenzoate and 2.0 g LiOH in 40 mL methanol and 10 mL water. After 2 hours at reflux the reaction was poured into 10 mL concentrated HCl and then 100 g ice. Extraction with ethyl acetate followed by concentration in vacuo gave a crude solid (70:30) product:starting material. Flash Chromatography using 50-50 ethyl acetate/hexanes as an eluent gave 1.15 g 2-methyl-4-hydroxybenzoic acid, m/e=193(M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].[C:14](=O)([O-])[O-].[Cs+].[Cs+].BrCCl>CN(C=O)C>[CH2:14]1[O:12][C:11]2[C:2](=[C:3]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:13])[CH2:6][CH2:5][CH2:4]3)[O:1]1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCCc2c1ccc(O)c2O
Agent: ClCBr
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1CCCc2c1ccc1c2OCO1
Temperature: 100 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of the product of Example 177 (30 g) in DMF (390 ml) was added cesium carbonate (83 g) followed by bromochloromethane (33 g) and the resulting mixture heated to 100 ° C. and mechanically stirred for 2 hours. The reaction was cooled, filtered and the solids washed with ethyl acetate. The filtrate concentrated and the residue taken up into water and toluene. The layers were separate and the aqueous layer reextracted with toluene. The extracts were combined, dried (MgSO4), filtered, treated with charcoal, refiltered and concentrated to provide 29.9 g of the desired product, m.p. 132°-136° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:42]([O:44][C:45]1[CH:54]=[CH:53][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:47][CH:46]=1)=[O:43]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:42]([O:44][C:45]2[CH:46]=[CH:47][C:48]([C:49]([O:51][CH3:52])=[O:50])=[CH:53][CH:54]=2)=[O:43])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of 220 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.104 mL of triethylamine in 4.0 mL of THF was added 127 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka) at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 264 mg of 4-(methoxycarbonyl)phenyl 4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidine-1-carboxylate in the form of a colorless amorphous substance as a crude product. ESI+: 623