Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1)[CH2:8]2.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=4)[CH2:34][CH2:33]3)[N:14]=1)[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cccc(Br)n1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCN(c3cccc(C(=O)NC4C5CC6CC(C5)CC4C6)n3)CC2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
N-(adamantan-2-yl)-6-bromopicolinamide (55 mg, 0.194 mmol), 1-(4-methoxyphenyl)piperazine (41 mg, 0.213 mmol), Pd2(dba)3 (3.5 mg, 0.00388 mmol), xantphos (6.7 mg, 0.0116 mmol), and sodium-tert-butoxide (27.4 mg, 0.285 mmol) were suspended in toluene (3 ml), and then stirred at 100° C. under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (30% EtOAc/Hexanes), to obtain 64 mg of pale yellow solid (84%). MS (ESI): 447 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[C:7]([CH3:24])[C:6]=2[C:5]([OH:25])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39](=[O:42])[CH2:40]Br>C(OCC)(=O)C>[CH3:37][O:38][C:39](=[O:42])[CH2:40][O:25][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:24])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Cc1ccc(S(C)(=O)=O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(S(C)(=O)=O)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 8-chloro-3-(4-methanesulfonylbenzyl)-2,4-dimethylquinolin-5-ol (0.31 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.46 g) and bromoacetic acid methyl ester (0.35 g) was stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate and this solution washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of toluene, dichloromethane and ethyl acetate (1:1:0 to 0:1:0 and 0:1:1 by volume) gave title compound as a white solid, 0.20 g.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[C:11]([F:14])[C:12]=1[F:13].Br[CH2:20][CH2:21][Cl:22].Cl>CCCCCC.C1COCC1.C(OCC)(=O)C>[Cl:22][CH2:21][CH2:20][CH:15]([C:9]1[CH:8]=[C:7]([F:6])[C:12]([F:13])=[C:11]([F:14])[CH:10]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(O)Cc1cc(F)c(F)c(F)c1
Reactant: ClCCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)C(CCCl)c1cc(F)c(F)c(F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A 2.66 M solution of butyl lithium in hexane (20 mL) was added to a solution of 3,4,5-trifluorophenylacetic acid (5.00 g) in THF (150 mL) in a nitrogen atmosphere at −78° C., and the reaction solution was stirred at −78° C. for 20 minutes. The reaction solution was further stirred at 0° C. for one hour. Then, 1-bromo-2-chloroethane (2.2 mL) was added at 0° C., and the reaction solution was stirred at room temperature for 14 hours. Ethyl acetate and 1 N hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 4.54 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Cl)[CH:13]=2)[N:8]=[C:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[O:25][CH3:26])[CH:6]=1)C=C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[O:25][CH3:26])[CH:6]=[C:5]2[NH2:4])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C=CCNc1cc(NCc2ccc(F)cc2OC)nc2ccc(Cl)cc12
Reactant: NCc1ccccc1
Product: COc1cc(F)ccc1CNc1cc(N)c2cc(NCc3ccccc3)ccc2n1

Procedure:
N4-Allyl-6-chloro —N2-(4-fluoro-2-methoxy-benzyl)-quinoline-2,4-diamine (prepared from (4-bromo-6-chloro-quinolin-2-yl)-(4-fluoro-2-methoxy-benzyl)-amine and allylamine as described in example 40, step A) was coupled with benzylamine as described in example 30, step D. The title compound was obtained as a light brown foam (16%), MS: m/e=403.4 (M+H+).
Reaction SMILES: [CH3:1][CH:2](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]3)[N:12]=2)=[CH:7][CH:6]=1.[C-:39]#[N:40].[Na+]>CN(C=O)C>[CH3:1][CH:2]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]3[CH2:19][C:20]([CH3:27])([CH3:26])[NH:21][C:22]([CH3:24])([CH3:25])[CH2:23]3)[N:12]=2)=[CH:9][CH:10]=1)[C:39]#[N:40]
Reactant: Cc1ccc(S(=O)(=O)OC(C)CCc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C#N)CCc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1

Procedure:
The title compound was prepared from toluene-4-sulfonic acid 1-methyl-3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propyl ester (Step A of Example 196) and NaCN in DMF. Yield 11 mg (72%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[CH:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30](I)[CH3:31].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][N:13]2[C:18]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)([CH2:30][CH3:31])[C:19]([O:21][CH3:22])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(NC(=O)OC(C)(C)C)cccc21
Reaction time: 0.5 h
Yield: 57 %

Procedure:
The compound from step C (1 g, 2.4 mml) and EtI (42 mg, 2.6 mmol) were dissolved in anhydrous DMF (10 mL) Then NaH (144 mg, 3.6 mmol, 60%) was added to the mixture slowly at 0° C. After 30 minutes, the reaction mixture was quenched by saturate NH4Cl (10 mL), extracted with EA, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (PE:EA=20:1 to 5:1 to give the title compound (0.608 g, 57%). LC/MS m/z=444.1[M+H]+. The two enantiomers were separated by SFC chiral separation.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[CH:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=C[C:21]1=[O:30]>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([OH:18])=[C:10]([CH:21]=[O:30])[C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccc2ccccc2[nH]1
Reactant: O=c1cc(O)c2ccccc2n1Cc1ccccc1
Product: O=Cc1c(O)c2ccccc2n(Cc2ccccc2)c1=O

Procedure:
Following the Procedure set forth in Preparation B, 1-benzyl-4-hydroxy-2(1H)-quinolinone was converted to 1-benzyl-3-formyl-4-hydroxy-(2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS (FAB): m/e 370 (M·+ +1); NMR (DMSO): δ5.50 (s, 2H, CH2 --Ar), 10.18 (s, 1H, CHO) ppm.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:11][CH:12]([CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:13]([CH3:15])[CH3:14]>CS(C)=O.ClCCl>[CH:9]([CH:10]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:11][CH:12]([CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:13]([CH3:14])[CH3:15])=[O:8]
Reactant: COCCCc1cn(C)c2ccc(CC(CC(CO)NC(=O)OC(C)(C)C)C(C)C)cc12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCCCc1cn(C)c2ccc(CC(CC(C=O)NC(=O)OC(C)(C)C)C(C)C)cc12
Temperature: 10 °C
Reaction time: 0.67 h

Procedure:
1.27 ml of triethylamine and then (over 20 minutes) a solution of 1.60 g of sulphur trioxide-pyridine complex in 6 ml of dimethyl sulphoxide are added dropwise at 0° C. to the solution of 1.44 g of tert-butyl {1-hydroxymethyl-3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methylpentyl}carbamate in 10 ml of dichloromethane. After 40 minutes, 10 ml of ice-water are added dropwise and the reaction mixture is stirred at 10° C. for a further 10 minutes. The reaction mixture is extracted with dichloromethane (3×)—the combined organic phases are washed successively with 10% aqueous sodium hydrogensulphate solution, water, 10% sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and concentrated by evaporation. The crude title compound is obtained as a yellowish foam from the residue. Rf=0.73 (2:1 EtOAc-heptane). Rt=5.48 (gradient I).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH3:20])=[O:18].Cl>O.O1CCOCC1>[CH3:20][O:19][C:17]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18]
Reactant: NCCCCC(=O)O
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)NCCCCC(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
5-Aminopentanoic acid hydrochloride (2 g, 13 mmol), and potassium carbonate (13 g, 94 mmol) were dissolved in water (30 ml) and dioxane (10 ml) then cooled to 0° C. Methyl chloroformate (5 ml, 65 mmol) was added over 30 seconds, then the mixture was stirred for 2.5 hours at 0° C. Concentrated HCl was added until the mixture became acidic then the mixture was diluted with water and extracted with ether. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 5-[(methoxycarbonyl)amino]pentanoic acid as a white powder (1.5 g).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1(=O)CCN(c2nc(N3CCNCC3)nc3c(SCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(1,1-dioxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 238°-239° C.) and piperazine.
Reaction SMILES: C[O:2][C:3](=[O:20])[C@H:4]([CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([O:17]C)=[CH:12][C:11]=1[CH3:19])[NH:5]C(=O)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[BrH:30]>C(O)(=O)C>[BrH:30].[CH3:16][C:15]1[CH:14]=[C:13]([OH:17])[CH:12]=[C:11]([CH3:19])[C:10]=1[CH2:9][C@@H:4]([C:3]([OH:20])=[O:2])[NH2:5]
Reactant: COC(=O)[C@H](Cc1c(C)cc(OC)cc1C)NC(C)=O
Agent: Br
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(O)cc(C)c1C[C@H](N)C(=O)O

Procedure:
2,6-Dimethyl-(S)-tyrosine hydrobromide was prepared by deprotecting N-acetyl-2,6-dimethyl-O-methyl-(S)-tyrosine methyl ester as follows: In a 100 ml round-bottom flask were placed 18.56 g (66 mmol) of N-acetyl-2,6dimethyl-O-methyl-(S)-tyrosine methyl ester, 0.63 g (3.3 mmol) sodium metabisulfite, 43 ml 48% hydrobromide acid and 21 ml acetic acid. After flushing with nitrogen, the flask was immersed in an oil bath at 120° C. and maintained there for 15 hours. After cooling, the volatiles were removed under reduced pressure at 100° C. to afford a tan solid of the desired product, contaminated with sodium metabisulfite. A sample was derivatized with Marfey's reagent and shown by HPLC analysis to be a 99.7/0.3 mixture of S and R isomers, respectively. 1H NMR analysis indicated: (δ, CD3OD) 6.55 (s, 2H), 4.07 (br t, J=7.5 Hz, 1H), 3.32 (dd, J=7.5 and 14.1 Hz, 1H), 3.15 (dd, J= 7.5 and 14.1 Hz, 1H) and 2.31 (s, 6H). Mass spectrum analysis indicated: 209 (M+), 135 (100%) and 91.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:20](=O)[CH2:21][CH2:22][C:23]#[CH:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[CH2:24]([NH:1][C:2]1([CH2:8][NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)[CH2:23][CH2:22][C:21]#[CH:20]
Reactant: NC1(CNC(=O)OCc2ccccc2)CCOCC1
Reactant: C#CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C#CCCCNC1(CNC(=O)OCc2ccccc2)CCOCC1
Reaction time: 2 h

Procedure:
To a solution of benzyl ((4-aminotetrahydro-2H-pyran-4-yl)methyl)carbamate (G17, 106 mg) and 4-pentynal (34 mg) in methylene chloride (4 mL), sodium triacetoxyborohydride (205 mg) and acetic acid (22 μL) were added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 0% hexane in ethyl acetate) to obtain benzyl ((4-((4-pentyn-1-yl)amino)tetrahydro-2H-pyran-4-yl)methyl)carbamate (G18, 74 mg).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](N)=[O:9])=[C:6]([O:13][CH:14]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]2)[CH:5]=1.Cl.S(Cl)([Cl:23])=O>O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[C:8](=[O:9])[N:16]([CH3:19])[CH2:15][CH:14]([CH2:18][CH2:17][Cl:23])[O:13][C:6]=2[CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CN1CCC(Oc2cc(Cl)ccc2C(N)=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CC(CCCl)Oc2cc(Cl)ccc2C1=O
Yield: 58.9 %

Procedure:
To a solution of 10.4 g (0.26 mole) of sodium hydroxide in 150 ml of water was added 32 g (0.13 mole) of 4-chloro-2-[(1-methyl-3-pyrrolidinyl)oxy]benzamide and the mixture was heated at reflux for 24 hr. The reaction mixture was adjusted to pH 6 with concentrated hydrochloric acid and filtered and the filtrate concentrated. The residue was boiled with 100 ml of isopropyl alcohol and the mixture filtered. The filtrate was concentrated and heated at reflux with 98 g (0.83 mole) of thionyl chloride for 1 hr. The excess thionyl chloride was evaporated under reduced pressure. The residue was dissolved in 70 ml of chloroform and the solvent evaporated under reduced pressure. The residue was redissolved in 75 ml of chloroform and 40 ml of triethylamine was added gradually. The mixture was heated at reflux for 1 hr. The solvent was evaporated under reduced pressure to give a dark-brown solid. The solid was dissolved in ethyl acetate and the resulting solution washed twice with 200 ml of water and twice with 250 ml of 20% sodium hydroxide. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 21 g (59%) of dark-brown solid. The solid was recrystallized from isopropyl alcohol to give the title compound, m.p. 85°-87° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](I)=[CH:9][N:10]([C@H:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:24]([C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=1)#[CH:25].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.[Cu]I.O>[Cl:1][C:2]1[C:7]2[C:8]([C:25]#[C:24][C:26]3[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=3)=[CH:9][N:10]([C@H:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cc(I)c3c(Cl)nccc32)C1
Reactant: C#Cc1cc(OC)cc(OC)c1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C#Cc2cn([C@H]3CCN(C(=O)OC(C)(C)C)C3)c3ccnc(Cl)c23)cc(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
PdCl2(dppf)CH2Cl2 (33 mg) was added to a mixture of the crude product of (S)-tert-butyl 3-(4-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)pyrrolidine-1-carboxylate (180 mg) obtained in Step 2, 1-ethynyl 3,5-dimethoxybenzene (97 mg), copper (I) iodide (15 mg), and triethylamine (1.0 ml) in THF (4.0 ml). After nitrogen purging, the resulting mixture was stirred at 50° C. for 30 minutes. Ethyl acetate and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, amorphous substance (133 mg). Physical properties: m/z [M+H]+ 482.4
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:32]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])(=[O:35])[CH:33]=[CH2:34].C(N(C(C)C)CC)(C)C.CN(C)C=O>CO>[C:37]([O:36][C:32]([CH2:33][CH2:34][N:11]1[CH2:10][CH2:9][N:8]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[N:17]=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:13][CH2:12]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N2CCNCC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)CCN1CCN(c2cc(-c3cccc(C(F)(F)F)c3)nc(C#N)n2)CC1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
4-(Piperazin-1-yl)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt (112 mg), tert-butyl acrylate (49 μl), diisopropylethylamine (59 μl) and dimethylformamide (0.2 ml) were combined and stirred at 45° C. for 16 hrs. After adding methanol, product was purified by using the prep-HPLC to generate 4-[4-(2-tert-butoxycarbonyl-ethyl)-piperazin-1-yl]-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile trifluoroacetic acid salt as a white solid (30 mg).
Reaction SMILES: [CH:1]1([N:7]([CH3:26])[C:8](=[O:25])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH:1]1([N:7]([CH3:26])[C:8](=[O:25])[C:9]2[CH:10]=[CH:11][C:12]([CH:15]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH3:27])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C(=O)c1ccc(Cn2cnc3ccccc32)cc1)C1CCCCC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(c1ccc(C(=O)N(C)C2CCCCC2)cc1)n1cnc2ccccc21
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 11 %

Procedure:
To a stirred solution of N-cyclohexyl-N-methyl 4-(1H-benzimidazylmethyl)benzamide (347 mg, 1 mmol) in dry THF (20 ml) at -78 ° C. was added sodium bis(trimethylsilyl)amide (1.1 ml of 1M solution in THF) under argon. The mixture was left to stir at -78° C. for 40 minutes, a solution of methyl iodide (170 mg, 1.2 mmol) in dry THF (2 ml) was added and the mixture left to warm to ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and brine, the organic layer dried (Na2SO4), concentrated to give a crude product which was purified by column chromatography (flash silica gel, 4% methanol in DCM) to yield N-cyclohexyl-N-methyl 4-(1-(1H-benzimidazyl)ethyl)benzamide (40 mg, 11%) as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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]([C:4]1[CH:9]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12])=[O:13]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)cc(C)c1N
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: COCCOC
Product: COC(=O)c1cc(-c2ccccc2)cc(C)c1N
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a solution of 5.0 g (0.021 mol) of 2-amino-5-bromo-3-methyl-benzoic acid methyl ester and 2.8 g (0.023 mol) of phenyl boronic acid in 150 mL of dimethoxyethane was added 20.5 mL of a 2.0M aqueous solution of Na2CO3 and 1.18 g (1.02 mmol) of Pd(PPh3)4. The reaction mixture was evacuated and filled with N2 three times and was then heated to reflux overnight. The reaction was then cooled to room temperature, and poured into ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel using gradient elution (100% hexane to 4/1 hexane/ethyl acetate) to provide 2.5 g (50%) of 4-amino-5-methyl-biphenyl-3-carboxylic acid methyl ester. Electrospray Mass Spec: 241.8 (M+H)+
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].FC1C=C([Br:32])C=CC=1C(O)=O>>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([Br:32])[CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CCOP(=O)(C=C1NCCN(C)c2ccccc21)OCC
Product: CCOP(=O)(C=C1NCCN(C)c2cc(Br)ccc21)OCC

Procedure:
(8-bromo-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester was prepared in an analogous fashion to (1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester, prepared in Example 1, by replacing 2-fluorobenzoic acid with 2-fluoro-4-bromobenzoic acid.