Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:15]([CH3:16])=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10]C(C)C)=[O:9])=[C:4]([CH3:17])[C:3]=1[NH:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:23]=[CH:22][C:21]=1[F:33].[Li+].[OH-].O>C1COCC1>[F:1][C:2]1[C:15]([CH3:16])=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:17])[C:3]=1[NH:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH:23]=[CH:22][C:21]=1[F:33]
Reactant: Cc1cc(OCC(=O)OC(C)C)c(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCC(=O)O)c(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of isopropyl 2-[4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methyl amino]-2,5-dimethyl-phenoxy]acetate (130 mg, 0.28 mmol, 1.0 eq) in THF (2 mL) was added LiOH (2M aqueous solution, 2 mL, 4 mmol, 14 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Water was added and THF was removed under reduced pressure. The aqueous layer was washed with MTBE and the organic extract was discarded. The aqueous layer was adjusted to pH 3-4 by addition of 3M HCl and then extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The crude product was recrystallized from CH2Cl2 (1 mL) and petroleum ether (3 mL) to give the target compound as an off-white solid (85 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:17]([F:16])[CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Nc1cccc(F)c1
Reactant: O=C1CCCc2c1[nH]c1ccc(Br)cc21
Product: Fc1cccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)c1

Procedure:
6-Bromo-N-(3-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (100 mg, 0.38 mmol) and 3-fluoroaniline (84 mg, 0.76 mmol) in a similar manner as described above to give 17 mg (12%) of a white solid; 1H-NMR (DMSO-d6): δ 11.08 (s, 1H), 7.56 (s, 1H), 7.23 (d, 1H), 7.14-7.04 (m, 2H), 6.53-6.48 (m, 2H), 6.36-6.26 (m, 2H), 4.78-4.76 (m, 1H), 2.69-2.53 (m, 2H), 2.00-1.85 (m, 2H), 1.81-1.76 (m, 2H); MS m/z (M+1) 357, 359.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2Cl)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[N:17]=[C:16]2[O:5][CH2:4][C:3]#[CH:2])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Solvent: c1ccncc1
Product: C#CCOc1nc(C(F)(F)F)c(F)c(=O)n1-c1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-5-[2-chloro-5-fluoro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and propargy alcohol with pyridine there is obtained isopropyl 2-chloro-4-fluoro-5-[5-fluoro-6-oxo-2-(2-propynyloxy)-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz): 7.85 ppm (d,1H), 7.43 ppm (d,1H), 5.27 ppm (m,1H), 5.01 ppm (d,2H), 2.54 ppm (t,1H), 1.39 ppm (d,3H), 1.38 ppm (d,3H);
Reaction SMILES: [CH2:1]([C:3]1[C:15]([N+:16]([O-])=O)=[CH:14][C:6]2[N:7]3[CH2:13][CH2:12][CH2:11][N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1)[CH3:2].[H][H]>[Pt].C(O)(=O)C>[CH2:1]([C:3]1[C:15]([NH2:16])=[CH:14][C:6]2[N:7]3[CH2:13][CH2:12][CH2:11][N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(cc1[N+](=O)[O-])N1CCCN=C1S2
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Product: CCc1cc2c(cc1N)N1CCCN=C1S2

Procedure:
A mixture of 5.26 parts of 8-ethyl-3,4-dihydro-7-nitro-2H-pyrimido[2,1-b]benzothiazole and 100 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 1 part of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is acidified with 2-propanol, saturated with gaseous hydrogen chloride. The precipitated product is filtered off and dissolved in 200 parts of water. The solution is alkalized with ammonium hydroxide. The precipitated product is filtered off, washed with water and crystallized from 2-propanol, yielding 2.2 parts of 8-ethyl-3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-amine; mp. 209.9° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1>C(O)C1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:22][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)Cc1ccccc1O
Solvent: OCc1ccccc1
Product: O=C(Cc1ccccc1O)OCc1ccccc1
Yield: 4264.7 %

Procedure:
A suspension of 22.6 g of 2-hydroxyphenylacetic acid, 0.5 g of paratoluenesulphonic acid in 15.5 cm3 of benzyl alcohol is heated at reflux for three hours. 2 g of 3S active carbon are added, the suspension is filtered over Supercel, and the filtrate is evaporated to dryness under reduced pressure (2.7 kPa). 30 g of benzyl [(2-hydroxy)phenyl]acetate are obtained in the form of crystals. M.p.K =104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(Cl)Cc1ccccc1
Product: COc1ccc(CCNC(=O)Cc2ccccc2)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine with phenyl acetyl chloride.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:10]=[CH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[CH2:11](Br)[CH:12]=[CH2:13]>CN(C=O)C>[CH2:13]([N:3]1[CH:10]=[CH:9][C:7](=[O:8])[NH:6][C:4]1=[O:5])[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1ccc(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
2.5 g (104 mmol, 80% suspension) of NaH was added to a suspension of 10.5 g (93 mmol) uracil in 100 ml DMF and the reaction allowed to continue for 2 hours at room temperature. After 2 hours 10.73 mL (15 g, 123 mmol) allylbromide was added and the mixture heated for 2 hours at 70° C. The solvent was removed under reduced pressure and the residue treated with methylene chloride. The residue from the methylene chloride extract was a mixture of mono-allyl- and di-allyl-uracil. 5.5 g (39%) of 1-allyluracil was isolated by preparative column chromatography, using chlormoform/methanol 40:1 as eluant (m.p. 108–109° C., Lit. 105–109° C., Beilstein).
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][C:11]#[CH:12])[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH2:25].Cl>O1CCCC1>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][C:11]#[CH:12])[CH:8]=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCC(C#N)(c1ccccc1)c1ccccc1
Reactant: O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C#CCC(C=O)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 2,2-diphenyl-2-(2-propynyl)acetonitrile (1.38 g) and lithium aluminum hydride (0.21 g) in tetrahydrofuran (15 ml) was refluxed for 2 hours. The reaction mixture was poured into cold water, acidified with hydrochloric acid and extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of n-hexane and benzene (1:1) as an eluent to give 2,2-diphenyl-2-(2-propynyl)acetaldehyde (0.46 g).
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:25])[C:21]([F:24])([F:23])[F:22])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CCOCC.C(Cl)Cl>[CH2:1]([N:8]([CH3:26])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)C(F)(F)F
Reaction time: 3 h
Yield: 50.8 %

Procedure:
A mixture of (1RS)-1-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl) propanoyl]pyrrolidin-2-yl]-2,2,2-trifluoroethanol (103 mg), Dess-Martin reagent (435 mg) and methylene chloride (1.5 ml) was stirred for 3 hrs. at room temperature. After reaction, the raction solution was diluted with ether. The diluted solution was added dropwise to a saturated aq. solution of sodium bicarbonate (30) wherein sodium thiosulfate (3.0 g) was dissolved. The mixture was stirred for 10 mins at room temperature. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (hexane - EtOAc) to give the title compound (52 mg) having the following physical data:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:19]=[O:20])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([Mg]Br)#[CH:22].O.CCOCC>O1CCCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:19]([OH:20])[C:21]#[CH:22])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C#C[Mg]Br
Reactant: COc1cccc(-c2nc3c(Cl)cccn3c2C=O)c1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C#CC(O)c1c(-c2cccc(OC)c2)nc2c(Cl)cccn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a cold (−78° C.) solution of 8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridine-3-carbaldehyde (1.06 g, 3.70 mmol) in tetrahydrofuran (20 mL) was added ethynyl magnesium bromide (18.53 mL, 0.5 M in tetrahydrofuran, 9.26 mmol). After 15 minutes, the resulting mixture was allowed to warm to room temperature and stirred an additional 30 minutes. Water was added and then ether. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (1:1 hexanes-ethyl acetate to 100% ethyl acetate) provided 1-[8-chloro-2-(3-methoxyphenyl)imidazo[1,2-α]pyridin-3-yl]-2-propyn-1-ol (910 mg, 79%) as a white solid. 1H NMR (CDCl3): δ 8.61 (d, 1 H), 7.33–7.26 (m, 2 H), 7.16–7.11 (m, 2 H), 6.88 (m, 1 H), 6.79 (m, 1 H), 6.14 (m, 1 H), 3.85 (s, 3 H), 3.27 (broad, 1 H), 2.64 (d, 1 H); 13C NMR (CDCl3): δ 159.64, 144.46, 134.12, 129.56, 124.99, 124.51, 123.03, 121.37, 119.43, 114.54, 114.13, 111.81, 111.27, 79.96, 75.03, 55.88, 55.38; MS m/z 313 (M+1); Anal. Calcd. for C17H13ClN2O2: C, 65.29; H, 4.19; N, 8.96. Found: C, 65.23; H, 4.34; N, 8.81.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:10]=1)=[O:5].[CH3:21][Mg]Br>C1COCC1>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:9]2[CH:10]=[C:6]([C:4](=[O:5])[CH3:21])[N:7]=[N:8]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(Cn2cc(C(=O)N(C)OC)nn2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(Cn2cc(C(C)=O)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.3 %

Procedure:
To a solution of N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-1,2,3-triazole-4-carboxamide (8.0 g, 0.03 mol) in anhydrous THF (75 mL) was added dropwise methyl magnesium bromide (3.0 M in hexane, 20 mL, 0.058 mol) at 0° C. After the addition, the mixture was stirred at RT overnight. The mixture was quenched with sat. aq. NH4Cl (30 mL) then extracted with CH2Cl2 (3×50 mL). The organics were combined, washed with 1 N aq. NaOH (3×20 mL), water (3×20 mL), brine (50 mL), dried over MgSO4 and evaporated to yield the title compound (8.0 g, 75.0%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]([CH3:19])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1)O.S(=O)(=O)(O)O>ClCCl>[Cl:24][C:22]1[CH:21]=[C:20]2[C:3](=[C:2]([Cl:1])[CH:23]=1)[CH2:4][N:5]([CH3:19])[CH2:6][CH:7]2[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1
Reactant: CC(=O)Nc1ccc(C(O)CN(C)Cc2ccc(Cl)cc2Cl)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)cc1
Temperature: 0 °C

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of N-(4-(2-((2,4-dichlorobenzyl)(methyl)amino)-1-hydroxyethyl)phenyl)acetamide (500 mg, 1.36 mmol, 1.00 equiv) in dichloromethane (3 mL). This was followed by the addition of sulfuric acid (3 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 5 h at 0-5° C. The reaction was then quenched by the addition of 20 mL of water/ice. The pH value of the solution was adjusted to 7-8 with sodium hydroxide. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10-1:5). This resulted in 25 mg (5%) of N-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)acetamide as a white solid. 1H-NMR (300 HMz, CDCl3, ppm): δ 7.46-7.49 (2H, d, J=8.4 Hz), 7.23-7.29 (1H, m), 7.12-7.15 (2H, d, J=8.4 Hz), 6.80 (1H, s), 4.314 (1H, s), 3.92 (1H, d), 3.58-3.63 (1H, d), 3.06 (1H, s), 2.61-2.68 (1H, m), 2.57 (3H, s), 2.20 (3H, s). MS (ES, m/z): 349 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH3:31])[N:23]=3)=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: COc1ccc(-c2ccc(-c3nc(CCN4CCC[C@H]4C)c(C)o3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 4-methoxybenzene boronic acid (218 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 61 mg (56%). MS (m/e) 377.2 (M+1)
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:5][C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:9]2[C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]=1)[CH3:4].[CH3:34]I.O>CN(C=O)C>[CH2:3]([N:5]([CH3:34])[C:6]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:16][CH:17]=2)[C:9]2[C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:28]=[CH:29][C:8]=2[N:7]=1)[CH3:4]
Reactant: CI
Reactant: CCNc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C)c1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 82 %

Procedure:
A mixture of sodium hydride (60% dispersion in mineral oil, 0.13 g) in DMF (5 ml) was stirred under ice-cooling for 5 min. and methyl 2-ethylamino-1-[(2′-cyanobiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (0.95 g) was added to the mixture, followed by stirring for 10 min. To the mixture was added methyl iodide (0.2 ml) and the mixture was stirred for 20 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give crude crystals, which were recrystallized from ethyl acetate-hexane to afford colorless needles (0.88 g, 82%), m.p. 66-69° C.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25]C=C[CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1.FC1C(F)=CC2C3C(C(=O)N(C4C=C[S:44]C=4)N=3)=CNC=2C=1.N1CCNCC1>>[F:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][S:44][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1
Reactant: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccsc1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Agent: C1CNCCN1
Product: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccsc1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27d and piperazine. 1H-NMR (DMSO-d6) δ (ppm): 2.92 (4H, brm), 3.05 (4H, brm), 7.21 (1H, m), 7.58 (1H, m), 7.79 (3H, m), 8.67 (1H, m). m/z 370.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].N1C=CC=CC=1.[Cl:19][CH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([CH2:20][Cl:19])[CH:22]=1
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Amino-5-chloro-benzoic acid methyl ester (1.5 g) was dissolved in anhydrous methylene chloride (25 ml). Pyridine (1.4 ml) and 3-(chloromethyl)benzoyl chloride (1.4 ml) were added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was then washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure to precipitate crystals. The precipitated crystals were collected by filtration through Kiriyama Rohto and were washed with ether to give 5-chloro-2-(3-chloromethyl-benzoylamino)-benzoic acid methyl ester as a useful intermediate (2.4 g, yield 90%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:6]=1.[Cl:16][C:17]1[C:18]([CH3:27])=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[Cl:16][C:17]1[C:18]([CH3:27])=[C:19]([S:23]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=3)[N:6]=2)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1

Procedure:
The title compound was prepared from 2-amino-4-(-3-nitrophenyl)thiazole and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (36.0 mg) with purity >90%. MS (pos) m/z 410.0.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][NH:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:42][C@H:43]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH3:44]>ClCCl.C(OCC)(=O)C>[NH:1]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C@H:2]([C:12]([NH:42][C@H:43]([C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH3:44])=[O:14])[CH2:3][NH:4][C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6]
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Cbz-Dap(Boc)-OH (0.41 g, 1.2 mmol) was treated with a mixture of 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide methiodide (0.374 g, 1.26 mmol) and N-hydroxybenzotriazole (0.17 g, 1.26 mmol) in N-methylmorpholine (0.28 mL, 2.1 mmol) in dichloromethane. H-Ala-OBn (0.26 g, 1.2 mmol) was added to the above solution and the resulting mixture was stirred for 14 h at room temperature, then diluted with ethyl acetate (40 mL). The organic solution was washed with 10% aqueous citric acid solution (2×30 mL), saturated aqueous sodium bicarbonate solution (2×30 mL) and brine (2×30 mL). The organic layer was dried over magnesium sulfate and then concentrated in vacuo. The crude compound (247) (0.51 g) was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[C@H:13]([O:18][CH3:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([N:25]2[CH2:31][C:30]([F:33])([F:32])[C:29](=[O:34])[N:28]([CH3:35])[C:27]3[CH:36]=[N:37][C:38]([NH:40][C:41]4[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][C:42]=4[O:50][CH3:51])=[N:39][C:26]2=3)[CH2:24][CH2:23][CH2:22][CH2:21]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:45](=[O:46])[C:44]2[CH:48]=[CH:49][C:41]([NH:40][C:38]3[N:37]=[CH:36][C:27]4[N:28]([CH3:35])[C:29](=[O:34])[C:30]([F:32])([F:33])[CH2:31][N:25]([CH:20]5[CH2:24][CH2:23][CH2:22][CH2:21]5)[C:26]=4[N:39]=3)=[C:42]([O:50][CH3:51])[CH:43]=2)[CH:13]([O:18][CH3:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CO[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C(=O)OCc3ccccc3)CC2OC)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
A mixture of 0.058 g (0.22 mmole) of (rac)-(3R,4R)-4-amino-3-methoxy-piperidine-1-carboxylic acid benzyl ester, 0.089 g (0.20 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.083 g (0.22 mmole) 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate, 0.057 g (0.44 mmole) of diisopropylethylamine and 2 mL of dimethylformamide was stirred at room temperature for 1 hour. The mixture was poured into 50 mL of water and extracted three times with 25 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated aqueous ammonium chloride solution, once with 25 mL of saturated aqueous sodium bicarbonate solution, once with 25 mL of brine and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2) to give 0.081 g of rac-(3R,4R)-4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-3-methoxy-piperidine-1-carboxylic acid benzyl ester (I-55) as a foam. Tritruration of the foam with diethyl ether gave a white solid.