Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=2)[CH:13]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:27][CH2:28][CH:29]([NH:32][CH2:13][C:12]2[CH:15]=[C:8]([C:7]3[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[CH:9]=[CH:10][C:11]=2[O:16][CH3:17])[CH2:30][CH2:31]1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1ccc(-c2cccnc2F)cc1C=O
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(N)CC1
Product: COc1ccc(-c2cccnc2F)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Following the synthetic protocol described in Method C′; {4-[5-(2-Fluoro-pyridin-3-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester is prepared starting from 5-(2-Fluoro-pyridin-3-yl)-2-methoxy-benzaldehyde and (4-Amino-cyclohexyl)-methyl-carbamic acid tert-butyl ester. The desired product is isolated in 70%.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([C:31]4[N:35](COCC[Si](C)(C)C)[C:34]5[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=5[N:32]=4)[C:19](=[O:30])[N:20](COCC[Si](C)(C)C)[N:21]=3)[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[NH:35]1[C:34]2[CH:44]=[CH:45][CH:46]=[CH:47][C:33]=2[N:32]=[C:31]1[C:18]1[C:19](=[O:30])[NH:20][N:21]=[C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:15]=2)[CH:17]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccnc(NCCN3CCOCC3)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]nc(-c2ccnc(NCCN3CCOCC3)n2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
88 mg of 6-[2-(2-morpholin-4-ylethylamino)pyrimidin-4-yl]-2-(2-trimethylsilanyl-ethoxymethyl)-4-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one are dissolved in 2 ml of a 1:1 mixture of dichloromethane and trifluoroacetic acid, and the mixture is stirred at room temperature for 2 hours. The volatile components are then distilled off, the residue is dissolved in 1 ml of methanol, and 1 ml of a two molar aqueous sodium hydroxide solution is added. The solution is stirred at room temperature for 12 hours and then put directly onto the preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)) to isolate the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:7][CH2:8][CH3:9])=[CH:5][CH3:6])[CH3:2].[C:10]([NH:13][CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[C:16]([O:18][CH3:19])=[O:17])(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([NH:13][C@@H:14]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:20]([CH3:21])[O:22][C:4]([O:7][CH2:8][CH3:9])([O:3][CH2:1][CH3:2])[C@H:5]1[CH3:6])(=[O:12])[CH3:11]
Reactant: COC(=O)C(=CNC(C)=O)C(C)=O
Reactant: CC=C(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC1(OCC)OC(C)=C(C(=O)OC)[C@@H](NC(C)=O)[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Diethoxyprop-1-ene (1.0 ml) was added to a solution of methyl 2-acetylaminomethylene-3-oxobutanoate (1.0 g) and tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octandionato)ytterbium (0.05 g) in toluene (3.0 ml) at 20° C. After stirring for 2 hr at ambient temperature, the reaction mixture was filtered to give methyl trans-4-acetylamino-2,2diethoxy-3,6-dimethyl-3,4-dihydro-2H-pyran-5-carboxylate (1.05 g), m.p. 153°-4° C.
Reaction SMILES: [OH-].[NH4+:2].[Cl:3][C:4]1[C:5]([F:17])=[C:6]([CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[C:12]=1F)[C:7]([OH:9])=[O:8].Cl>O>[NH2:2][C:12]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:17])[C:4]=1[Cl:3]
Reactant: [NH4+]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Nc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1Cl
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Ammonium hydroxide solution (6.88 g, ˜30% in water, 58.9 mmol) is added to a solution of 3-chloro-2,4-difluoro-5-nitro-benzoic acid 2a (3.5 g, 14.7 mmol) in water (16 mL) at 0° C. with stirring. Upon completion of the ammonium hydroxide addition the reaction mixture is warmed to room temperature. After 5 hours the reaction mixture is cooled to 0° C. and concentrated HCl is carefully added until the pH of the reaction mixture is near zero. The solid is collected by filtration and washed with water and diethyl ether. The solids are transferred to a round bottom flask as a solution in MeOH and EtOAc and concentrated under reduced pressure to give 2.96 g of a yellow solid. The filtrate is partitioned between diethyl ether and water and the organic layer is washed with brine. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 0.65 g of product. Recovered a total of 3.61 g (104%) of pure desired product that is carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH2:8])=[O:6].[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH3:43])[C:22]([NH:24][CH2:25][C:26]1[S:30][CH:29]=[C:28]([N:31]2[C:35]([C:36](O)=[O:37])=[CH:34][C:33]([C:39]([F:42])([F:41])[F:40])=[N:32]2)[CH:27]=1)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(Cl)CCl>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH:8][C:36]([C:35]1[N:31]([C:28]2[CH:27]=[C:26]([CH2:25][NH:24][C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:16])([CH3:14])[CH3:15])[CH3:43])[S:30][CH:29]=2)[N:32]=[C:33]([C:39]([F:40])([F:42])[F:41])[CH:34]=1)=[O:37])=[O:6]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)cs1
Reactant: COc1ccccc1C(=O)NN
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccccc1C(=O)NNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methoxybenzhydrazide (0.040 g, 0.238 mmol) and compound 7 (preparation described in scheme 2 example 1c, step 7) (0.11 g, 0.238 mmol) in dichloromethane (2 mL) under nitrogen was added EDC (0.046 g, 0.238 mmol) followed by DMAP (5.81 mg, 0.048 mmol). The reaction was left to stir for 16 hours at room temperature. Another portion of EDC (20 mg, 0.104 mmol) was added and the reaction continued for 4 hours. The solvent was then removed on the rotary evaporator and the crude purified by silica gel column chromatography with a Biotage 12M column and a gradient of 0-5% methanol in dichloromethane to give compound 16 as a yellow crust (73.7 mg, 51%). LRMS (ESI): calc. 610.2; found 511.2 (MH-Boc)+, 633.3 (MNa)+.
Reaction SMILES: [CH2:1]([NH:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][CH:23]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH3:24])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCN(C(C)C)C(C)C.[CH2:45]([O:47][C:48](=[O:52])[C:49](Cl)=[O:50])[CH3:46]>C(Cl)Cl>[CH2:45]([O:47][C:48](=[O:52])[C:49]([N:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:35])=[CH:20][CH:19]=1)[CH:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:50])[CH3:46]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CNC(C)c2cccc3ccccc23)cc1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN(C(=O)C(=O)OCC)C(C)c2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The resin-bound N-dodecyl-4-({[1-(1-naphthyl)ethyl]amino}methyl)benzamide (described in step c, 0.0426 mmol) was swelled in DCM (1.0 mL) for 15 min at 0° C. DIEA (28 mg, 0.213 mmol) and chloro-oxo-acetic acid ethyl ester (29 mg, 0.213 mmol) were added and the reaction mixture was shaken 3 h at 0° C. then 14 h at rt. The resin was washed successively with THF (1×15 min), MeOH (1×15 min), THF (1×15 min), MeOH (3×10 min), DMF (3×10 min), MeOH (1×5 min), THF (3×10 min), MeOH (1×5 min), DCM (3×10 min) and with Et2O (1×10 min). The resin was then dried under vacuum to afford the resin-bound ethyl{{4-[(dodecylamino)carbonyl]benzyl}[1-(1-naphthyl)ethyl]amino}-(oxo)acetate which was used directly in the next step.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:36])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:18]([CH3:20])[CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:36])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[C:18]([CH3:20])[CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.4 %

Procedure:
A solution of KOH (154 mg, 2.75 mmol) in ethanol (2 mL) was added to a solution 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.2 g, 2.50 mmol) in ethanol (10 mL) and methylene chloride (4 mL) at 0° C. The mixture was stirred for 18 h at room temperature. The mixture was concentrated under reduced pressure and the residue dissolved in water. Ethyl acetate was added and the organic layer was washed with 0.5 M HCl, water, brine and dried. After filtration and concentration under reduced pressure gave crude 2-(6-[N,N-bis(tert-butoxy-carbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.0 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+]>C(=O)(OC)OC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CCOC(C)=O
Product: CC(C#N)c1ccc(Br)cc1
Yield: 1498.8 %

Procedure:
A solution of 50.0 g (225.0 mmol) of 4-bromophenyl-acetonitrile and 1.8 g (12.8 mmol) of potassium carbonate in 387 mL of dimethyl carbonate was heated to 180° C. in a sealed vessel for 16 hours. The solution was then cooled, diluted with 200 ml of ethyl acetate and washed once with 100 ml water, once with 100 ml of 10% aqueous sodium bisulfate and once with 100 ml brine. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. The residue was distilled under vacuum through a short path distillation apparatus to afford 40.3 g (85%) of the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.C(OC([NH:35][C:36]1([C:39](O)=[O:40])[CH2:38][CH2:37]1)=O)(C)(C)C.CO>O>[NH2:35][C:36]1([C:39]([N:2]2[CH2:3][CH:4]([C:6]3[CH:27]=[CH:26][C:9]4[C:10]5[N:14]([CH:13]=[C:12]([C:18]6[N:19]([CH:23]([CH3:24])[CH3:25])[N:20]=[CH:21][N:22]=6)[N:11]=5)[CH2:15][CH2:16][O:17][C:8]=4[CH:7]=3)[CH2:5]2)=[O:40])[CH2:38][CH2:37]1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(C(=O)C4(N)CC4)C3)cc1OCC2

Procedure:
Following the procedure for 127, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid. The crude product was subjected to reverse phase HPLC (Gemini C18 column, gradient 20 to 95% MeOH in H2O+0.1% HCO2H) to give 193 as a white solid. 1H NMR δ (ppm) (DMSO-d): 8.36 (1 H, d, J=8.28 Hz), 8.09 (1 H, s), 7.88-7.86 (2 H, m), 7.14 (1 H, dd, J=8.35, 1.82 Hz), 7.01 (1 H, d, J=1.78 Hz), 5.88-5.80 (1 H, m), 4.50-4.44 (4 H, m), 3.83-3.71 (2 H, m), 1.44 (6H, d, J=6.60 Hz), 1.05 (2 H, d, J=4.13 Hz), 0.67 (2 H, d, J=4.01 Hz). 2 Exchangeable protons not seen. 4 protons obscured by water peak. LCMS: RT=6.73 min, M+H+=434
Reaction SMILES: C(#N)C.[Cl:4][CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=O)[C:10]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:9]=2[O:8]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25]>C1(C)C=CC=CC=1>[Cl:4][CH2:5][CH2:6][CH:7]1[CH2:13][N:12]([CH3:14])[C:11](=[S:25])[C:10]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:9]=2[O:8]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2ccc(C(F)(F)F)cc2C1=O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN1CC(CCCl)Oc2ccc(C(F)(F)F)cc2C1=S

Procedure:
To 30 ml of acetonitrile was added 1.25 g (0.004 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-7-(trifluoromethyl)-1,4-benzoxazepine-5(4H)-one and 0.92 g (0.002 mole) of phosphorus pentasulfide and the reaction mixture heated to reflux for 4 hr. After cooling, 30-40 ml of toluene was added and the mixture filtered. The filtrate was washed with 3×50 ml of saturated potassium carbonate, charcoaled, filtered, and concentrated by rotary evaporation. The residue was crystallized from isopropyl ether to give 0.65 g (50%) of yellow, analytically pure crystals, m.p., 146°-48° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]2[SH:16])=[CH:4][CH:3]=1.[CH3:17][NH:18][O:19][CH3:20].C(N=C=NCCCN(C)C)C.O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([N:18]([O:19][CH3:20])[CH3:17])=[O:15])=[CH:11][N:10]=[C:9]2[SH:16])=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1cnc(S)n1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylic acid (4) (2.2 g, 9.23 mmol), N,O-dimethylhydroxylamine (0.9 g, 9.23 mmol), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.77 g, 9.23 mmol) in pyridine was heated at 40° C. overnight. The reaction was cooled to room temperature, water was added and the solution was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield 1-(4-fluorophenyl)-2-mercapto-N-methoxy-N-methyl-1H-imidazole-5-carboxamide (5) as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].C(S[C:13]1[N:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][CH:26]=2)[C:15](=[O:24])[C:16]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[C:17]=2[N:18]=1)CC>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:13]1[N:14]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:29][CH:30]=2)[C:15](=[O:24])[C:16]2[CH:22]=[CH:21][NH:20][C:19](=[O:23])[C:17]=2[N:18]=1
Reactant: OCC(F)(F)F
Reactant: CCCSc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(OCC(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,2,2-trifluoroethanol (0.052 ml) in N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 24 mg) at room temperature, and the mixture was stirred for 5 min. A solution of 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (535 mg) in N,N-dimethylformamide (3 ml) was added to the reaction mixture, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was allowed to be cooled to room temperature, saturated brine was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from a mixed solvent of ethyl acetate/hexane to give the title compound (8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].Cl.[NH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>ClCCl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a stirred solution of 3-chlorobenzoyl chloride (6.0 mL, 58 mmol) in dichloromethane (150 mL) were added ethyl glycinate hydrochloride (10 g, 72 mmol) and triethylamine (20 mL, 142 mmol). After stirring for 1 h, the mixture was diluted with saturated NaHCO3 and the aqueous layer extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4 and evaporated to dryness in vacuo to give the desired product (9.8 g) as a white solid which was taken on without purification.
Reaction SMILES: C(Cl)Cl.[SH:4][C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=1.Br[CH:16]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:17]([OH:19])=[O:18]>C(N(CC)CC)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH:16]([S:4][C:5]2[N:9]([CH3:10])[C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[N:6]=2)[C:17]([OH:19])=[O:18])=[CH:25][CH:24]=1
Reactant: Cn1c(S)nc2ccccc21
Reactant: O=C(O)C(Br)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(SC(C(=O)O)c2ccc(Cl)cc2)nc2ccccc21
Yield: 41 %

Procedure:
A methylene chloride solution of 3.3 g (0.02M) of 2-mercapto-1-methyl-1H-benzimidazole, 5.0 g (0.02M) of α-bromo-(p-chlorophenyl)acetic acid and 4.0 g (0.04M) of triethylamine is heated to reflux overnight. The reaction mixture is neutralized with a diluted HCL solution. The layers are separated and the organic layer is dried over anhydrous magnesium sulfate. After removal of methylene chloride the residue is recrystallized from acetonitrile. The recrystallized material weighs 4.1 g (41% yield) and has a melting point of 161°-3° C. dec.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[NH2:1][C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CC(=O)O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: N[C@H](CC(=O)O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.67 h

Procedure:
(±)-3-Amino-3-phenylpropanoic acid (2.378 g, 14.4 mmol), 2.0 ml of acetic acid, and 236 mg (2.88 mmol) of anhydrous sodium acetate were charged into a 30-ml two-necked round-bottomed flask equipped with a stirrer and a calcium chloride tube and cooled down to a temperature not higher than 10° C. using an ice bath. Acetic anhydride (4 ml, 42.8 mmol) cooled to a temperature of not higher than 10° C. was added dropwise to the solution, and the mixture was stirred for 40 minutes at that temperature and then stirred for 80 minutes at room temperature.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:19]=2)=[O:16])[N:13]=1.[Cl-].[Be+2].[Cl-].CC[O:36]C(C)=O>C1(C)C=CC=CC=1>[OH:36][C:6]1[CH:5]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[N:19]=3)=[O:16])[N:13]=2)[CH:3]=[CH:8][CH:7]=1
Reactant: COc1ccccc1-c1nc(NC(=O)Nc2cccc(CN3CCCCC3)n2)cs1
Reactant: CCOC(C)=O
Agent: [Be+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(Nc1cccc(CN2CCCCC2)n1)Nc1csc(-c2cccc(O)c2)n1

Procedure:
A mixture of 1-[2-(3-methoxyphenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea (Example 218) and beryllium chloride (5.0 eq) in dry toluene (0.2 M) and 4A molecular sieves was heated at reflux for 10 h. The starting material was not totally soluble in toluene. The mixture was brought to RT, diluted with EtOAc and washed with saturated NH4Cl. The organic phase was separated, dried over MgSO4, filtered, concentrated by rotary evaporation and purified by prep HPLC (Column Phenomenex type Prodigy 50 ODS3 100A size 250×21.20 mm 5u, Gradient 10% to 90% CH3CN:H2O containing 1% TFA over 20 min, Detector 254 nm, 4 nm Band) to afford the title compound as an off white solid. EI-MS m/z 410 (M+H). Calc'd for C21H23N5O2S: 409.16.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.[CH:10](Cl)([Cl:12])[Cl:11].CC(C)([O-])C.[K+].Cl>CN(C=O)C.C1COCC1>[Br:1][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[C:5]([CH:10]([Cl:12])[Cl:11])[CH:6]=1
Reactant: ClC(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Br)s1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1sc(Br)cc1C(Cl)Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-bromo-5-nitrothiophene (29 g, 139 mmol) and chloroform (12.37 mL, 153 mmol) in DMF (110 mL) was added dropwise to a solution of potassium tert-butoxide (62.6 g, 558 mmol) in THF (225 mL)/DMF (180 mL). The internal temperature was monitored and maintained at <−60° C. during the addition. Upon complete addition, the reaction was stirred at −78° C. for 30 minutes. 2 N HCl was added and the products were extracted into EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (0-10% EtOAc-hexanes) gave the title compound as a brown oil.
Reaction SMILES: [NH2:1][C:2]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:17][O:18][C:19]([CH2:21][CH:22]([CH3:26])[C:23](O)=[O:24])=[O:20]>>[CH3:17][O:18][C:19]([CH2:21][CH:22]([CH3:26])[C:23]([NH:1][C:2]1([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:24])=[O:20]
Reactant: NC1(C(=O)OCc2ccccc2)CCCC1
Reactant: COC(=O)CC(C)C(=O)O
Product: COC(=O)CC(C)C(=O)NC1(C(=O)OCc2ccccc2)CCCC1

Procedure:
1-[(3-Methoxycarbonyl-2-methylpropanoyl)amino]-1-cyclopentanecarboxylic acid, benzyl ester was prepared as described in Example 3 from 10.96 g (0.050 mol) of 1-amino-1-cyclopentanecarboxylic acid, benzyl ester and 7.31 g (0.050 mol) of 3-methoxycarbonyl-2-methylpropionic acid. Crude di-ester crystallized to give 13.57 g (78%) of an off-white solid, mp: 88°-93°. This was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([CH2:14][OH:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([CH2:14][O:15][CH3:17])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: O=C(NC1(CO)CC1)OCc1ccccc1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCC1(NC(=O)OCc2ccccc2)CC1
Reaction time: 5 h
Yield: 42.5 %

Procedure:
To a solution of benzyl[1-(hydroxymethyl)cyclopropyl]carbamate (0.32 g, 0.0014 mol) in methylene chloride (5.0 mL) was added sequentially powdered MS 4 Å, N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (0.77 g, 0.0036 mol), and trimethyloxonium tetrafluoroborate (0.43 g, 0.0029 mol) at RT. The mixture was stirred for 5 h, filtered through a pad of Celite, and washed with EtOAc. The filtrate was washed with 1N HCl, water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with EtOAc in hexanes (0-30%) to afford the desired product (140 mg, 41%). LCMS: (M+H)=236.1.