Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccccc2F)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (38.2 mg, 0.081 mmol), 2-fluorobenzyl bromide (11.3 μL, 0.09 mmol, 1.05 equiv), and potassium carbonate (28.0 mg, 0.2 mmol) were combined in dimethylformamide (1.0 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 26.0 mg (56%). Mass spec.: 580.38 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[CH2:12]1COCC1.C[Mg+].[Br-]>CCOCC>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]([OH:6])[CH3:12]
Reactant: C1CCOC1
Reactant: O=Cc1cc(F)cc(Br)c1F
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(O)c1cc(F)cc(Br)c1F
Reaction time: 1 h

Procedure:
To a stirred mixture of 13.3 g of 3-bromo-2,5-difluorobenzaldehyde and 300 mL of THF cooled to -35°/-20° under an N2 atmosphere is added 30 mL of 2.85M of MeMgBr in Et2O over 10 minutes. The cooling bath is removed and the mixture stirred 1 hour and finally poured into 1 L of ice/H2O. 10% HCl is added to bring the pH to ~2 and the mixture extracted with 3×200 ml of CH2Cl2. The CH2Cl2 extracts are washed with H2O, saturated NaHCO3, H2O (250 mL each) and stripped to furnish 14.5 g of crude 3-bromo-2,5-difluoro-α-methylbenzyl alcohol. M+1 ions are observed at 236 and 238 in the mass spectrum. The crude material is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:35])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].[C:36](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[F:1][C:2]1[C:3]([O:35][CH3:36])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(O)c(F)c3o2)cc1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Yield: 78.2 %

Procedure:
348 mg (0.710 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl )-7-hydroxy-5-pivaloylamino-4H-1-benzopyran-4-one obtained in Example 86 (3) was dissolved in 35 mL of acetone, 166 mg (1.20 mmol) of potassium carbonate and 0.45 mL (7.1 mmol) of iodomethane were added and the mixture was heated at reflux for 40 minutes. The reaction solution was filtered, the filtrate was concentrated, water was added to the residue and the mixture was extracted once with ethyl acetate. The organic layer was washed twice with a 1N aqueous solution of sodium hydroxide, once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give 280 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methoxy-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 78%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[CH:7]=[C:6]([C:21]([O:23]CC)=[O:22])[C:5]2=[O:26].[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(#N)C>[F:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:9](=[CH:10][C:11]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[N:8]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:26]
Reactant: C1CNCCN1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)c(C)c2c1=O
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Yield: 69.5 %

Procedure:
A solution of 0.76 g (2.00 mmol) of ethyl 6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylate, 0.69 g (8.00 mmol) of anhydrous piperazine, and 30 mL of acetonitrile was refluxed for 18 hours, cooled, and concentrated. The residue was dissolved in 20 mL 6N hydrochloric acid and refluxed for 3 hours. The suspension was cooled, concentrated by half and filtered, and the solids were washed with water. The crude product was suspended in water which was made basic (pH 12), and the resulting solution was filtered and neutralized to pH 6.8. The precipitate which formed was filtered, washed with water, and dried to give 0.58 g of the title compound, mp 198°-200° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:11][CH3:12].[Br:17][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][C:21]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[C:20](I)[CH:19]=1>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.[Br-].[Zn+2].[Br-].O1CCCC1>[CH2:15]([O:14][C:10]([C:11]1[N:28]([S:29]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=[O:31])=[O:30])[C:21]2[C:20]([CH:12]=1)=[CH:19][C:18]([Br:17])=[C:23]([C:24]([F:27])([F:25])[F:26])[CH:22]=2)=[O:13])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(C(F)(F)F)c(Br)cc2I)cc1
Reactant: CCOC(=O)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(Br)c(C(F)(F)F)cc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
N,N-diisopropylethyl amine (0.42 ml, 2.4 mmol), ethyl propionate (0.12 ml, 1.2 mmol), and tetrakis(triphenylphosphine)palladium (46 mg, 0.04 mmol) were added to an anhydrous tetrahydrofuran (THF) solution (3.2 ml) containing N-(4-bromo-2-iodo-5-trifluoromethyl-phenyl)-4-methyl-benzenesulfonamide (208 mg, 0.4 mmol) and zinc bromide (270 mg, 1.2 mmol). Then, the mixture was evacuated, and backfilled with argon. This was stirred at 80° C. for 13 hours. After cooling it to room temperature, the reaction mixture was filtered through Celite, and washed with ethyl acetate. The wash solution was washed with an aqueous solution saturated with sodium bicarbonate and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and concentration was performed. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 5-bromo-1-(toluene-4-sulfonyl)-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester was obtained as a pale brown solid (195 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[C:22]([CH:26]([CH:34]2[CH2:36][CH2:35]2)[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH:23]=[N:24][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[C:22]([CH:26]([CH:34]3[CH2:36][CH2:35]3)[NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:29])=[O:30])[CH:23]=[N:24][CH:25]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Reactant: CC(C)S(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC(c1cncc(-c2ccc(C#N)c(Cl)c2)c1)C1CC1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
A mixture of 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (198 mg, 0.75 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)propane-2-sulfonamide (250 mg, 0.75 mmol), PdCl2(PPh3)2 (43 mg, 0.06 mmol) and Na2CO3 (2 M in water, 0.94 mL, 1.88 mmol) in DMF(6 mL) was heated at 100° C. for 2 h. After concentration, the resulting residue was dissolved in DCM and filtered. The filtrates were concentrated and purified by flash column (EtOAc/Heptane, v/v, 0-40%) to give the title compound (195 mg, 67%); ESI-MS m/z: 390 [M+1]+; 1H-NMR (MeOD, 400 MHz) δ 8.84 (1H, s), 8.71 (1H, s), 8.25 (1H, s), 8.05 (1H, bs), 7.98 (1H, d, J=8.0 Hz), 7.86 (1H, d, J=8.0 Hz), 3.97 (1H, d, J=9.2 Hz), 3.16-3.09 (1H, m), 1.37-1.33 (1H, m), 1.36 (3H, d, J=7.2 Hz), 1.29 (3H, d, J=7.2 Hz), 0.81-0.76 (1H, m), 0.66-0.63 (2H, m), 0.53-0.48 (1H, m); Enantiomers were separated by chiral HPLC (ChiralPak IA-H, EtOH/Heptane, v/v, 60/40) to give the first peak (enantiomer 1, t=10.11 min) and the second peak (enantiomer 2, t=12.95 min).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[OH-].[Na+].Cl.[CH3:25][CH2:26][OH:27]>>[CH2:26]([O:27][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1)[CH3:25]
Reactant: CCO
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 112 mg, 0.380 mmol) was suspended in EtOH (1 mL). 2 M NaOH (950 μL, 1.900 mmol) was added and the RM was stirred at 80° C. for 1 h. The mixture was neutralized with 2 M HCl until pH=6 and then concentrated. The residue was diluted with DCM and the obtained solution was dried over Na2SO4, filtered and concentrated. The residue was crystallized in Et2O and small amount of isopropanol. The resulting solid was purified by flash chromatography (Flashmaster, with a 20 g silica gel column, TBME/MeOH: 100:0→85:15) and crystallized again in Et2O to afford the title compound as a yellow solid (tR 1.67 min (conditions 6), MH+=305.2, 1H-NMR in DMSO-d6: 8.85 (m, 1H); 8.30 (m, 1H); 7.95 (m, 2H); 7.89 (m, 1H); 7.75 (m, 1H); 7.56 (s, 1H); 7.50 (dd, 1H); 6.80 (d, 1H); 4.44 (s, 2H); 4.35 (q, 2H); 1.31 (t, 3H)).
Reaction SMILES: O.[OH-].[Na+:3].[NH2:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[C:11](Cl)([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>C1(C)C=CC=CC=1>[Na+:3].[C:11]([NH:4][CH2:5][CH2:6][S:7]([O-:10])(=[O:9])=[O:8])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: NCCS(=O)(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCCS(=O)(=O)[O-])OCc1ccccc1
Temperature: 25 °C

Procedure:
To 1000 ml of water in the RBF charge 192 gm of (3.0 eq) of sodium hydroxide under cooling followed by 200 gm of Taurine and dissolve it until clear solution is obtained. Cool to 0° C. to 5° C., and Charge 50% CBZ-Cl in toluene at 0° C. to 5° C. After completion of addition, maintain at room temperature for 14 h. Separate the toluene layer and wash the aqueous layer with 2×200 ml of ethyl acetate. Add slowly 27 gm of sodium hydroxide in 60 ml of water to the aqueous layer and adjust pH to 12-14. Cool to 0° C. to 5° C. and a white solid separates from the solution. Filter the solid and dry the solid at 60-70° C. Weight of the solid: 320 g
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.Cl>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH:13]=[CH:21][C:20]2[CH:23]=[CH:24][C:17]([N:16]([CH3:25])[CH3:15])=[CH:18][CH:19]=2)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: CC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: Cl
Solvent: CO
Product: CN(C)c1ccc(C=CC(=O)c2cc(O)c(O)c([N+](=O)[O-])c2)cc1

Procedure:
A solution containing 0.5 g of the product obtained in Example 19 and 0.38 g of 4-dimethylaminobenzaldehyde in 5 ml of methanol was saturated with gaseous hydrogen chloride. The solution was refluxed for 1 h. After cooling the product was filtered and washed with methanol. Yield 0.26 g (70%), decomp. on heating.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](B1OC(C)(C)C(C)(C)O1)([CH3:30])=[CH2:29].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]([CH3:30])=[CH2:29])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(CC(=O)N2CCc3ccc(Br)cc32)CCN1C(=O)OC(C)(C)C
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
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: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1ccc2c(c1)N(C(=O)CN1CCN(C(=O)OC(C)(C)C)[C@H](C)C1)CC2
Temperature: 85 °C
Yield: 80.5 %

Procedure:
Pd(PPh3)4 (32 mg, 0.03 mmol), (R)-4-[2-(6-bromo-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (246 mg, 0.56 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (113 mg, 0.67 mmol) were dissolved in DMF (1.87 mL). Cs2CO3 (549 mg, 1.7 mmol) dissolved in water (0.37 mL) was added to the DMF solution. The reaction was degassed and heated to 85° C. for 18 h then was filtered and concentrated. Column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), gave (R)-4-[2-(6-isopropenyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.18 g) as a yellow oil. 10% Pd/C (48 mg, 0.05 mmol) and (R)-4-[2-(6-isopropenyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.18 g) were mixed with MeOH (4.5 mL). The reaction was hydrogenated at 1 bar for 30 min at ambient temperature then filtered under vacuum and concentrated, to give the title compound (157 mg, 86%) as a colourless oil. 1H NMR (Me-d3-OD): 8.08 (1H, s), 7.15 (1H, d), 6.95 (1H, d), 4.35-4.18 (3H, m), 3.83 (1H, d), 3.30 (2H, s), 3.25-3.12 (3H, m), 2.97-2.76 (3H, m), 2.33 (1H, dd), 2.20-2.08 (1H, m), 1.48 (9H, s), 1.31 (3H, d), 1.25 (6H, d).
Reaction SMILES: C(C(C1C=C([NH:16][C:17](=[O:40])[NH:18][CH2:19][C:20]([N:22]2[CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:32][CH2:31][CH:23]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:21])C=CC=1)=O)C1C=CC=CC=1.CC1C=C(C2NC(C(OC(C)(C)C)=O)CC2)C=CC=1.[CH2:60]([O:67][C:68]([C:70]1[CH:71]=[C:72](NC(=O)NCC(O)=O)[CH:73]=[CH:74][CH:75]=1)=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH2:60]([O:67][C:68]([C:70]1[CH:75]=[C:74]([NH:16][C:17](=[O:40])[NH:18][CH2:19][C:20]([N:22]2[CH:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:32][CH2:31][CH:23]2[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[O:21])[CH:73]=[CH:72][CH:71]=1)=[O:69])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: O=C(O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)Cc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1cccc(C2CCC(C(=O)OC(C)(C)C)N2)c1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1

Procedure:
tert-Butyl (2RS,5SR)-1-{2-[3-(3-benzylcarbonylphenyl)ureido]acetyl}-5-phenylprolinate may be prepared as described in Example 41 §A, but starting from 0.4 g of tert-butyl (2RS,5SR)-5-(3-methylphenyl)-prolinate, 0.5 g of 2-[3-(3-benzyloxycarbonylphenyl)-ureido]acetic acid and 0.31 g of N,N'-dicyclohexyl-carbodiimide in 20 cm3 of acetonitrile. After treatment, 0.8 g of tert-butyl (2RS,5RS)-1-{2-[3-(3-benzyloxycarbonylphenyl)ureido]-acetyl}-5-phenylprolinate is obtained in the form of a meringue-like product, used as it is in the subsequent syntheses.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][NH:15][CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:12][CH:13]=1.[C:25]([O-])(=[O:27])C.[Na+]>CN(C=O)C>[CH:25]([C:13]1[CH:12]=[CH:11][C:10]([CH2:14][NH:15][CH2:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:9][C:8]=1[O:7][CH3:6])=[O:27]
Reactant: CC(=O)[O-]
Reactant: COc1cccc(CNCCOC(=O)C(C)(C)C)c1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(CNCCOC(=O)C(C)(C)C)ccc1C=O
Reaction time: 0.67 h

Procedure:
POCl3 (5.8 g, 37.7 mmol) was added to 20 ml of DMF in an ice bath. After 40 minutes, 2,2-dimethylpropionic acid 2-[(3-methoxyphenyl)methylamino]ethyl ester (10 g, 37.7 mmol) dissolved in DMF (10 ml) was added dropwise. After the mixture was stirred for 16 hours, an aqueous sodium acetate solution (20%, 100 ml) was added dropwise thereto and the oily matter was subjected to extraction with ethyl acetate. Washing was performed with a saturated aqueous NaHCO3 solution (100 ml) and then with a saturated saline solution (100 ml). After drying over Na2SO4 and concentration, the residue was purified by silica gel chromatography to give a light yellow crystal (yield: 8.7 g (78.9%)).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH3:44])[C:8]([C:10]1([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[CH:12]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][C:24]=3[S:23](=[O:37])(=[O:36])[N:22]=2)[C:11]1=[O:38])=[O:9])(=O)C.C(OC[C@H]1CCCN1C([C@@]1(CCC(C)C)C2C(=CC=CC=2)C(O)=C(C2NC3C=CC(NS(C)(=O)=O)=CC=3S(=O)(=O)N=2)C1=O)=O)(=O)C>>[OH:4][CH2:5][CH2:6][N:7]([CH3:44])[C:8]([C:10]1([CH2:39][CH2:40][CH:41]([CH3:42])[CH3:43])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[CH:12]([C:21]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][C:24]=3[S:23](=[O:36])(=[O:37])[N:22]=2)[C:11]1=[O:38])=[O:9]
Reactant: CC(=O)OCCN(C)C(=O)C1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)C(=O)c2ccccc21
Agent: CC(=O)OC[C@H]1CCCN1C(=O)[C@]1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Product: CC(C)CCC1(C(=O)N(C)CCO)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)C(=O)c2ccccc21

Procedure:
The title compound was prepared using the procedure described for Example 172 substituting the product of Example 176G for the product of Example 171G. The title compound was purified by column chromatography on silica gel using a solvent gradient of 2-6% methanol in chloroform, and was obtained as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 0.49 (m, 1 H), 0.62 (d, J=6.62 Hz, 3 H), 0.67 (d, J=6.62 Hz, 3 H), 0.92 (m, 2 H), 1.27 (m, 1 H), 1.86 (m, 1 H), 2.15 (m, 1 H), 2.33 (s, 3 H), 3.00 (s, 3 H), 3.14 (m, 1 H), 3.47 (m, 2 H), 6.96 (m, 1 H), 7.42 (m, 5 H), 8.08 (m, 1 H), 9.90 (s, 1 H), 14.99 (br s, 1 H); MS (ESI) m/z=605 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10](=[O:25])[NH:11][C:12]2[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:34]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:25])[NH:11][C:12]2[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[CH:26][CH:27]=1)(=[S:34])[NH2:2]
Reactant: CCOC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1

Procedure:
In a similar manner to Example, starting material step 1 (b), the product of step (a) (10.12 g), pyridine (500 ml), triethylamine (80 ml) and H2S gas were reacted to give ethyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]phenoxyacetate (11 g) as a yellow solid: NMR Spectrum (DMSO-d6) 1.21 (3H, t), 4.18 (2H, q), 4.74 (2H, s), 6.93 (2H, d), 7.49 (2H, d), 7.95 (2H, d), 8.03 (2H, d), 9.64 (1H, br s), 10.03 (1H, br s), 10.60 (1H, s), 11.04 (1H, s); Mass Spectrum m/Z 402 (M+H)+.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Cl[CH2:14][CH:15]([O:18][CH2:19][O:20][CH3:21])[CH2:16]Cl>CS(C)=O.C(OCC)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:16][CH:15]([O:18][CH2:19][O:20][CH3:21])[CH2:14]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: COCOC(CCl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COCOC1CC(C#N)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
Potassium hydroxide (2.57 g) was dissolved in dimethyl sulfoxide (8.0 mL). (4-Chlorophenyl)acetonitrile (1.58 g, 10.4 mmol) and 1,3-dichloro-2-(methoxymethoxy)propane (1.993 g) were dissolved in ethyl ether (3 mL), and this mixture was added dropwise to the vigorously stirred potassium hydroxide solution at room temperature. After stirring at room temperature for one hour, the reaction was quenched by adding ice-cold water (5.5 mL). The mixture was filtered through a pad of celite which was washed with ether (30 mL). The filtrate was added to a separatory funnel, and the aqueous layer was extracted with ether (3×15 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The product was purified by silica gel chromatography to provide 1-(4-chlorophenyl)-3-(methoxymethoxy)cyclobutanecarbonitrile (1.28 g) as a mixture of isomers (ca. 2:1).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40]Cl>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: CN(C)CCCCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Agent: Cl
Product: CN(C)CCCN1CN(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=591.1 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 3-dimethylaminopropylchloride hydrochloride.