Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:4]=2[N:3]=1.[CH:21]1[CH:22]=[CH:23]C2N(O)N=[N:27][C:25]=2[CH:26]=1.N1CCCCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:14]=[CH:15][C:16]([C:18]([N:27]3[CH2:23][CH2:22][CH2:21][CH2:26][CH2:25]3)=[O:20])=[CH:17][C:4]=2[N:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1cccc(-n2c(C)nc3cc(C(=O)O)ccc32)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: Cc1cccc(-n2c(C)nc3cc(C(=O)N4CCCCC4)ccc32)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
The compound obtained in Step 3 (80.0 mg, 0.300 mmol) was dissolved in DMF, and then HOBT (81 mg, 0.6 mmol), TEA (126 uL, 1.2 mmol), and piperidine 28.1 mg (0.330 mmol) were added thereto. EDC hydrochloride (25 mg, 0.13 mmol) was put thereinto at 0° C., and then stirred at room temperature for 12 hours. The reacted mixture was diluted with ethyl acetate (32 mL), and then washed with water (32 mL). The organic layer was dried over anhydrous magnesium sulfate, followed by filtering and concentrating under reduced pressure, and then subjected to column chromatography (MC:MeOH=30:1), to obtain a target compound (79.4 mg, 79%).
Reaction SMILES: C([O:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]#[N:13])[CH2:7][CH2:6]1)=C.Cl.O>ClCCl.O1CCOCC1>[OH:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]#[N:13])[CH2:7][CH2:6]1
Reactant: C=COCC1CCC(CC#N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: N#CCC1CCC(CO)CC1
Reaction time: 0.5 h

Procedure:
4-[(Vinyloxy)methyl]cyclohexylacetonitrile (0.9 g, 0.005 mol) was dissolved in dichloromethane (5 mL), and 1.5 mL of 4 N hydrogen chloride (0.22 g, 0.0060 mol) in dioxane was added with water (0.2 mL). The reaction was stirred for 30 min. and then concentrated to give the product as a 3:1 mixture of diastereomers, (0.75 g). 1H NMR (400 MHz, CDCl3): δ 3.451-3.467 d, 2H, J=6.4 Hz), 2.58 (br s, 1H), 2.271-2.288 (d, 2H, J=6.8 Hz), 1.85-1.93 (m, 4H), 1.2-1.8 (m, 4H), 0.95-1.19 (m, 4H) (major diastereomer).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:21]=1[C:22]([OH:24])=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:35][C:36]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:37]=1[C:38]#[N:39]>C(Cl)Cl.N1C=CC=CC=1>[CH2:12]([O:19][C:20]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:25][C:21]=1[C:22]([NH:35][C:36]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:37]=1[C:38]#[N:39])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: O=C(O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc(Cl)cc1NC(=O)c1cc(N2CCCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N,N-Dimethylformamide (0.010 mL) and oxalyl chloride (0.21 mL) were sequentially added to a methylene chloride (3.0 mL) suspension of 2-(benzyloxy)-5-(piperidin-1-yl)benzoic acid (0.56 g), followed by stirring at room temperature for 1 hour and 20 minutes. Under ice-cooling, the reaction mixture was added to a solution mixture of 2-amino-4-chlorobenzonitrile (0.23 g) in methylene chloride (3.0 mL) and pyridine (0.30 mL), followed by stirring at room temperature for 2 hours and 30 minutes. The solvent was evaporated under reduced pressure, and a 10% aqueous solution of citric acid and chloroform were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 2-(benzyloxy)-N-(5-chloro-2-cyanophenyl)-5-(piperidin-1-yl)benzamide as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=C2C(=O)[N:12]3[C:15](=[O:22])[C:16]([CH3:21])([CH:18]([CH3:20])[CH3:19])[N:17]=[C:11]3[C:7]2=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:23][O-].[Na+].[C:26]([OH:29])(=[O:28])[CH3:27]>CO>[C:1]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([C:11]2[NH:12][C:15](=[O:22])[C:16]([CH:18]([CH3:19])[CH3:20])([CH3:21])[N:17]=2)=[C:27]([CH:5]=1)[C:26]([O:29][CH3:23])=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(nc1C)C1=NC(C)(C(C)C)C(=O)N1C2=O
Reactant: C[O-]
Reactant: CC(=O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C(C)=O)c(C)nc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: 25 °C

Procedure:
A solution of 0.68 g of 7-acetyl-2,8-dimethyl-2-isopropyl-5H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-3(2H),5-dione in 50 mL methanol is stirred at 5° and 0.06 g of sodium methoxide is added. The reaction is stirred and allowed to warm to room temperature over 3 hours, at which point it is acidified with acetic acid and concentrated in vacuo. The residue is dissolved in methylene chloride, washed with water, dried and concentrated in vacuo to afford the desired product. Recrystallization from methylene chloride-hexanes gives a solid, mp 118°-120°.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:34])[CH:10]([N:16]1[C:20]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=2[N:18]=[C:17]1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:46]([O-])=[O:47].[Na+]>>[CH2:1]([N:8]([N:46]=[O:47])[C:9](=[O:34])[CH:10]([N:16]1[C:20]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:19]=2[N:18]=[C:17]1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: O=C(NCc1ccccc1)C(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=NN(Cc1ccccc1)C(=O)C(C1CCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a ice-cold solution of 9.50 g (19.79 mmol) N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopentyl-acetamide in 64.53 ml (1128 mmol) acetic acid and 135.84 ml (2395 mmol) acetic anhydride were added in portions over 60 min. 6.83 g (99 mmol) sodium nitrite. The reaction mixture was stirred for 1 h in an ice-bath, then at room temperature overnight. The mixture was evaporated and the residue was taken up in saturated aqueous sodium bicarbonate solution and ethyl acetate and solid sodium bicarbonate was added to adjust the pH to 7. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The remaining brown foam was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane and ethyl acetate (100:0 to 50:50). Yellow solid (72%). MS (Turbo Spray): m/z=509.2 [M+H].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[C:10]([CH:17]1[CH2:22][CH2:21][N:20](N)[CH2:19][CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[N:24]1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:10]([CH:17]1[CH2:22][CH2:21][N:20]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:19]([NH2:24])[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)C1CCN(N)CC1
Reactant: c1ccncc1
Reactant: OB(O)c1ccncc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCN(c2ccncc2)C(N)C1
Reaction time: 48 h
Yield: 90 %

Procedure:
The mixture of 4-pyridineboronic acid (0.97 g, 7.8 mmol), 4-Boc-aminopiperidine (3.25 g, 15.8 mmol), Cu(OAc)2 (2.88 g, 15.8 mmol), DMAP (catalytic amount), pyridine (2.5 mL, 32 mmol), 4A activated molecular sieve in 50 mL dry DCM was stirred for over 2 days. It was diluted with DCM, filtered through celite. It was washed with brine and water, dried, filtered through a silica plug, evaporated in vacuuo to give 4-(4-Boc-aminopiperidin-1-yl)pyridine in 90% yield. ES-MS: (+H) 278.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].C[O:12]C1C=CC([Mg]Br)=CC=1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32](=O)[C:31]=3[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:24][C:23]=2[O:22]1>CCOCC.C1COCC1>[OH:12][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:38]=1[C:30]([C:25]1[CH:26]=[CH:27][C:28]3[O:29][CH2:21][O:22][C:23]=3[CH:24]=1)=[C:31]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:32]2[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cc1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1=O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2c(O)cccc2C1c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A solution of 4-bromoanisole (0.89 g, 5.0 mmol) in 9:1 Et2O/THF (10 ml) was added to magnesium turnings (0.105 g, 5.0 mmol), and the resulting mixture was allowed to stir for 30 min. The resultant 4-methoxyphenyl magnesium bromide was added dropwise to a solution of ethyl 3-(3,4-methylenedioxyphenyl)-1-oxoindene-2-carboxylate (0.77 g, 2.4 mmol) in 10:1 Et2O/THF (55 ml) at 0° C. The resulting mixture was stirred at 0° C. for 1 h and was then partitioned between EtOAc and 1M HCl. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with 5% aqueous NaHCO3 and saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel, eluting with 10% EtOAc/hexanes to afford the title compound as a yellow glassy solid (0.80 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:4].[CH2:25]([NH:32][CH2:33][CH3:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:25]([N:32]([CH2:33][CH3:34])[C:16](=[O:18])[CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:20][CH:19]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)O)cc1
Reactant: CCNCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
(4-{2-[2-(methoxycarbonyl)phenoxy]ethyl}phenoxy)acetic acid (0.150 g, 0.454 mmol) was dissolved in DMF (10 ml), N-benzyl-N-ethylamine (0.061 g, 0.454 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)-(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.160 g, 0.499 mmol) and N-ethyl-N,N-diisopropylamine (0.123 g, 0.954 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×, 10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation to give 0.138 g of methyl 2-[2-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoate (yield 67.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10]Cl)[CH2:7][C:6]=2[CH:12]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:7][C:6]=2[CH:12]=1
Reactant: C1CNCCN1
Reactant: ClCC1Cc2cc(Cl)ccc2O1
Product: Clc1ccc2c(c1)CC(CN1CCNCC1)O2
Temperature: 135 °C
Reaction time: 15 h
Yield: 65.1 %

Procedure:
To 5-chloro-2-(chloromethyl)-2,3-dihydro-1-benzofuran (1.6 g, 7.9 mmol) was added piperazine (2.72 g, 31.6 mmol, 4 eq) with stirring for 15 hours at 135° C. in an oil bath. The crude material was purified by silica gel chromatography using 3% dichloromethane in methanol to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine as a light yellow solid (1.3 g, 65%); (ES, m/z): [M+H]+ 253; 1H NMR (300 MHz, CDCl3): δ 7.03-7.11 (m, 2H), 6.68 (d, J=8.4 Hz, 1H), 4.93-5.03 (m, 1H), 3.20-3.29 (m, 1H), 2.88-2.99 (m, 6H), 2.72-2.79 (m, 1H), 2.49-2.63 (m, 5H).
Reaction SMILES: [NH:1]([C:5]1[C:6]([CH3:20])=[C:7]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:2]([CH3:4])=[O:3].CC1C([N+:28]([O-])=O)=CC(C)=CC=1O>>[C:2]([N:1]1[C:5]2[C:6](=[C:7]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[C:9]([CH3:11])[CH:10]=2)[CH:20]=[N:28]1)(=[O:3])[CH3:4]
Reactant: Cc1cc(O)c(C)c([N+](=O)[O-])c1
Reactant: CC(=O)Nc1cc(C)cc(OCc2ccccc2)c1C
Product: CC(=O)n1ncc2c(OCc3ccccc3)cc(C)cc21

Procedure:
The (3-acetamino-2,5-dimethyl-phenyl)-benzyl ether used as starting material in Example 2 is prepared from 2,5-dimethyl-3-nitrophenol by the following reactions:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[Br:8][CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]>>[Br-:8].[CH3:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=1[CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Cc1ccccn1
Reactant: CCCCC(=O)CBr
Product: CCCCC(=O)C[n+]1ccccc1C
Product: [Br-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
30.21 g of 2-picoline (0.32 mole) was slowly added to 83 g of 1-bromo-2-hexanone (0.46 mole) and stirred for 4 hours at ambient temperature. A viscous medium was obtained which was used as is for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N:10]([CH2:13][CH3:14])=[C:11]=S.C(N=C=NC(C)C)(C)C.C(OCC)(=O)C>CN1C(=O)CCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:11]([NH:10][CH2:13][CH3:14])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN=C=S
Reactant: Nc1cc(Br)cnc1N
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCNc1nc2cc(Br)cnc2[nH]1
Temperature: 65 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a cooled (0° C.) solution of 5-bromopyridine-2,3-diamine (5.0 g, 27 mmol) in NMP (20 mL) was added isothiocyanatoethane (2.3 mL, 26 mmol). The resulting solution was heated (65° C.) for four hours and then cooled to ambient temperature before 1,3-diisopropylcarbodiimide (4.2 mL, 27 mmol) was added. The reaction mixture was stirred for 18 hours, diluted with water and the resulting suspension was collected by filtration. Trituration with ethyl acetate provided 6-bromo-N-ethyl-3H-imidazo[4,5-b]pyridin-2-amine (4.8 g, 75% yield) as a brown solid. 1H NMR (400 MHz, d6-DMSO) δ 11.41 (bs, 1H), 7.91 (s, 1H), 7.53 (s, 1H), 7.17 (s, 1H), 3.33 (q, 2H), 1.17 (t, 3H); MS (ES) for C8H9BrN4: 241 (MH+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:49]([C:45]2[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH3:41])[CH:44]=2)(=[O:51])=[O:50])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) was added a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran (5 mL) at 0° C., and 15-crown-5 (330 mg) and 3-methoxybenzenesulfonyl chloride (310 mg) were added at the same temperature. The mixture was stirred at room temperature for 30 min, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as a colorless oil (yield 551 mg, quantitative).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:15]1(O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:15]1([O:1][C:2]2[C:7]3[C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[O:11][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Reactant: OC1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)c2c(OC3CCCCC3)cccc2O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a cold mixture of 5-hydroxy-2,2-dimethyl-benzo[1,3]dioxin-4-one (1 g, 5.21 mmol) and cyclohexanol (1.98 g, 19.8 mmol) and triphenyl phosphine (2.46 g, 9.38 mmol) in THF in an ice bath was added diisopropyl azodicarboxylate (DIAD) (1.94 g, 9.59 mmol). Resulting mixture was stirred at 0° C. for 15 min and then at rt for 1 h. Reaction mixture was concentrated and the residue was purified by silica gel chromatography (eluting with 50%-100% CH2Cl2 in hexanes) to provide the title compound (0.97 g). 1H NMR (200 MHz, CDCl3): δ (ppm)=7.36 (t, J=8.2 Hz, 1H), 6.60 (d, J=8.6 Hz, 1H), 6.47 (d, J=8.2 Hz, 1H), 4.39 (m, 1H), 1.93-1.37 (m, 10H), 1.69 (s, 6H).
Reaction SMILES: [CH2:1]([N:3]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:4](=[O:27])[CH2:5][N:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7](=[O:20])[CH2:8][N:9]1C(=O)C2=CC=CC=C2[C:10]1=[O:19])[CH3:2].O.NN.[CH3:37][C:38]1[CH:39]=[C:40]([N:44]=C=O)[CH:41]=[CH:42][CH:43]=1>>[CH2:1]([N:3]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:4](=[O:27])[CH2:5][N:6]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:7](=[O:20])[CH2:8][NH:9][C:10]([NH:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH3:37])[CH:39]=1)=[O:19])[CH3:2]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCN(C(=O)CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccccc1)c1ccccc1
Agent: NN
Solvent: O
Product: CCN(C(=O)CN(C(=O)CNC(=O)Nc1cccc(C)c1)c1ccccc1)c1ccccc1
Yield: 30.5 %

Procedure:
The procedure is analogous to that described in Example 23, but 3.1 g of N-ethyl-N-phenyl-2-(N-phenyl-2-phthalimidoacetamido)acetamide, 0.4 g of hydrazine hydrate and 0.54 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 20 g of silica (0.065-0.200 mm) contained in a column 1.7 cm in diameter [eluent: methylene chloride], collecting 20 cm3 fractions. Fractions 10 to 23 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from diethyl ether, 0.55 g of N-ethyl-N-phenyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 158° C. is obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[CH:14][C:13](=[O:16])[CH2:12][N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C(=O)([O-])[O-].[K+].[K+].[I:31]I>CN(C)C1C=CN=CC=1.C1COCC1.CCOCC>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([I:31])[C:13](=[O:16])[CH2:12][N:11]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CC(=O)C=C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(=O)C(I)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
To a solution of (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 50, 10 g, 29.28 mmol) and 4-dimethylaminopyridine (0.894 g, 7.32 mmol) in THF (100 mL)/water (100 mL) at room temperature was added potassium carbonate (3.24 g, 23.42 mmol) and iodine (8.92 g, 35.14 mmol). After stirring for 15 minutes, the reaction mixture was diluted with ether and washed with saturated sodium thiosulfate twice, then 5% citric acid and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-15% ethyl acetate/hexanes) afforded the desired product as a tan oil (11.6 g, 85%).
Reaction SMILES: [CH:1]([C:4]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)([CH2:7][CH2:8][CH2:9]Cl)[C:5]#[N:6])([CH3:3])[CH3:2].CN[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:38][N:39](P(N(C)C)(N(C)C)=O)C>>[CH2:23]([CH2:38][NH:39][CH2:9][CH2:8][CH2:7][C:4]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:1]([CH3:3])[CH3:2])[C:5]#[N:6])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CNCCc1ccccc1
Reactant: COc1cc(OC)cc(C(C#N)(CCCCl)C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(OC)cc(C(C#N)(CCCNCCCc2ccccc2)C(C)C)c1
Temperature: 80 °C
Yield: 81 %

Procedure:
29.5 g (0.1 mole) of α-isopropyl-α-(3-chloropropyl)-3,5-dimethoxyphenylacetonitrile and 13.5 g (0.1 mole) of N-methylphenethylamine were dissolved in 45 ml of hexamethylphosphorotriamide, and 30 g of powdered anhydrous potassium carbonate were added. The reaction mixture was heated at 80° C. for 4 hours and then cooled, after which 500 ml of water were added and the mixture was extracted twice with ether. The ether phase was washed several times with water and dried over potassium carbonate, and the ether was distilled off. The resulting base was converted to the hydrochloride. 34.8 g (81%) of a product of melting point 126°-127° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][CH:35]=1>ClCCl>[F:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:42])=[CH:36][CH:35]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (33.6 mg, 0.33 mmol) (Aldrich), followed by the addition of 1-fluoro-4-isocyanato-benzene (39.7 mg, 0.22 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (4-fluoro-phenyl)-amide as a white solid (Yield 40 mg, 59%).