Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:13][OH:14]>>[CH3:13][O:14][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=1[Cl:1]
Reactant: COc1ccc(C(=O)Cl)c(Cl)n1
Reactant: CO
Product: COC(=O)c1ccc(OC)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of 2-chloro-6-methoxy-nicotinoyl chloride (340 g, 1650 mmol) in MeOH (4500 mL) was stirred at RT for 1 h. The solvent was evaporated in vacuo. The mixture was basified with a saturated solution of NaHCO3 and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; petroleum ether/EtOAc 10/1). The desired fractions were collected and the solvents evaporated in vacuo to yield 2-chloro-6-methoxy-nicotinic acid methyl ester (280 g, 90%) as a solid.
Reaction SMILES: C1O[C@H](CO)[C@@H](O)[C@H]1O.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].C(OC(=O)C)(=O)C.[Br:25]Br.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:25][C:14]1[CH:13]=[CH:12][C:11]([NH2:16])=[C:10]([NH2:17])[CH:15]=1
Reactant: Nc1ccccc1N
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: OC[C@H]1OC[C@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(Br)cc1N
Temperature: 0 °C

Procedure:
A method for synthesizing a deoxyribofuranose compound having a structure represented by the above-mentioned formula (12) will be explained. The compound can be synthesized according to the scheme shown in FIG. 2. First, 4-bromo-phenylene diamine (compound 13) is synthesized. The synthesis can be conducted by a method disclosed in Japanese Laid-Open Patent Application Nos. 63-22091 and 63-179870. Specifically, o-phenylene diamine is added to acetic acid, and further mixed with acetic anhydride under cooling, and the resultant reaction mixture is heated. After cooling, a bromine solution in acetic acid is slowly added to the reaction mixture. Then, an acidic sodium sulfite solution dissolved in ice water is added into the reaction mixture. The resultant white precipitate is collected to obtain compound 13, 4-bromo-o-phenylene diamine. By reacting compound 13 and 1,2-bis(chlorodimethylsilyl)ethane, compound 14 of which two amino groups attached to the benzene ring are protected, can be obtained. By lithiating compound 14 by reacting with butyl lithium (n-BuLi), compound 15 can be obtained. Then, 2,3,5-tri-o-benzyl ribonolactone (compound 16) dissolved in THF (20 ml) is reacted with compound 15. The protecting groups of the amino groups on the benzene ring are removed by using trifluoroborane and triethylsilane to obtain compound 17. Compound 18 can be obtained by treating compound 17 with benzoyl chloride. Treatment of compound 18 with boron tribromide in dichloroethane to convert all benzyloxy groups at 2', 3' and 5' positions of compound 18 to hydroxyl groups gives ribofuranose compound 11. Then compound 11 is reacted with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane so as to obtain compound 19 where 3' and 5' hydroxyl groups of the ribofuranose compound 11 are protected. The hydroxyl group at the 2' position of compound 19 is reacted with p-trichlorothinoformate so as to obtain compound 20. Compound 20 is reacted with tributyltin hydride in the presence of a catalytic amount of azoisobutylonitrile (AIBN) to obtain compound 21. By reacting compound 21 with tetrabutyl ammonium fluoride in THF at room temperature to remove the protection group, a deoxyribonucleoside having a deoxyribofuranose ring represented by the above-mentioned formula 12, which does not have a hydroxyl group at the 2' position, can be obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[C:5]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:4]=2[O:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:20])[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[C:5]2[CH:15]=[C:16]([NH:19][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)N=C(n2ccccc2=O)c2cc(N)ccc2O1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)C(n1ccccc1=O)=NC(C)(C)O2
Reaction time: 16 h

Procedure:
A mixture of 1 g of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-amino-2H-1,3-benzoxazine, 10 ml of acetic anhydride and 10 ml of pyridine is left to stand at 20° for 16 hours. The mixture is evaporated, and the residue is purified by chromatography to give 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-acetamido-2H-1,3-benzoxazine.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O)([O-:11])=[O:10].C([O-])(O)=O.[Na+]>COCCOC.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>[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: O=Cc1sccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1sccc1-c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.5 %

Procedure:
The compound 3-bromothiophen-2-aldehyde (2) (5.20 g, 27 mmol), solubilized in ethylene glycol dimethyl ether (105 ml) was treated with (Ph3P)4Pd (936 mg, 0.81 mmol), with 2-nitrophenylboronic acid (5 g, 30 mmol) and an aqueous solution of 2M NaHCO3 (70 ml). The reaction mixture was then refluxed for 5 hrs. Then the mixture was cooled to room temperature, the solvent was partially removed under reduced pressure and the resulting mixture was extracted with ethyl acetate (4×100 ml). The combined organic layer was washed with a saturated solution of NaCl, dried (Na2SO4), and evaporated under reduced pressure. The mixture was chromatographed using 80/20 petroleum ether/ethyl acetate, thus giving the derivative (8) (4.5 g, 83% yield).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([N:13]([CH2:22][CH3:23])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH3:12]>>[CH2:11]([N:13]([CH2:22][CH3:23])[C:14]1[CH:21]=[CH:20][C:17]([CH:18]([NH:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[NH:10][C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:16][CH:15]=1)[CH3:12]
Reactant: CCCCCCCC(N)=O
Reactant: CCN(CC)c1ccc(C=O)cc1
Product: CCCCCCCC(=O)NC(NC(=O)CCCCCCC)c1ccc(N(CC)CC)cc1
Yield: 68 %

Procedure:
Compound 54 was prepared from octanamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 68%. 1H NMR (400 MHz, DMSO) δ 8.21 (d, J=8.0 Hz, 2H), 7.07 (d, J=8.8 Hz, 2H), 6.61 (d, J=8.8 Hz, 2H), 6.42 (t, J=8.0 Hz, 1H), 3.29-3.31 (m, 4H), 2.06-2.14 (m, 4H), 1.47-1.50 (m, 4H), 1.08-1.24 (m, 16H), 1.06 (t, J=7.2 Hz, 6H), 0.94 (t, J=7.2 Hz, 6H). LC-MS (ESI): m/z 446.3 (M+H)+. HRMS (ESI) for C27H48N3O2 (MH+): calcd, 446.3741. found 446.3734.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=1)[N:13]=[C:12]([Cl:18])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:10]2[Cl:25].CN([CH:29]=[O:30])C>C1COCC1>[Cl:18][C:12]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:10]([Cl:25])[C:9]2[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]([CH:29]=[O:30])[CH:8]=2)[N:13]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)cc2c(Cl)c(-c3ccccc3)c(Cl)nc12
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
A −71° C. solution of n-BuLi (6.14 mL, 1.59 M in hexane, 9.77 mmol) under argon was treated with a solution of 6-bromo-2,4-dichloro-8-methyl-3-phenylquinoline (3.26 g, 8.81 mmol, Intermediate 3: step a) in THF (27 mL) as an intermittent fine stream over 28 minutes. After a few minutes, DMF (1.38 mL, 17.8 mmol) was added dropwise over 2 minutes to the reddish-brown reaction, and the resulting greenish-black mixture was stirred at −72° C. for 30 minutes. The reaction was removed from the cold bath and allowed to stir under ambient conditions for 10 minutes, and was then quenched in one portion with 5 M aqueous NH4Cl (7 mL), partitioned with 4:1 EtOAc/heptane (50 mL) and 5:3 4 M aqueous NaCl/5 M aqueous NaBr (40 mL), and filtered. The filter cake was dissolved in 9:1 DCM/MeOH (15 mL), and this was combined with the clear yellow organic layer filtrate and dried (Na2SO4), filtered, and concentrated. The residue was dry load flash chromatographed with a 20% DCM/heptane to 100% DCM gradient to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:28][CH:29]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 18-mL vial was charged with methyl 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]acetate (11.8 mg, 0.029 mmol, 1 eq.) and LiOH/H2O (42 mg, 1 mmol, 34 eq.). THE (1 ml) and H2O (0.5 ml) was added to the vial. The resulting mixture was stirred at room temperature overnight. 2 N HCl aq. (0.5 ml) was added and the volatile material was removed under reduced pressure. The residue was purified by chromatography on silica gel using dichloromethane followed by 10% of methanol in dichloromethane as eluent to give 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]acetic acid, which was treated with 4N HCl in dioxane (2 ml). After the volatile material was removed under reduced pressure, 2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]acetic acid HCl salt was obtained (8 mg, 65% yield). MW=431.31. 1H NMR (DMSO-D6, 360 MHz) δ 7.88 (s, 1H), 7.70 (s, 1H), 7.47 (m, 2H), 7.23 (m, 2H), 6.94 (m, 3H), 4.67 (s, 2H), 2.95 (m, 2H), 2.82 (m, 2H), 2.09 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:5]([O:7][CH3:8])=[O:6].[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C(OCC)(=O)C>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:5]([O:7][CH3:8])=[O:6])=[O:25]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1ccc(NCC2CCOCC2)c(N)c1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NCC2CCOCC2)c(NC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67.7 %

Procedure:
To a solution of methyl 3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]benzoate (step B, 527 mg, 1.93 mmol) in ethyl acetate (16 mL) was added pivaloyl chloride (256 mg, 2.12 mmol) at room temperature. After stirring for 14 h at room temperature, the mixture was quenched with saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound (455 mg, 71%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH2:31])[N:23]=2)=[CH:15][CH:14]=1)(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].N1C=CC=CC=1>ClCCl>[C:6]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:2]([CH3:1])(=[O:4])=[O:3])[N:23]=2)=[CH:17][CH:18]=1)(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C(=O)Oc1ccc(-c2nnn(Cc3ccccc3N)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc(-c2nnn(Cc3ccccc3NS(C)(=O)=O)n2)cc1
Reaction time: 15 h
Yield: 69.9 %

Procedure:
Methanesulfonyl chloride (114.5 mg) was added to a solution of 4-[2-(2-aminobenzyl)tetrazol-5-yl]phenyl pivalate (0.351 g), obtained in example 78, and pyridine (79 mg) in dichloromethane (2 ml) under ice cooling, and stirring was continued for 15 h. The mixture was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel with ethyl acetate-hexane (1/2) as an eluate. Recrystallization from ethyl acetate-hexane gave 300 mg (70%) of the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[N:7]=[CH:8][CH:9]=2)[N:4]([CH3:13])[CH:3]=1.C([Li])CCC.C(O[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)(C)C>>[CH3:12][O:11][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:2]([B:23]3[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]3)=[CH:3][N:4]([CH3:13])[C:5]=12
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COc1nccc2c(I)cn(C)c12
Agent: [Li]CCCC
Product: COc1nccc2c(B3OC(C)(C)C(C)(C)O3)cn(C)c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
3-Iodo-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine (3.89 g, 13.50 mmol) was flow purged with nitrogen for 30 minutes, then treated with tetrahydrofuran (135 mL). The reaction mixture was cooled to −78° C. Butyllithium (5.40 mL, 13.50 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.75 mL, 13.50 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 2.5 hours. The reaction mixture was poured onto water and extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 100% heptane to 30% ethyl acetate/heptane) to provide the title compound (2.75 g, 70% yield).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:25](=[C:26]([C:37]3[CH:45]=[CH:44][C:40]4[O:41][CH2:42][O:43][C:39]=4[CH:38]=3)[C:27]=1[CH2:28]OCC1C=CC=CC=1)[C:21]1[O:22][CH2:23][O:24][C:20]=1[CH:19]=[CH:18]2)=[O:14])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([C:15]1[CH:16]=[C:17]2[C:25](=[C:26]([C:37]3[CH:45]=[CH:44][C:40]4[O:41][CH2:42][O:43][C:39]=4[CH:38]=3)[C:27]=1[CH3:28])[C:21]1[O:22][CH2:23][O:24][C:20]=1[CH:19]=[CH:18]2)=[O:14]
Reactant: O=C(OCCCOCc1ccccc1)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1COCc1ccccc1)OCO3
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1c(C(=O)OCCCO)cc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3
Yield: 93 %

Procedure:
A mixture of 6 (48 mg, 0.079 mmol) and 10% Pd/C (12 mg) in dry THF (5 mL) was stirred for 14 h at room temperature under 1 atm of hydrogen. The mixture was filtered, and the filtrate evaporated at reduced pressure. The residue was purified by column chromatography on silica gel using CH2Cl2/MeOH (40:1, v/v) to yield 7 (30 mg, 93%) as a yellow oil. 1H NMR (CDCl3) δ 8.32 (s, 1H, H4), 7.50 (d, 1H, H5, J=8.7 Hz), 7.18 (d, 1H, H6, J=8.7 Hz), 6.87 (d, 1H, H5′, J=7.8 Hz), 6.72 (d, 1H, H2′, J=1.5 Hz), 6.68 (dd, 1H, H6′, J=1.5, 7.8 Hz), 6.05 (AB, 2H, 3′,4′-OCH2O—, Δδ=9.6 Hz, J=1.5 Hz), 5.83 (AB, 2H, 7,8-OCH2O—, Δδ=1.5 Hz, J=1.5 Hz), 4.54 (t, 2H, 3-COOCH2(CH2)2OH, J=6.3 Hz), 3.83 (t, 2H, 3-COO(CH2)2CH2OH, J=6.3 Hz), 2.34 (s, 3H, 2-CH3), 2.06 (quintet, 2H, 3-COOCH2CH2CH2OH, J=6.3 Hz); MS (EI) m/z 408 [M]+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)([Cl:16])=[O:15]>ClC1C=CC=CC=1>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:14]([Cl:16])=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C(Cl)N(c1ccccc1)c1ccccc1

Procedure:
By way of illustration, one mole of diphenylamine is reacted with a 10% molar excess of phosgene in a suitable solvent such as monochlorobenzene, to yield diphenylcarbamyl chloride. The carbamyl chloride thus produced is reacted further with n-propyl amine in stoichiometric amounts, in the presence of a mole of caustic soda. Diphenyl propyl urea (DPPU) is formed in essentially stoichiometric amounts. The DPPU formed may be either separated from the solvent or, if desired, supplied as a solution in its reaction solvent. DPPU pyrolyzes at 210°-220° C. to yield n-propyl isocyanate of 99% purity and greater than 90% yield. The diphenylamine remaining may be returned easily in tankcars or tankwagons for reprocessing.
Reaction SMILES: ClC1C=C(C2N(C3C=CC=C(Cl)C=3)N=C(C(O)=O)C=2)C=C(F)C=1.[Cl:24][C:25]1[CH:26]=[C:27]([N:32]2[C:36]([C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([Cl:44])[CH:38]=3)=[CH:35][C:34]([C:45]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:46])=[N:33]2)[CH:28]=[CH:29][C:30]=1F>>[Cl:44][C:39]1[CH:38]=[C:37]([C:36]2[N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=3)[N:33]=[C:34]([C:45]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:46])[CH:35]=2)[CH:42]=[C:41]([F:43])[CH:40]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 72A in analogy to the synthesis of the compound of Example 1. 50 mg (84% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([O:38][C:39](=[O:57])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]>C(OCC)(=O)C.[Pd]>[C:1]([NH:18][C@H:19]([C:23]([O:25][CH2:26][CH:27]([O:38][C:39](=[O:57])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:28]([OH:30])=[O:29])=[O:24])[CH:20]([CH3:22])[CH3:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)OC(COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)O

Procedure:
A solution of benzyl 3-(N-FMOC-L-valyloxy)-2-stearoyloxypropionate (0.78 g, 1 mmole) in 20 ml ethyl acetate was hydrogenated with 10% palladium on charcoal (0.2 g) at normal pressure for three hours at room temperature. The catalyst was filtered and washed with ethyl acetate and 1,4-dioxane. The solution was evaporated under reduced pressure. Yield: 0.63 g=90%
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].CC(C)(C)[CH2:10][NH:11][CH2:12][C:13]1[O:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1.[CH3:43][C:44](C)(C)CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:10]([N:11]([CH2:12][C:13]1[O:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:32][CH2:31]2)[CH:14]=1)[CH2:43][CH3:44])[CH3:2]
Reactant: CC(C)(C)CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(CNCC(C)(C)C)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)co1
Yield: 12 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 2M diethylamine (102.4 mg, 1.4 mmol) for 2,2-dimethyl-1-propanamine to afford 10.1 mg of the title compound (12%).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[CH:18]([C:20]1[N:25]=[C:24]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=3)[N:29]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:28]=2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:23]=[CH:22][CH:21]=1)=O.O>CS(C)=O.[Cl-].[Na+].O>[C:1](/[CH:3]=[CH:18]/[C:20]1[N:25]=[C:24]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][C:32]([O:36][CH3:37])=[CH:33][CH:34]=3)[N:29]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C:28]=2[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:23]=[CH:22][CH:21]=1)#[N:2]
Reactant: COc1ccc2c(Cc3cccc(C=O)n3)c(-c3ccccc3)n(C(=O)OC(C)(C)C)c2c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(Cc3cccc(/C=C/C#N)n3)c(-c3ccccc3)n(C(=O)OC(C)(C)C)c2c1
Reaction time: 0.5 h

Procedure:
To a solution of diethyl cyanomethylphosphonate (0.173 mL) in dimethylsulfoxide (6 mL) was added potassium tert-butoxide (127 mg) at room temperature, and the mixture was stirred for 30 minutes. Then a solution of tert-butyl 3-(6-formylpyridin-2-ylmethyl)-6-methoxy-2-phenyl-1H-indole-1-carboxylate (385 mg) in dimethylsulfoxide (3 mL) was added dropwise at room temperature, and the mixture was stirred overnight. To the reaction mixture were added water and saturated brine, followed by extraction with ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (192 mg). 1H-NMR (CDCl3) δ ppm: 1.23 (9H, s), 3.89 (3H, s), 4.04 (2H, s), 6.55 (1H, d, J=15.8 Hz), 6.82-6.90 (1H, m), 6.96-7.03 (1H, m), 7.04-7.12 (1H, m), 7.23-7.46 (7H, m), 7.48-7.57 (1H, m), 7.82-7.90 (1H, m).
Reaction SMILES: C([N:4]1[C@H:9]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:7][CH2:6][C@@H:5]1[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1)C=C.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:15]1[C:10]([C@H:9]2[CH2:8][CH2:7][CH2:6][C@@H:5]([C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:4]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=CCN1[C@@H](c2ncccc2C)CCC[C@H]1c1ncccc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reaction time: 20 h
Yield: 85 %

Procedure:
To a solution of 1′-allyl-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (142 mg, 0.462 mmol) in CH2Cl2 was added 1,3-dimethylbarbaturic acid (361 mg, 2.31 mmol) and Pd(PPh3)4 (53 mg, 0.046 mmol) and the reaction mixture was stirred for 20 h. Saturated solution of NaHCO3 (10 mL) was added and the mixture was extracted with CH2Cl2 (3 times 20 mL). The organic extracts were dried (MgSO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (9:1:0.2 CH2Cl2-MeOH—NH4OH) to provide 105 mg (85%) of the 3,3″-dimethyl-1′,2′,3′,4′,5′, 6′-hexahydro-cis-[2,2′;6′,2″]terpyridine as a clear oil. 1H NMR(CDCl3) δ 1.51-1.63 (m, 2H), 1.76-1.85 (m, 3H), 2.11-2.15 (m, 1H), 2.37 (s, 6H), 3.10-3.30 (m, 1H), 4.22 (d, 2H, J=10.8 Hz), 7.02 (dd, 2H, J=7.5, 4.5 Hz), 7.38 (d, 2H, J=7.5 Hz), 8.45 (d, 2H, J=4.5 Hz); 13C NMR (CDCl3) δ 18.68, 25.84, 32.28, 57.60, 121.96, 129.73, 138.04, 147.31, 160.94; ES-MS m/z 269.1 (M+H). Anal. Calcd. for C17H21N3.0.1CH2Cl2: C, 74.45; H, 7.75; N, 15.23. Found: C, 74.70; H, 7.80; N, 15.18.