Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:13]([F:16])([F:15])[F:14])=[CH:5][C:6](=[O:12])[NH:7]2.C(NC(C)C)(C)C.[Br:24]N1C(=O)CCC1=O.Cl>CCOC(C)=O>[Br:24][C:11]1[C:2]([OH:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:12])[CH:5]=[C:4]2[C:13]([F:16])([F:14])[F:15]
Reactant: O=c1cc(C(F)(F)F)c2c(O)cccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: O=c1cc(C(F)(F)F)c2c(O)c(Br)ccc2[nH]1
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 5-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one (4.38 g, 19.1 mmol) and diisopropylamine (14 mL, 100 mmol) in 100 mL EtOAc was added a solution of N-bromosuccinimide (3.74 g, 21.0 mmol) in 70 mL EtOAc at −10° C. over 30 min. The reaction mixture was stirred for 1 h, then acidified to pH 1 by the addition of 6M HCl. The mixture was extracted with EtOAc (3×150 mL) and the combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Recrystallization from chloroform:hexanes afforded 4.5 g (77%) of 6-bromo-5-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one, an off-white solid. Rf0.4 (1:1 EtOAc:hexanes); 1H NMR (400 MHz, acetone-d6) δ 11.1 (broad s, 1H), 8.75 (broad s, 1H), 7.76 (d, 1H, J=8.8), 7.04 (d, 1H, J=8.8), 6.98 (s, 1H).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].CCN(CC)CC.[CH3:14][O:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24](OS(C(F)(F)F)(=O)=O)=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:17]>CN(C=O)C.[Cu]I.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>[CH3:14][O:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2cc(C#C[Si](C)(C)C)ccc12
Reaction time: 15 h

Procedure:
A solution of 15.6 ml (113 mMol) ethynyl-trimethylsilane (Fluka; Buchs/Switzerland) and 15.7 ml (113 mMol) Et3N in 250 ml degassed DMF is added to 34 g (102 mMol) 6-trifluoromethanesulfonyloxy-naphthalene-1-carboxylic acid methyl ester, 1.0 g (5.2 mMol) CuI and 5.0 g (7.1 mMol) Pd(PPh3)2Cl2 in 250 ml of degassed DMF. After 15 h at rt, the mixture is concentrated partially in vacuo at 40° C. and the residue re-dissolved in sat. NaHCO3 solution and EtOAc. The aq. phase is separated off and extracted twice with EtOAc. The organic layer is washed twice with sat. NaHCO3 solution, water/sat. NaHCO3 solution 1:1 and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; hexane/EtOAc 199:1) gives the title compound as an oil: MS: [M+1]+=283; TLC(hexane/EtOAc 19:1): Rf=0.22.
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:21])[CH:15]=[CH:16][C:17](OC)=[O:18].CCCCCC.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:23][Si:2]([CH3:1])([CH3:22])[O:3][CH:4]1[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:13])[CH:5]1[CH2:6][CH2:7][C@@H:8]2[C@H:14]([CH3:21])[CH:15]=[CH:16][CH2:17][OH:18]
Reactant: COC(=O)C=C[C@@H](C)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C[C@H](C=CCO)[C@H]1CCC2C(O[Si](C)(C)C)CCC[C@@]21C
Temperature: -95 °C
Reaction time: 1 h

Procedure:
A 3.66 g amount of methyl(4R)-4-[(1R,7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-yl]-2-pentenoate was placed in a 500 ml eggplant-shaped flask, and 100 ml of hexane and 40 ml of toluene were then added to dissolve it. The solution was cooled to −95° C., then 12.2 ml of diisobutylaluminum hydride was slowly added and the solution stirred at the same temperature for 1 hour. Next, a further 24 ml of diisobutylaluminum hydride was added, followed by stirring for 2 hours. The consumption of the material was confirmed by thin layer chromatography, then the excess reducing agent was broken down by methanol and a saturated aqueous solution of sodium sulfate and then 300 ml of ethyl acetate and 80 ml of a saturated aqueous solution of ammonia chloride were added for separation. Extraction was performed from the aqueous layer by 100 ml of ethyl acetate, then the organic layer was washed with saturated saline and was dried by anhydrous magnesium sulfate. The desiccant was filtered out, then the filtrate was concentrated under reduced pressure to obtain a crude product in an amount of 3.61 g. This was purified by a silica column (hexane/ethyl acetate=19/1 to 4/1) to obtain (4R)-4-[(1R, 7aR)-octahydro-4-trimethylsilyloxy-7a-methyl-1H-inden-1-y l]-2-penten-1-ol in an amount of 3.31 g (98%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]([CH2:15][CH2:16][CH:17]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH3:18])[CH2:5]2.C(Cl)(Cl)Cl.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:30]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]([CH2:15][CH2:16][CH:17]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH3:18])[CH2:5]2)#[N:31]
Reactant: CCCN(CCC)C(C)CCC1Cc2cc(Br)ccc2C1OCOC
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)C(C)CCC1Cc2cc(C#N)ccc2C1OCOC
Temperature: 80 °C
Reaction time: 48 h

Procedure:
The compound (552.4 mg) obtained in Example 127-8 was dissolved in DMF (1.67 ml) and added with zinc cyanide (94.3 mg) and tetrakistriphenyl phosphine palladium (61.8 mg), followed by stirring at 80° C. for 48 hours. The reaction solution was added with chloroform and washed with a 7% aqueous ammonium solution and saturated saline solution. The solution was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (436.8 mg) as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.C[Si]([N:31]=[C:32]=[O:33])(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:32](=[O:33])[NH2:31])[CH2:20][CH2:21]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(N)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.4 %

Procedure:
To a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (610 mg) in methylene chloride (30 ml) is added trimethylsilyl isocyanate (180 mg) under ice-cooling, and the mixture is stirred at room temperature for 15 hours. The reaction mixture is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by basic silica gel column chromatography (eluent; chloroform: methanol=40:1) to give 4-amino-5-chloro-N-[1-(1-carbamoyl-4-piperidinylmethyl)-4-piperidinyl]-2-methoxybenzamide (440 mg) as white amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1.C[Si](C)(C)[C:27]([F:30])([F:29])[F:28].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1COCC1>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:15])([C:27]([F:30])([F:29])[F:28])[C:6]=2[CH:5]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1
Reactant: CCOC(=O)CCCOc1cc(Cl)c2c(c1)C(=O)c1ccccc1-2
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere, ethyl 4-(4-chloro-9-oxo-9H-fluorene-2-yloxy)butyrate (69.4 g) was dissolved in THF (700 ml), and N-(4-tert-butylbenzyl)cinchonidium 4-methoxyphenoxide (6.4 g) was added. To the reaction mixture was added dropwise a solution of trimethyl(trifluoromethyl)silane (52.0 ml) in THF (140 ml) at −16° C., and the mixture was stirred at the same temperature for 15 min. To the reaction mixture were successively added acetic acid (23.0 ml) and 1M tetrabutylammonium fluoride/THF solution (222 ml), and the mixture was stirred at room temperature for 1 hr. The solvent in the reaction mixture was evaporated, and to the obtained residue were added toluene (500 ml) and saturated aqueous sodium hydrogen carbonate (200 ml) to allow for layer separation. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate (150 ml, twice), 1N aqueous sodium hydroxide (100 ml), water (100 ml), 1N hydrochloric acid (100 ml), water (100 ml) and saturated brine (100 ml). To the obtained organic layer were added anhydrous magnesium sulfate and silica gel (150 g), and the mixture was stirred for 10 min. The insoluble material was filtered off, and the insoluble material was washed successively with toluene (300 ml) and ethyl acetate (800 ml). The obtained filtrate and the toluene washing were combined and the solvent was evaporated to give the title compound (72.1 g). Also, the solvent in the ethyl acetate washing was evaporated, to the obtained residue were added silica gel (40 g) and a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane 2:1, 300 ml), and the mixture was stirred at room temperature. The insoluble material was filtered off, and the insoluble material was washed with a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane=2:1, 300 ml). The solvent in the obtained filtrate was evaporated to further give the title compound (20.3 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:17](=[O:18])[C:16](=[CH:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:15]2[N:11]([C:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:13][N:14]=2)[C:10]2[CH:35]=[CH:36][CH:37]=[CH:38][C:9]1=2)([CH3:4])([CH3:3])[CH3:2]>CCO.CCOC(C)=O>[C:1]([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:17](=[O:18])[CH:16]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:15]2[N:11]([C:12]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[N:13][N:14]=2)[C:10]2[CH:35]=[CH:36][CH:37]=[CH:38][C:9]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(=Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Yield: 87.5 %

Procedure:
Following the procedure described for Example 1(A), Step B, [4-(1H-indol-3-ylmethylene)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid tert-butyl ester (4.84 g, 9.37 mmol) was reduced in EtOH (150 mL) for 3 hours at 80° C. The residue was dissolved in EtOAc and was washed with aqueous NH4Cl (1×) and brine (1×). The organic solution was dried (Na2SO4), filtered and concentrated to provide 4.26 g of [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid tert-butyl ester. 1H NMR (DMSO-d6), δ 7.65 (d, 1H), 7.53-7.38 (m, 7H), 7.27 (m, 1H), 7.18 (m, 2H), 6.98 (m, 1H), 6.89 (m, 2H), 4.75 (d, 1H), 4.43 (d, 1H), 3.82 (t, 1H), 3.59 (m, 2H), 1.22 (s, 9H).
Reaction SMILES: [N:1](=[C:3]1[CH:7]([CH3:8])[O:6][CH2:5][S:4]1)[OH:2].[Cl:9][CH2:10][CH2:11][N:12]=[C:13]=[O:14].C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>CCOCC>[Cl:9][CH2:10][CH2:11][NH:12][C:13]([O:2][N:1]=[C:3]1[CH:7]([CH3:8])[O:6][CH2:5][S:4]1)=[O:14]
Reactant: CC1OCSC1=NO
Reactant: O=C=NCCCl
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CCOCC
Product: CC1OCSC1=NOC(=O)NCCCl

Procedure:
4-Oximino-5-methyl-1,3-oxathiolane was caused to react with 2-chloroethylisocyanate in the presence of dibutyltin diacetate in ether. The reaction mixture was worked up and recrystallized in the manner described in Example I. The product had a mp 88.5°-90.5°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].C[O:19][C:20](=O)[C:21]([CH2:29][CH3:30])([CH2:24][NH:25][CH:26]([CH3:28])[CH3:27])[CH2:22][CH3:23].C(O)(=O)C>CC(C)=O.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([NH:9][C:20](=[O:19])[C:21]([CH2:22][CH3:23])([CH2:29][CH3:30])[CH2:24][N:25]2[CH:26]([CH3:28])[CH3:27])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCC(CC)(CNC(C)C)C(=O)OC
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCC1(CC)CN(C(C)C)c2nc(Cl)ncc2NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (Aldrich; 5.1 g, 26.4 mmol) and K2CO3 (4.4 g, 31.6 mmol) in acetone (150 mL) was slowly added methyl2-ethyl-2-[(propan-2-ylamino)methyl]butanoate (Intermediate 200; 5.3 g, 26.4 mmol) in acetone (30 mL). The mixture was stirred at room temperature for 18 hours. The reaction was filtered and the solvent evaporated. The residue and iron (4.4 g, 79.2 mmol) were added to acetic acid (175 mL) and heated at 80° C. overnight. The resulting solution was filtered and the solvent evaporated and the residue quenched with 2.0 N NaOH(aq) (75 mL), to the resultant emulsion, was added 10% MeOH/DCM (100 ml) and the suspension filtered through a pad of celite. The obtained filtrate was extracted with 10% MeOH/DCM (3×150 mL, dried and the solvent removed. The resultant material was dissolved in DCM and filtered. Acetonitrile was added to the DCM and the DCM was slowly removed in vacuo to give a precipitate, which was filtered and dried to yield the title compound as a white solid. (3.1 g, 33%)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1.Cl[CH2:21][C:22]1[N:26]([CH3:27])[N:25]=[CH:24][N:23]=1.O>CN(C)C=O>[CH3:27][N:26]1[C:22]([CH2:21][N:9]2[CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:5][C:4]2=[O:3])=[N:23][CH:24]=[N:25]1
Reactant: Cn1ncnc1CCl
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1CN1CCN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 281 mg, 7.0 mmol) was added to a solution of phenylmethyl 3-oxo-1-piperazinecarboxylate (1.5 g, 6.4 mmol) in dry dimethyl formamide (5 mL) and the mixture was stirred at room temperature for 30 minutes. 5-(Chloromethyl)-1-methyl-1H-1,2,4-triazole (WO0023449, 920 mg, 7.0 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water (150 mL) and extracted with diethyl ether (2×100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a pale oil (2 g, 94%). m/z (ES+) 330 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]([NH2:12])([CH3:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=1.CCN(C(C)C)C(C)C>CC#N>[Cl:13][C:14]1[N:15]=[C:16]([NH2:21])[N:17]=[C:18]([NH:12][C:3]([CH3:2])([CH3:11])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:19]=1
Reactant: CC(C)(N)Cc1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Cc1ccccc1)Nc1cc(Cl)nc(N)n1
Temperature: 160 °C
Yield: 50.5 %

Procedure:
A mixture of 2-methyl-1-phenyl-2-propanamine hydrochloride (742 mg, 4 mmol), 4,6-dichloro-2-pyrimidinamine (438 mg, 2.67 mmol) and Hunig's base (1.55 g, 12 mmol) in CH3CN (8 mL) was stirred and heated for 6 hours at 160° C. in a Biotage Initiator microwave synthesizer. The mixture was cooled to room temperature and concentrated to dryness. The resulting solids were partitioned between EtOAc and water, and the organic layer was dried over Na2SO4, filtered and concentrated to dryness. Purification by reverse phase chromatography using CH3CN in water from 45% to 65% (0.08% ammonium hydrogen carbonate) in 18 min, afforded the title compound (373 mg) as a white solid. LC-MS (ES) m/z=277.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1)([CH2:5][CH:6]([C:11](=[O:27])[NH:12][CH:13]([C:23](=[O:26])[NH:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4].[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH3:1][O:2][P:3]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=1)([CH2:5][CH:6]([C:11](=[O:27])[NH:12][CH:13]([C:23](=[O:26])[NH:24][CH3:25])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])=[O:4]
Reactant: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)CP(=O)(Cc1cccc(N)c1)OC
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNC(=O)C(Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)CP(=O)(Cc1cccc(NCc2ccccc2)c1)OC
Yield: 74.7 %

Procedure:
(3-Aminobenzyl){2-[2-(4-methoxyphenyl)-1-methylcarbamoyl ethylcarbamoyl]-4-methylpentyl}phosphinic acid methyl ester (prepared as described in Example 4/Step A) (150 mg, 0.30 mmole), benzaldehyde (38 mg, 0.36 mmole), sodium cyanoborohydride (23 mg, 0.357 mmole) and acetic acid (1 drop) in methanol were stirred at room temperature for 3 hours. The reaction was quenched with 1N hydrochloric acid (few ml's) and the reaction mixture concentrated. The residue was dissolved in ethyl acetate (20 ml) and washed with 1N hydrochloric acid (20 ml), saturated sodium bicarbonate solution (20 ml) and dried with magnesium sulfate. Filtration and concentration gave the crude product which was purified by chromatography (3:97--methanol:methylene chloride) yielding 133 mg (75%) of (3-Benzylamino benzyl)-{2-[2-(4-methoxyphenyl)-1-methylcarbamoylethylcarbamoyl]-4-methylpentyl}phosphinic acid methyl ester as an oil.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:24]=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)CS(=O)(=O)NC(C)(C)C
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccccc1)S(=O)(=O)NC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
11.2 g (0.05 mol) of ethyl 2-(tert.butylaminosulfonyl)acetate (see J. Org. Chem. 43, p. 4535 (1978)) are dissolved in 50 ml of benzaldehyde, 2 g of ammonium acetate and 2 ml of glacial acetic acid are added, and the mixture is stirred for 2 hours at 60° C. under a water pump vacuum (20 mm). The excess aldehyde is subsequently distilled off, and the residue is digested using n-hexane and recrystallized from isopropanol. 11.2 g (72% of theory) of ethyl 3-phenyl-2-(tert.butylaminosulfonyl)prop-2-enoate of melting point 111°-113° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.COCN[C:13](=[O:24])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:13](=[O:24])[CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:6][CH:7]=1
Reactant: COCNC(=O)CCNC(=O)OC(C)(C)C
Reactant: Brc1ccc(Br)nc1
Product: CC(C)(C)OC(=O)NCCC(=O)c1ccc(Br)nc1

Procedure:
The sub-title compound was prepared from 2,5-dibromopyridine and [3-(methoxymethylamino)-3-oxopropyl carbamic acid, 1,1-dimethylethyl ester by the method of Example 58(a).
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[CH2:16][NH2:17].[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33]([NH:17][CH2:16][C:11]4[N:12]=[CH:13][CH:14]=[CH:15][N:10]=4)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:19][CH2:20]1
Reactant: NCc1ncccn1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ncccn1
Yield: 58 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyrimidin-2-ylmethanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 58% yield: mp 218-220° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.71 (d, J=4.9 Hz, 2H), 7.24-7.21 (m, 1H), 7.15-7.11 (m, 1H), 4.83 (d, J=4.4 Hz, 2H), 4.16-4.11 (m, 2H), 3.74-3.68 (m, 2H), 3.20 (d, J=7.1 Hz, 2H), 2.66 (s, 3H), 1.01-0.91 (m, 1H), 0.59-0.54 (m, 2H), 0.28-0.25 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 165.4, 162.5, 157.7, 157.1, 155.2, 152.7, 119.5, 117.6, 48.6, 45.5, 42.2, 42.1, 17.2, 8.9, 3.4; MS (ES+) m/z 373.3 (M+1).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>S(=O)(=O)(O)O>[N+:1]([C:13]1[CH:12]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:10][CH:14]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cccs1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])cs1
Temperature: 0 °C
Yield: 96 %

Procedure:
A solution of nitric acid/sulfuric acid (1:2.5) was added dropwise to a stirred solution (2.7 M) of ethyl 2-thiophene carboxylate in sulfuric acid at −10° C. After stirring for an additional half an hour, the reaction mixture was poured into ice-water. The resulting precipitate was filtered, washed with water and dried to give the title compound (96%) as a mixture 1:1 of 4-nitro and 5-nitro regioisomers.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][CH2:15][C:16]([N:18]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>ClCCl>[C:19]1([N:18]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:16](=[O:17])[CH2:15][NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:13])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1
Reactant: O=C(O)c1ccc2ccccc2n1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(C(=O)CNC(=O)c1ccc2ccccc2n1)c1ccccc1
Reaction time: 3 h
Yield: 38 %

Procedure:
A solution of 0.85 g of N,N'-carbonyldiimidazole in 10 cm3 of anhydrous dichloromethane is added dropwise, at a temperature close to 20° C., to a solution of 0.87 g of 2-quinolinecarboxylic acid in 15 cm3 of anhydrous dichloromethane. The suspension obtained is stirred for 3 hours at a temperature close to 20° C. and a solution of 2.6 g of tert-butyl 2-(2-amino-N-phenylacetamido)acetate in 25 cm3 of anhydrous dichloromethane is then added. The reaction mixture is stirred for 16 hours at a temperature close to 20° C. and 50 cm3 of water are then added. The aqueous phase is separated off by decanting and then reextracted with twice 15 cm3 of 1,2-dichloroethane. The organic phases are combined, washed with twice 25 cm3 of a saturated aqueous sodium bicarbonate solution and then with twice 25 cm3 of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization of the residual solid from a mixture of cyclohexane and ethyl acetate (90/10 by volume), 0.8 g of tert-butyl 2-(N-phenyl-2-quinolinecarboxamidoacetamido)acetate melting at 114° C. is obtained.