Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14]OS(C)(=O)=O)[C@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[N:21]([CH2:14][C@H:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@H:10]1[OH:20])=[N+:22]=[N-:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](COS(C)(=O)=O)[C@H](O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H](CN=[N+]=[N-])[C@H](O)C1
Temperature: 60 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
To a solution of cis-1-tert-butoxycarbonyl-3-hydroxy-4-methanesulfonyloxymethylpiperidine (4.44 g) in dimethylformamide (60 ml) were added sodium azide (1.4 g) and ammonium chloride (1.15 g), and the resulting mixture was stirred at 60° C. for 6 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=40:1) to give 3.4 g of cis-4-azidomethyl-1-tert-butoxycarbonyl-3-hydroxypiperidine.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Si:13]([N:20]1[C@H:23]([CH:24]2[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][O:25]2)[C@@H:22]([C@H:31]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH3:32])[C:21]1=[O:41])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH3:42][Si:43]([CH3:46])([CH3:45])Cl.[Cl-].[NH4+]>C1COCC1>[Si:13]([N:20]1[C@H:23]([C@@H:24]2[C:29]([O:30][Si:43]([CH3:46])([CH3:45])[CH3:42])=[CH:28][CH2:27][CH2:26][O:25]2)[C@@H:22]([C@H:31]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH3:32])[C:21]1=[O:41])([C:16]([CH3:17])([CH3:19])[CH3:18])([CH3:15])[CH3:14]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C1OCCCC1=O
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1[C@H]1OCCC=C1O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (0.294 ml) in dry THF (5 ml) was added butyllithium (1.25 ml, 1.6M in hexane) dropwise at 0° C. and the mixture was stirred for 10 minutes. This solution was cooled to -78° C. and a solution of (3S,4S)-1-(tert-butyldimethylsilyl)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(2RS)-3-oxotetrahydropyran-2-yl)azetidin-2-one (441 mg) in dry THF (2 ml) was added dropwise. The mixture was stirred for 30 minutes, after which trimethylchlorosilane (0.267 ml) was added. This mixture was stirred at -20° C. for 10 minutes. The reaction mixture was then poured in a saturated aqueous solution of ammonium chloride (20 ml) and extracted with ether (20 ml). The organic layer was washed successively with water (20 ml), 2% HCl (20 ml), saturated aqueous sodium hydrogen carbonate (20 ml) and saturated aqueous sodium chloride (20 ml). The extract was then dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. Finally, the residue was purified by silica gel column chromatography (230-400 mesh, 26 g; ethyl acetate-hexane=1:15) to give (3S,4S)-1-(tert-butyldimethylsilyl)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(2R)-3-trimethylsilyloxy-5,6-dihydropyran-2-yl]azetidin-2-one (228 mg) as a colorless oil.
Reaction SMILES: II.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:29]([NH:32][NH:33][C:34](=O)[CH2:35][N:36]1[C:40]([CH2:41][CH3:42])=[C:39]([O:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)[C:38]([CH2:52][CH3:53])=[N:37]1)(=[O:31])[CH3:30]>ClCCl>[CH2:52]([C:38]1[C:39]([O:43][C:44]2[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[CH:48][CH:49]=2)=[C:40]([CH2:41][CH3:42])[N:36]([CH2:35][C:34]2[O:31][C:29]([CH3:30])=[N:32][N:33]=2)[N:37]=1)[CH3:53]
Reactant: CCc1nn(CC(=O)NNC(C)=O)c(CC)c1Oc1ccc(C#N)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nn(Cc2nnc(C)o2)c(CC)c1Oc1ccc(C#N)cc1
Reaction time: 0.17 h
Yield: 49 %

Procedure:
Iodine (243 mg, 0.95 mmol) was added portionwise to a solution of triphenylphosphine (250 mg, 0.95 mmol) in dichloromethane (10 ml). The reaction mixture was then stirred for 10 minutes, after which time triethylamine (194 mg, 1.9 mmol) was added, followed by the acetylacetohydrazide of step (b) above (170 mg, 0.48 mmol). The reaction mixture was then stirred at room temperature for 12 hours after which time it was evaporated to dryness and purified by flash chromatography on silica gel eluting with ethyl acetate:pentane (1:1, by volume) to provide the title compound (80 mg, 49%) as 4:1 mixture product:triphenylphosphine oxide.
Reaction SMILES: [C:1]1([C@H:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.CC1CCCO1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24].Cl>O>[C:1]1([C@H:7]([O:9][C:23](=[O:24])[O:25][C:26]2[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](O)c1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A mixture of (R)-1-phenyl-ethanol (60.6 g, 0.496 mol), pyridine (42.5 mL, 0.526 mol) and 2-methyl-tetrahydrofuran (600 mL) was cooled to 0° C. and p-nitrophenyl chloroformate (100 g, 0.496 mol) was added over 15 min keeping the internal temperature below 5° C. The reaction mixture was warmed to room temperature and stirred for 2 h. To the reaction mixture was added 1.0 M HCl in water (300 mL). Layers were separated. The organic layer was washed with 1N HCl (300 mL) and brine (300 mL), filtered, concentrated to dryness by rotary evaporation, and dried under vacuum to give the title compound (140 g) as a clear yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[C:21]([CH3:33])[N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[C:21]([CH3:33])[N:20]=2)[N:9]=1)[CH3:1]
Reactant: Cc1nc(N[N+](=O)[O-])[nH]c(=O)c1Cc1cccnc1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: CCO
Product: Cc1nc(NCCSCc2csc(CN(C)C)n2)[nH]c(=O)c1Cc1cccnc1

Procedure:
A reaction mixture was prepared from 1.16 g. of 2-[2-dimethylaminomethyl-4-thiazolylmethylthio]ethylamine, 1.31 g. of 2-nitroamino-5-(3-pyridyl)methyl-6-methyl-4-pyrimidone and 25 ml. of anhydrous ethanol. The reaction mixture was heated at reflux temperature for about 5 days after which time the ethanol was removed by evaporation. The residue was chromatographed using high pressure liquid gradient elution chromatography (silica-ethanol/ethyl acetate/ammonium hydroxide). Fractions containing 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methyl-6-methyl-4-pyrimidone were combined and the solvents removed from the combined fractions. 1.1 g. of crystalline material was obtained which melted at about 130°-131° C. after recrystallization from a mixture of ethanol and ether; yield=1.03 g. 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methyl-6-methyl-4-pyrimidone thus prepared had the following analysis:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: NCC1CCNCC1
Product: Clc1ccc(NCC2CCNCC2)cc1
Yield: 61.4 %

Procedure:
Using the general procedure, 4-bromochlorobenzene (192 mg, 1.0 mmol) was coupled with 4-aminomethylpiperidine (171 mg, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using methanol/dichloromethane (saturated with ammonia) (1:20) as eluent afforded the desired product as a light yellow solid (138 mg, 62% yield). Rf=0.3 (methanol/dichloromethane (saturated with ammonia) (1:20)).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[Cl:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([CH3:18])=[CH:13][N:12]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[K+]>O1CCOCC1.CC(O)=O.CC(O)=O.[Pd]>[Cl:10][C:11]1[N:16]=[C:15]([NH:17][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=2)[C:14]([CH3:18])=[CH:13][N:12]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: Cc1cc(C)cc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(C)cc(Nc2nc(Cl)ncc2C)c1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
A mixture of 1-bromo-3,5-dimethylbenzene (104 μL, 0.77 mmol), 2-chloro-5-methyl-pyrimidin-4-ylamine (104 mg, 0.72 mmol), Pd(OAC)2 (15 mg, 0.07 mmol), Xantphos (83 mg, 0.14 mmol) and potassium tert-butoxide (159 mg, 1.42 mmol) in dioxane (8 mL) was microwaved at 160° C. for 20 min. The reaction mixture was cooled to room temperature and filtered rinsing with DCM and methanol. The filtrate was concentrated and purified using gradient flash chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a yellow oil (89 mg, 50%). MS (ES+): m/z 248 (M+H)+.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:10](=[O:20])[CH2:9]2)C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].O.CO>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1=[O:20]
Reactant: O=C1CN(Cc2ccccc2)CCN1c1ccccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: O=C1CNCCN1c1ccccn1
Yield: 46.1 %

Procedure:
A slurry of palladium on carbon (5%, 3.6 g) in water was added to a solution of 4-phenylmethyl-1-(2-pyridinyl)piperazin-2-one (Description 150, 3.6 g, 13.48 mmol) and ammonium formate (4.25 g, 67.5 mmol) in methanol (100 mL) and the mixture was heated under reflux for 4 hours, cooled and filtered through Hyflo™, washing with methanol. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with CH2Cl2/MeOH (90:10), to give the title compound as an orange oil (1.1 g, 46%). m/z (ES+) 178 (M+1).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CO.O.[C:44](#N)[CH3:45]>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH2:40][CH2:44][CH3:45])[CH:34]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC#N
Reactant: COc1cccc(-c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c1
Solvent: CO
Solvent: O
Product: CCCOc1cccc(-c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c1

Procedure:
(1.25 g, 83%) was obtained from (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and 1-iodo-3-propoxybenzene using the procedure described for (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-methoxyphenyl)-1H-indol-3-yl)propanoic acid. 1H NMR (400 MHz, chloroform-d) δ 8.28 (s, 1H), 7.80-7.70 (m, 3H), 7.53-7.09 (m, 13H), 6.94-6.87 (m, 1H), 5.23 (d, J=8.0 Hz, 1H), 4.68 (d, J=6.0 Hz, 1H), 4.22-4.15 (m, 2H), 3.93 (t, J=6.7 Hz, 2H), 3.60 (d, J=5.3 Hz, 1H), 3.52 (d, J=7.0 Hz, 1H), 1.85-1.72 (m, 2H), 1.01 (t, J=7.4 Hz, 3H); [α]20D −11.34° (4.25 mg/mL, MeOH). LCMS retention time=1.972 min., m/z=561 (M+H), 99.0% purity. The LCMS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using The following set of conditions: PHENOMENEX® Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a rate of 1 mL/minute.
Reaction SMILES: [NH:1]([C:39]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@H:2]([C:24]([NH:26][C@H:27]([C:35]([O:37]C)=[O:36])[CH2:28][S:29][CH2:30][NH:31][C:32]([CH3:34])=[O:33])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[NH:1]([C:39]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@H:2]([C:24]([NH:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][S:29][CH2:30][NH:31][C:32]([CH3:34])=[O:33])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](CSCNC(C)=O)NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NCSC[C@H](NC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5.63 g of Trt-Cys(Trt)-Cys(Acm)-OMe are dissolved in 75 ml of dioxane and 17.5 ml of water and 3.71 ml of 2 N sodium hydroxide solution are cautiously added thereto. After 1 hour at 20°C, the mixture is cooled to 0°C, 3.71 ml of 2 N hydrochloric acid are added and the solution is concentrated under reduced pressure, at room temperature, to approx. 30 ml and is then diluted with 200 ml of chloroform. The solution is washed three times with water and is dried over sodium sulphate. On evaporating off the solvent, the product, which is pure according to thin layer chromatography, is obtained as a white foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:19])[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:21]([O:25][C:26](=[O:37])[C@H:27]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH2:28])([CH3:24])([CH3:23])[CH3:22].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[C:21]([O:25][C:26](=[O:37])[C@H:27]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:28][C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:19])([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
To N-benzyloxycarbonyl-N-methyl-L-valine (0.50 g, 1.9 mmol), L-aspartic acid di-tert-butyl ester hydrochloride (0.53 g, 1.9 mmol), WSC hydrochloride (0.43 g, 2.3 mmol), and 1-hydroxybenzotriazole monohydrate (0.35 g, 2.3 mmol) were added tetrahydrofuran (10 ml) and triethylamine (0.39 mL, 2.8 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20) to give the title compound (0.91 g, 1.8 mmol, 98%).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH:5]([P:7]([O:12]CC)([O:9]CC)=[O:8])[CH3:6])C>Cl>[P:7]([CH:5]([CH3:6])[C:4]([OH:15])=[O:3])([OH:12])([OH:9])=[O:8]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: Cl
Product: CC(C(=O)O)P(=O)(O)O

Procedure:
A mixture of ethyl-2-(diethoxyphosphinyl)propionate (15 g., 0.063 moles) in 6 N hydrochloric acid (150 ml.) is heated to reflux for 2.5 hours. After this time, the reaction vessel is fitted with a Dean-Stark trap and heated at reflux an additional thirty minutes. The reaction mixture is concentrated in vacuo to yield 2-phosphonopropionic acid (quantitative).
Reaction SMILES: Cl[C:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)=[O:3].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([NH:29][C:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:5]=1)=[O:3])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)c1cn(S(=O)(=O)c2ccccc2)c2ccccc12

Procedure:
Reaction of 3-chlorocarbonyl-1-(phenylsulfonyl)-indole [XXIII] (Ketcha D. M., Gribble G. W., J. Org. Chem. 1985;50:5451-5457) with an excess of benzylamine in CH2Cl2) (method of Ketcha and Gribble) gave N-benzyl-1-(phenylsulfonyl) indole-3-carboxamide [XXIV: R8 =CH2Ph]; mp (MeOH) 188°-189° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:45])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33](OC3C=CC([N+]([O-])=O)=CC=3)=[O:34])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][C:47]([CH3:65])([CH3:64])[CH2:48][C:49]1[CH:63]=[CH:62][C:52]([CH2:53][NH:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])=[CH:51][CH:50]=1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([O:23][C:24](=[O:45])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33](=[O:34])[N:54]([CH2:53][C:52]3[CH:62]=[CH:63][C:49]([CH2:48][C:47]([CH3:46])([CH3:65])[CH3:64])=[CH:50][CH:51]=3)[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:21][CH2:22]2)=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCNCc1ccc(CC(C)(C)C)cc1
Reactant: O=C(NCCCCCCOC(=O)Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCN(Cc1ccc(CC(C)(C)C)cc1)C(=O)OCCCCCCNC(=O)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Yield: 112.5 %

Procedure:
A solution of the carbonate (2.0 g, 3.2 mmol) produced in Example 5, 4-(2,2-dimethyl-propyl)-benzyl-heptylamine (1.1 g, 3.9 mmol) and triethylamine (2.2 ml, 16 mmol) in 30 ml of anhydrous dimethylformamide was stirred under nitrogen at room temperature overnight. The reaction was diluted with methylene chloride, extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 2.73 g of a light brown oil. Purification of this oil by chromatography on silica gel (230-400 mesh) using 10% ethyl acetate-methylene chloride as the eluent gave 2.11 g (87%) of the title compound as a clear oil, MS m/e 758 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[CH:3]=1>C(O)C>[C:9]([NH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[CH:3]=1)(=[O:14])[CH2:8][CH2:13][CH3:12]
Reactant: CCCOc1ccccc1-c1nc(N)cc(=O)[nH]1
Solvent: CCO
Product: CCCOc1ccccc1-c1nc(NC(=O)CCC)cc(=O)[nH]1

Procedure:
A stirred solution of 6-amino-2-(2-propoxyphenyl)-pyrimidin-4[3H]-one (0.68 g) and n-butyric anhydri was heated at 140° C. for 5 hours. Ethanol was added to the cooled reaction mixture which was then evaporated under reduced pressure to yield a residue which was azeotroped and washed with water. The residue was eluted from silica with chloroform and the combined fractions containing product were evaporated under reduced pressure to yield a crude product which was recrystallised from isopropanol: diethyl ether to yield the title compound, 0.21 g, m.p. 177°-8° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([CH:36]1[CH2:38][CH2:37]1)(=[O:35])=[O:34]>>[CH:36]1([S:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[CH:18]=[C:19]4[CH:25]=[CH:24][NH:23][C:20]4=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:34])=[O:35])[CH2:38][CH2:37]1
Reactant: O=S(=O)(c1ccccc1Br)C1CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4c3)c(F)c2)OC1(C)C
Product: O=S(=O)(c1ccccc1-c1ccc(-c2cnc3[nH]ccc3c2)c(F)c1)C1CC1

Procedure:
The title compound was prepared using methods analogous to those described in Example 376 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine and 1-bromo-2-(cyclopropylsulfonyl)benzene. MS (ESI): mass calcd. for C22H17FN2O2S, 392.10; m/z found, 393.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 8.62-8.52 (m, 1H), 8.24-8.12 (m, 2H), 7.71-7.63 (m, 1H), 7.62-7.53 (m, 2H), 7.45-7.31 (m, 4H), 6.64-6.55 (m, 1H), 2.19-2.08 (m, 1H), 1.18-1.08 (m, 2H), 0.93-0.82 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@@H:5]([C:16]([O:18]C)=[O:17])[NH:4]1.[OH-].[Na+]>CO>[OH:1][CH2:2][C@H:3]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH2:6][C@@H:5]([C:16]([OH:18])=[O:17])[NH:4]1
Reactant: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](CO)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](CO)N1
Yield: 90 %

Procedure:
In the same manner as described in Reference Example 2-(1) using methyl (1RS,3RS)-cis-1-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (3.124 g), 1N NaOH (13.2 ml) and methanol (550 ml), there is obtained the title compound (2.66 g, 90%), m.p. 241°-242° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](O)(=[O:11])[CH:9]=[CH2:10]>>[N:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8](=[O:11])[CH2:9][CH:10]=1
Reactant: C=CC(=O)O
Reactant: Nc1ccccc1
Product: O=C1CC=Nc2ccccc21

Procedure:
The process of Scheme IX begins with the reaction of an aniline (structure 37) with an unsaturated acid, for example acrylic acid, followed by a cyclization reaction mediated by, for example, polyphosphoric acid to afford a 4-quinolinone. The nitrogen atom is then protected by treatment with a base, for example, 4-dimethylaminopyridine, followed by the addition of an acylating agent such as di-tert-butyldicarbonate, to afford a compound of structure 38. Addition of an organomagnesium or organolithium reagent, with, for example, ethyl magnesium bromide, affords an alcohol. Reduction of the alcohol with, for example hydrogen over palladium on carbon, followed by deprotection of the nitrogen atom, affords a compound of structure 39. Nitration of a compound of structure 39 by the action of nitric acid in the presence of, for example, sulfuric acid, followed by reduction of the nitro group with, for example, hydrogen over palladium on carbon, affords a 7-amino-1,2,3,4-tetrahydroquinoline of structure 40. A Knorr cyclization with a β-keto ester effected by, for example, zinc chloride, affords a compound of structure 41. A compound of structure 41 may be further transformed into a compound of structure 42 by acylation of the quinoline nitrogen, which may be accomplished in one of two ways. Treatment of structure 41 with an acid chloride, for example, acetyl chloride, followed by treatment with a base, for example, potassium carbonate, to afford a compound of structure 42. Alternatively, treatment of structure 41 may be treated with an anhydride, for example, trifluoroacetic anhyride, likewise to afford a compound of structure 42.