Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[N:18][C:19]2[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([CH:27]=2)[C:24]([OH:26])=[O:25])=[CH:13][CH:12]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CS(C)=O.CCOC(C)=O>[N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[N:18][C:19]2[CH:20]=[CH:21][C:22]([OH:28])=[C:23]([CH:27]=2)[C:24]([OH:26])=[O:25])=[CH:13][CH:12]=1)=[N+:30]=[N-:31]
Reactant: O=C(O)c1cc(N=Nc2ccc(OCCCCCCCCBr)cc2)ccc1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCCCCCCCCOc1ccc(N=Nc2ccc(O)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.1 %

Procedure:
5-((4-(8-Bromooctyloxy)phenyl)diazenyl)-2-hydroxybenzoic acid (2.50 g, 5.6 mmol) was dissolved in DMSO (40 mL) and NaN3 (1.10 g, 16.9 mmol) was added slowly to the reaction mixture with stirring at room temperature. After 48 h, the mixture was diluted with EtOAc (100 mL), washed with water (4×20 mL), brine (20 mL), dried over Na2SO4, and filtered. Volatiles were removed in vacuo and the residue subjected to column chromatography on silica gel 60 (230-400 mesh) using EtOAc and methanol (98:2) as the elutant to give 2.10 g (5.1 mmol, 91%) of the product as a red-brown solid, mp 54-56° C. 1H NMR (500 MHz, CDCl3) δ 1.27-1.58 (m, 8H), 1.62-1.64 (m, 2H), 1.81-1.86 (m, 2H), 3.31 (t, J=5 Hz, 2H), 4.06 (t, J=6.5 Hz, 2H), 6.88-7.01 (m, 3H), 7.84 (d, J=10 Hz, 2H), 7.91 (dd, J=15 Hz, 2.5 Hz, 1H), 8.47 (d, J=2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3+CD3OD) δ 22.0, 25.3, 25.4, 28.5, 28.6, 28.8, 31.2, 50.8, 67.7, 114.1, 116.5, 117.5, 123.6, 126.2, 144.6, 146.2, 160.7, 175.0; HRMS (ESI) calculated for C21H26N5O4 (M+H)+412.1979, observed 412.1971.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=O)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21]
Reactant: CN1Cc2c(C(N)=O)ncn2-c2ccc(F)c(Cl)c2C1=O
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CN1Cc2c(C#N)ncn2-c2ccc(F)c(Cl)c2C1=O
Reaction time: 3 h
Yield: 88.6 %

Procedure:
14.4 g (0.0466 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide was suspended in 60 ml of dioxan and 8 ml of pyridine and treated dropwise at a temperature of ~8° within 10 min. with 10.3 g (0.049 mol) of trifluoroacetic anhydride. The mixture was stirred at 50° for 3 hours and poured into 400 ml of water. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in 300 ml of hot ethyl acetate, the solution was suction filtered over 100 g of silica gel, the silica gel was rinsed with 200 ml of ethyl acetate and the filtrate was evaporated. There were obtained 12 g (89%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile as light yellowish crystals; m.p. 221°-223°.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14][CH:15]([CH:21](O)[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:16]2=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(Cl)(=O)=O.C(N(CC)CC)C.N12CCCN=C1CCCCC2>C1C=CC=CC=1.O>[Si:1]([O:8][CH:9]([CH2:30][O:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)/[CH:10]=[CH:11]/[CH:12]1[CH2:19][CH2:18][CH:17]2[CH:13]1[CH2:14]/[C:15](=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])/[C:16]2=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)CCCC(O)C1CC2C(/C=C/C(COc3ccccc3)O[Si](C)(C)C(C)(C)C)CCC2C1=O
Agent: CS(=O)(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)CCC/C=C1\CC2C(/C=C/C(COc3ccccc3)O[Si](C)(C)C(C)(C)C)CCC2C1=O
Reaction time: 2.5 h
Yield: 65.4 %

Procedure:
A stirred solution of 6-[(E)-3-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-(1-hydroxy-4-methoxycarbonylbut-1-yl)bicyclo[3,3,0]octan-2-one (38 mg), prepared as described in Reference Example 47 and in the form of (±)-6β-[(E)-3β-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-(1-hydroxy-4-methoxycarbonylbut-1-yl)bicyclo[3,3,0]octan-2-one, in dry benzene (0.28 ml) was treated with methanesulphonyl chloride (0.0072 ml) at the ambient temperature and then with triethylamine (0.012 ml) and stirred for 2 hours. It was then treated with 1,8-diazabicyclo[5,4,0]undec-7-ene (65 mg) and stirred for 150 minutes. The mixture was treated with water (15 ml) and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The resulting residue was then subjected to medium pressure, short column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane (23:77 v/v), to give 6-[(E)-3-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one (24 mg), in the form of (±)-6β-[(E)-3β-tert-butyldimethylsilyloxy-4-phenoxybut-1-enyl]-3-[(E)-4-methoxycarbonylbutylidene]bicyclo[3,3,0]octan-2-one, otherwise known as (±)-methyl (5E,13E)-(9S,15S)-6a-oxo-6,9-methano-15-tert-butyldimethylsilyloxy-16-phenoxy-17,18,19,20-tetranorprosta-5,13-dienoate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1.[CH3:21][C:22]([Mg]Br)=[CH:23][CH3:24].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:23]([CH3:24])=[C:22]([CH3:21])[NH:18][C:5]2=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[N:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1N1CCc2ccccc2C1
Reactant: CC=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(Cl)cc2c1C
Temperature: -20 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
2-(6-Chloro-3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (16 g, 56.6 mmol) prepared in Preparation 7 was dissolved in anhydrous tetrahydrofuran (300 ml) under a nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 283 ml, 141.5 mmol) was slowly added at −78° C. to the solution. The reaction mixture was stirred for 2 hours at −20° C. and then 20% (w/v) ammonium chloride solution was added thereto. The reaction mixture was extracted with ethyl acetate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/10, v/v) to give 7.8 g of the titled compound as yellow oil. (Yield: 45%)
Reaction SMILES: [CH:1]1[N:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[NH:5][C:6]2=O.P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:18][C:6]1[C:7]2[C:2](=[CH:1][N:10]=[CH:9][CH:8]=2)[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[N:5]=1
Reactant: O=c1[nH]c2ccccc2c2cnccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Clc1nc2ccccc2c2cnccc12

Procedure:
Benzo[c][2,6]naphthyridin-5(6H)-one (1.0 eq, 813 mg, 4.15 mmol) was stirred in phosphorus oxychloride (5.0 eq, 2 ml, 21.84 mmol) and acetonitrile (10 ml). The mixture was stirred at reflux for 5 hours. The mixture was poured on ice, and the resulting solid filtered and dried. 5-chlorobenzo[c][2,6]naphthyridine was isolated as a grey solid (459 mg, 52% yield). LCMS (ES): 95% pure, m/z 215 [M+1]+.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7])(=[O:4])=[O:3].FC(F)(F)C(O)=O.C([O-])(=O)C.[Na+].O>ClCCl.C(OCC)(=O)C>[CH3:1][S:2]([CH2:5][C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7])(=[O:3])=[O:4]
Reactant: C[C@H](CS(C)(=O)=O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@H](CS(C)(=O)=O)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Yield: 36.8 %

Procedure:
2-(6-Chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-methanesulfonyl-1-methyl-ethyl)-amide (65 mg, 0.113 mmol) was dissolved in dichloromethane (0.8 ml) and then stirred in an ice bath. Trifluoroacetic acid (0.4 ml) was slowly added and the ice bath was removed. The reaction was stirred at room temperature for 3 h then cooled in ice bath. Sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was dissolved in absolute ethanol (7 ml) and sodium acetate (185 mg, 2.25 mmol) was added. The mixture was stirred for 20 h at 60° C. The reaction was cooled, and water and ethyl acetate were added. The aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with sodium chloride solution, dried over sodium sulfate and evaporated to a residue. After purification by silica gel chromatography (methanol/dichloromethane), 18.6 mg (37%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-methanesulfonyl-1-methyl-ethyl)-amide was obtained. MS: (M+H)+=447; mp=287-290° C. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.91 (s, 1H) 9.10 (s, 1H) 8.54 (d, J=8.7 Hz, 1H) 8.47 (s, 1H) 8.26 (d, J=7.9 Hz, 1H) 7.97-8.02 (m, 1H) 7.35 (dd, J=8.7, 1.5 Hz, 1H) 4.60-4.72 (m, 1H) 4.18 (s, 3H) 3.45-3.63 (m, 2H) 3.06 (s, 3H) 1.52 (d, J=6.8 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]=O)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C[Si](Br)(C)C.CO>CN(C=O)C>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1/[CH:18]=[CH:16]/[C:14]1[N:15]=[C:8]2[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:12][CH:11]=[N:10][N:9]2[CH:13]=1
Reactant: O=Cc1cn2nccc(N3CCOCC3)c2n1
Reactant: Cc1ccc2ccccc2n1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: CN(C)C=O
Product: C(=C/c1cn2nccc(N3CCOCC3)c2n1)\c1ccc2ccccc2n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of compound 5e (10 g, 43 mmol) and 2-methylquinoline (4.6 g, 32 mmol) in DMF (10 mL) was added TMSBr (2.9 g, 19 mmol) dropwise. The reaction mixture was stirred at 80° C. for 2 h. MeOH (10 mL) was added. The solids formed were collected by filtration and washed with Et2O (2×50 mL) to obtain compound 57c as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H19N5O: 358.2 (M+H). Found: 358.3.
Reaction SMILES: N1C2C(=CC=CC=2)C(C(=O)[CH2:11][C:12]2([OH:29])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[N:14]([CH2:22][CH2:23][CH2:24][N:25]=[N+:26]=[N-:27])[C:13]2=[O:28])=C1.N(CCCN1C2C(=CC(C)=CC=2)C(=O)C1=O)=[N+]=[N-].[CH3:49][O:50][C:51]1[N:56]=[C:55]([C:57](=[O:59])C)[CH:54]=[CH:53][CH:52]=1>>[N:25]([CH2:24][CH2:23][CH2:22][N:14]1[C:15]2[C:20](=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:12]([OH:29])([CH2:11][C:57]([C:55]2[CH:54]=[CH:53][CH:52]=[C:51]([O:50][CH3:49])[N:56]=2)=[O:59])[C:13]1=[O:28])=[N+:26]=[N-:27]
Reactant: COc1cccc(C(C)=O)n1
Reactant: Cc1ccc2c(c1)C(O)(CC(=O)c1c[nH]c3ccccc13)C(=O)N2CCCN=[N+]=[N-]
Agent: Cc1ccc2c(c1)C(=O)C(=O)N2CCCN=[N+]=[N-]
Product: COc1cccc(C(=O)CC2(O)C(=O)N(CCCN=[N+]=[N-])c3ccc(C)cc32)n1

Procedure:
This compound was made in a similar manner to 3-(2-(1H-indol-3-yl)-2-oxoethyl)-1-(3-azidopropyl)-3-hydroxy-5-methylindolin-2-one using 1-(3-azidopropyl)-5-methylindoline-2,3-dione and 1-(6-methoxypyridin-2-yl)ethanone (commercially available from Fisher Scientific).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].O.CCOC(C)=O>CC(N(C)C)=O>[C:30]([O:29][C:28]([NH:27][C@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]1[NH:20][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:3]=1)=[O:34])([CH3:33])([CH3:31])[CH3:32]
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1-c1cnn(C)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(1-methyl-1H-pyrazol-4-yl)nicotinate (155 mg, 0.560 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (144 mg, 0.672 mmol) in DMA (2 mL) was stirred at 150° C. for 1 h under microwave irradiation. To the resulting mixture were added H2O and EtOAc. The organic phase was washed with H2O (3×) and brine, dried over MgSO4, and evaporated. The residue was purified by chromatography on SiO2 to give the title compound as a yellow oil (100 mg, 39.3%). 1H NMR (500 MHz, CDCl3) δ ppm 1.34-1.95 (m, 17H), 3.92 (s, 3H), 3.93 (s, 3H), 4.87 (br s, 1H), 5.66 (br s, 1H), 6.52 (s, 1H), 7.78-7.83 (m, 2H). [M+H] calc'd for C23H30N6O4, 455. found, 455.
Reaction SMILES: [CH2:1]([C:16]([OH:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O.O.C1CCC(N=C=NC2CCCCC2)CC1.[K+].[Br-]>C1COCC1.CC(C)=O>[CH2:12]1[C:13](=[O:15])[O:18][C:16](=[O:17])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(O)CCCCCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCCCCCCCCCCCC(=O)O1
Reaction time: 0.12 h

Procedure:
A flame dried 500 ml round bottom flask was allowed to cool before 8 g (0.031 mole) of solid 1,12-dodecanedicarboxylic acid was added. Dry THF (~100 ml) was added to suspend the diacid. After stirring for 5-10 minutes the mixture was warmed with tap water to about 40° to effect dissolution of the diacid. A few particles were usually visible in the reaction flask at this point DCC was weighed in a flame dried beaker. DCC (6.4 gm, 0.031 mole) was dissolved in 20 ml of THF. The concentrated DCC solution was transferred to the reaction vessel using a disposable pipette. Throughout all procedures the reaction vessel was purged with nitrogen. The reaction was sealed under nitrogen pressure and allowed to stir at room temperature for 15 hours. After 15 hours a thick, white paste formed and stopped the stirring bar. (Ideally, sufficient THF should be added initially to the reaction to prevent paste formation.) After 15 hours, 500 ml of reagent grade acetone was added followed by filtration through a scintered glass funnel (medium, 300 ml capacity). The filtrate was stored in the refrigerator overnight to crystallize the product. The cyclic anhydride was collected by filtration through a medium scintered glass funnel. The product was rinsed with reagent grade acetone and dried under vacuum, room temperature, overnight. Typical yields are 50-70% based only on the first crop of crystals. Reactions were monitored by FTIR using KBr pellets prepared from aliquots of the reaction mixture taken to dryness by rotoevaporation. See FIG. 6.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:11]([C:13]([OH:15])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:23]([O:25][CH2:26][CH3:27])[CH3:24]>>[C:1]([NH:9][C@@H:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@H:11]([C:13]([O:15][CH:23]([O:25][CH2:26][CH3:27])[CH3:24])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](c1ccccc1)[C@@H](O)C(=O)O)c1ccccc1
Reactant: CCOC(C)Cl
Product: CCOC(C)OC(=O)[C@H](O)[C@@H](NC(=O)c1ccccc1)c1ccccc1

Procedure:
The N-benzoyl-(2R,3S)-3-phenyl-isoserine, as prepared in Example 34, is treated with 1-chloroethyl ethyl-ether in the presence of a tertiary amine to produce optically pure (2R,3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine (2). 7-tri-ethylsilyl baccatin III (1), as synthesized according to Denis et at. (J. Amer. Chem. Soc. 110:5417, 1988), is added to 6 equiv of optically pure (2R,3S)-N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine (2), 6 equiv of di-2-pyridyl carbonate (DPC), and 2 equiv of 4-(dimethylamino) pyridine (DMAP) in toluene solution (0.02M). This mixture reacts at 73° C. for 100 hours to produce the C-2', C-7-protected taxol derivative (3).
Reaction SMILES: [S:1]1(=[O:13])(=[O:12])[C@@H:5]2[CH2:6][C:7](=[O:8])[N:4]2[C@@H:3]([C:9]([OH:11])=[O:10])[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:23]([O:29][CH2:30]Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O>[S:1]1(=[O:13])(=[O:12])[C@@H:5]2[CH2:6][C:7](=[O:8])[N:4]2[C@@H:3]([C:9]([O:11][CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:10])[CH2:2]1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=C(O)[C@H]1CS(=O)(=O)[C@@H]2CC(=O)N12
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)[C@H]1CS(=O)(=O)[C@@H]2CC(=O)N12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2.05 g of (3S, 5R)-penam-3-carboxylic acid 1,1-dioxide in 10 ml of N,N-dimethylformamide is added 1.30 g of diisopropylethylamine followed by 1.50 g of chloromethyl pivalate and 50 mg of sodium iodide at ca. 0° C. The reaction mixture is stirred at ca. 0° C. for 30 minutes and then at room temperature for 24 hours. The reaction mixture is then diluted with ethyl acetate and water and the pH of the aqueous phase is adjusted to 7.5. The ethyl acetate layer is separated and washed three times with water and once with saturated sodium chloride solution. The ethyl acetate solution is then dried using anhydrous sodium sulfate, and evaporated in vacuo to give the title compound.
Reaction SMILES: [CH2:1]1[C@H:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]2[CH2:4][CH2:3][NH:2]1.Br[CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>>[C:25]1(=[O:34])[N:24]([CH2:23][CH2:22][CH2:21][N:2]2[CH2:3][CH2:4][N:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][C:8]4[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=4[C@@H:6]3[CH2:1]2)[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNC[C@@H]21
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN2c3ccccc3Cc3ccccc3[C@@H]2C1

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bR)-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and N-(3-bromopropyl)phthalimide, the title compound was obtained in a quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][C:37]([CH3:41])([CH3:40])[CH2:38][NH2:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:39][CH2:38][C:37]([CH3:41])([CH3:40])[CH3:36])=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CC(C)(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCC(C)(C)C)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.6 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-4-methylbenzoic acid (30 mg, 0.062 mmol) in dichloromethane (2.0 mL) and DMF (0.5 mL) were added (2,2-dimethylpropyl)amine (10.9 μL, 0.093 mmol), HBTU (25.6 mg, 0.068 mmol) and triethylamine (35.0 μL, 0.25 mmol). The reaction mixture was stirred at room temperature for 16 hours then was applied to HPLC to afford the titled compound 14.9 mg (44%). LC-MS m/z 552 (M+H)+; 1H-NMR (MeOD) 0.99 (s, 9H), 2.33 (s, 3H), 2.76 (s, 6H), 3.15 (s, 2H), 3.24 (s, 2H), 3.54 (m, 2H), 4.16 (m, 2H), 7.18 (m, 2H), 7.51 (m, 2H), 7.72 (s, 1H), 7.89 (m, 1H).
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19].C1CCN2C(=NCCC2)CC1>CC(C)=O>[I:1][C:2]1[C:3]([S:12]([NH:15][C:21]([NH:20][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22])(=[O:14])=[O:13])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cccc(S(N)(=O)=O)c1I
Reactant: CCCCN=C=O
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCNC(=O)NS(=O)(=O)c1cccc(C(=O)OC)c1I
Temperature: 25 °C

Procedure:
27.3 g of 2-iodo-3-methoxycarbonylbenzenesulfonamide and 9.0 ml of n-butyl isocyanate in 300 ml of absolute acetone are treated with 12 ml of DBU at room temperature and heated at the boil for 3 hours. The reaction solution is cooled to room temperature, concentrated to approximately 1/3 of its volume and poured into 1 l of water. The aqueous phase is acidified with concentrated hydrochloric acid to a pH of 1-2, and the precipitate obtained is filtered off with suction. 31.3 g of methyl 2-iodo-[[[(n-butylamino)carbonyl]amino]sulfonyl]benzoate of melting point 163°-7° C. are obtained.
Reaction SMILES: [S:1]1[C:5]([CH:6]=[CH:7][C:8](OC)=[O:9])=[CH:4][N:3]=[CH:2]1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.C(OCC)(=O)C>[S:1]1[C:5]([CH:6]=[CH:7][CH2:8][OH:9])=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)C=Cc1cncs1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCC=Cc1cncs1
Reaction time: 0.83 h
Yield: 47.8 %

Procedure:
700 mg of methyl β-(5-thiazolyl)acrylate [see Chem. Pharm. Bull., 35 823 (1987)] was dissolved in 10 ml of tetrahydrofuran, and under a nitrogen atmosphere, 8.1 ml of a 1M toluene solution of diisobutylaluminum hydride was added dropwise at -70° C. The mixture was stirred at this temperature for 50 minutes, and water and ethyl acetate were added to the solution. The precipitate was removed by filtration, and the filtrate was worked up in a customary manner to give 279 mg of 3-(5-thiazolyl)-2-propen-1-ol as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][Cl:6])[CH3:2].[CH2:8]([O:10][C:11](=[O:13])C)[CH3:9]>C(O)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][C:11]([O:10][CH2:8][CH3:9])=[O:13])[CH3:2].[CH2:1]([O:3][C:4](=[O:7])[CH2:5][Cl:6])[CH3:2]
Reactant: CCOC(C)=O
Solvent: CCOC(=O)CCl
Solvent: CCO
Product: CCOC(=O)CC(=O)OCC

Procedure:
As described in Example 1, but with 160 g of an 8.85% solution of Co2 (CO)8 in ethanol, 2.7 moles out of 4 moles of chloroacetic acid ethyl ester are reacted at 7.5 at. CO and 55° C. in 51/4 hours. 400 g of malonic acid diethyl ester is obtained (93% yield) and 3.5 g of acetic acid ethyl ester plus 160 g of chloroacetic acid ethyl ester.