Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([CH2:11][Br:12])=[C:6]([Br:13])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[Br:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[C:6]([Br:13])[C:7]=1[CH2:11][Br:12]
Reactant: COC(=O)c1cc(Br)c(CBr)c(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc(Br)c(CBr)c(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A solution of 3,5-dibromo-4-bromomethyl-benzoic acid methyl ester (57) (5.2 g, 13.44 mmol) in tetrahydrofuran (50 mL) at 0° C. was treated with a 1M solution of diisobutylaluminum hydride in tetrahydrofuran (30 mL, 30 mmol). The reaction mixture was stirred for 2 h at 0° C. TLC revealed starting material was still present. Additional 1M solution of diisobutylaluminum hydride in tetrahydrofuran (16 mL, 16 mmol) was added at 0° C. and the reaction mixture was stirred for 30 min at 0° C. The reaction was quenched cautiously by pouring it onto a mixture of ice and concentrated hydrochloric acid (100 mL) and the mixture was extracted with ethyl acetate (3×150 mL). The organic layers were combined, dried with magnesium sulfate, filtered, and concentrated under vacuum to afford a solid which was dried under high vacuum to afford (3,5-dibromo-4-bromomethyl-phenyl)-methanol (58) (4.56 g, 94%) as an off-white solid; LRMS-EI(+) for C8H7Br3O (M+) m/z=356. MW=358.8564, Exact Mass=355.8047
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]Br)=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCC=C2.Cl>O1CCCC1>[C:1]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[CH2:22])=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)NS(=O)(=O)c2ccc(CCBr)cc2)cc1
Agent: C1=CN2CCCN=C2CCC1
Agent: Cl
Solvent: C1CCOC1
Product: C=Cc1ccc(S(=O)(=O)NC(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
A solution of 34.00 g (0.08 mol) of N-(4-t-butylbenzoyl)-4-(2-bromoethyl)benzenesulfonamide, 26.79 g (0.176 mol) of 1,8-diazabicyclo[5.4.0]undecen-7-ene (DBU) and 300 ml of tetrahydrofuran was stirred at room temperature for 22 hrs. The reaction mixture was poured into dilute HCl and extracted with methylene chloride twice. The combined extracts were washed twice with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from toluene, collected, washed with toluene and ligroine and dried.
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18](OC)=[O:19])=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1>CO>[NH:2]([C:18](=[O:19])[C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([N:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[CH:11][CH:12]=1)=[O:22])[NH2:3]
Reactant: COC(=O)C(=O)Nc1ccc(N2CCOCC2)cc1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)C(=O)Nc1ccc(N2CCOCC2)cc1
Temperature: 75 °C
Yield: 95.7 %

Procedure:
Hydrazine hydrate (1.25 mL, 25 mmol) was added to a stirred suspension of methyl [(4-morpholin-4-ylphenyl)amino](oxo)acetate (intermediate 1, 6.6 g, 25 mmol) in methanol (150 mL). The reaction was heated to 75° C. for 2 h during which time the precipitate thickened. After cooling the precipitate was filtered and washed with diethyl ether (50 mL) and dried to give the title compound (6.32 g, 94%):
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:6]2[CH:5]=[C:4]1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH3:2]>CCOC(C)=O.CCO>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([NH2:12])[CH:11]=[C:6]2[CH:5]=[C:4]1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCn1c(-c2ccc(C)cc2)cc2cc([N+](=O)[O-])cnc21
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCn1c(-c2ccc(C)cc2)cc2cc(N)cnc21

Procedure:
A solution of 1-ethyl-2-(4-methylphenyl)-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.36 g, 1.3 mmol) in a EtOAc/EtOH (absolute)=4:7 mixture (110 ml) was hydrogenated in H2 atmosphere with the presence of 10% Pd(C) (110 mg) for 2 h. The residue was filtered under vacuum through Celite to remove the catalyst and the solvent evaporated to give crude 1-ethyl-2-(4-methylphenyl)-1H-pyrrolo[2,3-b]pyridin-5-amine which was used without any further purification:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:20]3[C:15](=[C:16]([O:34][CH3:35])[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([F:33])[CH:25]=4)=[O:22])[CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:37]1C=C(S(Cl)(=O)=O)C=C(Cl)[CH:42]=1>>[CH2:37]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[C:20]3[C:15]([CH2:14][CH2:13][N:12]3[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])=[C:16]([O:34][CH3:35])[CH:17]=2)=[O:22])=[CH:25][C:26]=1[F:33])[CH3:42]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(F)c2)cc2c1CCN2S(=O)(=O)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(Cl)cc(Cl)c2)CC3)cc1F

Procedure:
4-{[1-(3,5-Dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 539.26 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 5 was performed using 3,5-dichloro-benzenesulfonyl chloride and yielded 4-{[1-(3,5-dichloro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH3:8].[S:9]1(=[O:20])(=[O:19])[C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][CH2:11][NH:10]1>C(#N)C.O>[CH3:8][N:10]1[CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[S:9]1(=[O:20])=[O:19]
Reactant: O=S1(=O)NCNc2cccnc21
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN1CNc2cccnc2S1(=O)=O
Temperature: 50 °C

Procedure:
0.52 g of potassium carbonate and 0.94 g of iodomethane are added to a solution of 0.25 g of 2,3- dihydro-4H-pyrido[3,2-e][1,2,4]thiadiazine 1,1-dioxide (Example 1) in 10 cm3 of acetonitrile. The suspension is heated at 50° C. for 3 hours. The acetonitrile is then removed by evaporation under partial vacuum and the residue obtained is taken up in 10 cm3 of water. The suspension is extracted with chloroform (5 times 100 cm3). The extraction solvent is dried over MgSO4 and then concentrated to dryness. The solid obtained is purified by chromatography on a silica column (elution solvent: 1/9 MeOH/CHCl3).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10]([O:12][C@H:13]3[CH2:16][C@H:15]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:14]3)=[N:9][C:8]([NH:22][C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)=[N:7][C:6]=2[N:5](COCC[Si](C)(C)C)[CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[C:1]([C:3]1[C:11]2[C:10]([O:12][CH:13]3[CH2:16][CH:15]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])[CH2:14]3)=[N:9][C:8]([NH:22][C:23]3[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=3)=[N:7][C:6]=2[NH:5][CH:4]=1)#[N:2]
Reactant: C=CC(=O)N[C@H]1C[C@H](Oc2nc(Nc3cnn(C)c3)nc3c2c(C#N)cn3COCC[Si](C)(C)C)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)NC1CC(Oc2nc(Nc3cnn(C)c3)nc3[nH]cc(C#N)c23)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of a 1:1 isomeric mixture of cis:trans N-{3-[(5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}prop-2-enamide in DCM (10 mL) was added TFA (1.9 mL). The solution was stirred at rt for 5 hrs and the solvents were removed. EtOH (20 mL), water (5 mL), and K2CO3 (424 mg) were added and the reaction mixture was stirred at rt for 30 min. The volatiles were removed to give a pale yellow solid. Water (20 mL) was added and the solid that precipitated out was collected by filtration, washed with water (5 mL) and dried to afford (185.6 mg, 80% yield) of N-[3-({5-cyano-2-[(1-methyl-1H-pyrazol-4-yl)amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)cyclobutyl]prop-2-enamide as a pale yellow solid (cis:trans mixture 1:1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66-9.47 (m, 1H) 8.58 (br. s., 1H) 7.84-8.08 (m, 1H) 7.74 (d, J=6.29 Hz, 1H) 7.48 (d, J=11.58 Hz, 1H) 5.99-6.34 (m, 2H) 5.40-5.71 (m, 2H) 4.06-5.20 (m, 2H) 3.71-3.90 (m, 3H) 2.90 (br. s., 1H) 2.12 (br. s., 1H). m/z (APCI+) for C18H18N8O2 379.1 (M+H)+. The cis/trans mixture (148 mg, 0.39 mmol) was subjected to further purification using supercritical fluid chromatography to separate the isomers: 64 mg of peak 1 and 60 mg of peak 2 was recovered from this separation. 1H NMR analysis of both peaks revealed that peak 1 corresponded to the cis isomer: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.29 (br. s., 1H) 9.16 (s, 1H) 8.50 (d, J=7.81 Hz, 1H) 7.90 (s, 1H) 7.86 (s, 1H) 7.54 (s, 1H) 6.01-6.27 (m, 2H) 5.53-5.70 (m, 1H) 5.13 (quin, J=6.92 Hz, 1H) 4.13 (sxt, J=7.76 Hz, 1H) 3.82 (s, 3H) 2.82-2.99 (m, 2H) 2.04-2.21 (m, 2H). m/z (APCI+) for C18H18N8O2 379.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23](O)=[O:24])=[CH:13][C:12]=2[N:11]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[H-].[Na+]>C1C=CC=CC=1.S(Cl)(Cl)=O.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:21]2[C:16]3[N:17]=[C:18]([CH3:20])[O:19][C:15]=3[C:14]([C:23]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=3)=[O:24])=[CH:13][C:12]=2[N:11]=1
Reactant: Cc1nc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Reactant: Nc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Cc1nc2c(o1)c(C(=O)Nc1ccc(F)cc1)cc1nc(Nc3c(Cl)cccc3Cl)[nH]c12
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
To a solution of 7-[(2,6-dichlorophenyl)amino]-2-methyl-8H-imidazo[4,5-e][1,3]benzoxazole-4-carboxylic acid (Intermediate-55, 0.100 g, 0.276 mmol) in benzene (4 mL), thionyl chloride (5.0 mL) was added at 5-10° C. The reaction mass was refluxed for 3 h. Thionyl chloride was removed under vacuum and stripped out with benzene. The solution of 4-fluoroaniline (0.091 g, 0.828 mmol) in THF (5.0 mL) was added 60% NaH (0.033 g, 0.825 mmol) under N2-atmosphere at 0-5° C. The solution was stirred for 30 minutes at same temperature and above prepared solution was added to reaction mixture. The reaction mass was stirred at RT for 1 h. The reaction mass was quenched in ice water and extracted with ethyl acetate. The obtained product was further purified by column chromatography on neutral alumina eluting with 1.5-2.0% MeOH:DCM to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 2.65 (s, 3H), 7.17-7.20 (m, 4H), 7.38-7.50 (m, 1H), 7.61 (s, 2H), 7.79 (s, 1H), 8.96-9.04 (m, 1H), 9.40-9.60 (s, 1H), 11-12 (s, 1H); MS [M+H]+: 470.23.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OCC)(=[O:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:36](=[O:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@@H](C)O1
Product: CCOC(=O)C(=O)c1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(N2C[C@@H](C)O[C@H](C)C2)c(F)c1F

Procedure:
Starting materials: (2R,6R)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (11.96 g, 24.13 mmol) (Intermediate 43) and diethyl oxalate.
Reaction SMILES: O=C1N(CC(OC(C)(C)C)=O)C2C=CC=CC=2N1.[CH3:19][O:20][C:21](=[O:43])[CH2:22][N:23]1[C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[N:25]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:24]1=[O:42]>>[CH3:19][O:20][C:21](=[O:43])[CH2:22][N:23]1[C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[N:25]([CH2:34][C:35]([OH:37])=[O:36])[C:24]1=[O:42]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)OC(C)(C)C)c2cc(C)cc(C)c21
Agent: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Product: COC(=O)Cn1c(=O)n(CC(=O)O)c2cc(C)cc(C)c21

Procedure:
Essentially following the procedures described for Intermediate 7, but using tert-butyl [3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetate from Step C in place of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, the title compound was prepared. MS: m/z=293 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([NH:11][CH3:12])=[O:10])=[C:4]([F:14])[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[N:25][C:26]([NH2:29])=[N:27][CH:28]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O1CCOCC1.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>[NH2:29][C:26]1[N:27]=[CH:28][C:23]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([NH:11][CH3:12])=[O:10])=[C:4]([F:14])[CH:3]=2)=[CH:24][N:25]=1
Reactant: CNC(=O)C(O)c1ccc(Br)cc1F
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
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: [K+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)C(O)c1ccc(-c2cnc(N)nc2)cc1F
Temperature: 100 °C

Procedure:
A mixture of 2-(4-bromo-2-fluorophenyl)-2-hydroxy-N-methylacetamide (0.4 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (0.11 g, 0.48 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, 0.01 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in toluene (0.6 mL) and 1,4-dioxane (0.6 mL) was heated at 100° C. for 1.5 h. After cooling to RT, the mixture was filtered through a pad of silica gel, washed with 10% methanol in dichloromethane. The filtrate was concentrated under reduced pressure and the residue purified by chromatography on silica gel with 10% methanol in dichloromethane to afford the desired product. LCMS: (M+H)=277.0.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[C:16]([OH:25])(=[O:24])[CH:17]([CH:19]([C:21]([OH:23])=[O:22])[OH:20])[OH:18]>CO>[C:21]([CH:19]([CH:17]([C:16]([OH:25])=[O:24])[OH:18])[OH:20])([OH:23])=[O:22].[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C@@H:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CO
Product: CCCC[C@H]1OC(=O)c2cc(N)ccc21
Reaction time: 8 h

Procedure:
A hot solution of 10.26 g (0.05 mol) of compound obtained in Example 4 in 115 ml of anhydrous methanol is mixed with a warm solution of 7.51 g (0.05 mol) of (+)-tartaric acid in 60 ml of methanol. The mixture is put aside at room temperature overnight, and then at 0-5° C. for 2 hours. The separated crystals are collected and washed with a small amount of methanol to give white crystals. Recrystallisation from methanol (1:8) three times gives the title compound containing one molecule of methanol, as white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].[C:11](#[N:15])/[CH:12]=[CH:13]/[CH3:14].Cl.[OH-].[Na+].[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>OCC[N+](C)(C)C.O>[NH2:15][C:11]1[CH2:12][CH:13]([CH3:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:10]=1
Reactant: C/C=C/C#N
Reactant: NNc1ccc(Cl)cc1Cl
Agent: C[N+](C)(C)CCO
Agent: Cl
Agent: [Mg+2]
Solvent: O
Product: CC1CC(N)=NN1c1ccc(Cl)cc1Cl

Procedure:
A mixture of 7.8 g. of 2,4-dichlorophenylhydrazine (prepared from 2,4-dichlorohydrazine hydrochloride by treatment with 1 N sodium hydroxide), 9.9 g. of crotononitrile and 3 drops of choline (45% in methanol) is heated on a steam bath for 18 hours. The solution is mixed with 200 ml. of water then 20 ml. of concentrated hydrochloric acid is added and the mixture is refluxed for 1/2 hour, cooled and made basic with 10% sodium hydroxide to give a gummy solid. The solid is placed on a chromatography column containing 300 g. of a 200 mesh synthetic magnesium silicate adsorbent. The column is eluted with 1% acetone-hexane, 5% acetone-hexane and 10% acetone-hexane to remove most of the less polar material. The elution procedure is monitored by thin layer chromatography using the upper phase of a mixture of 2 parts benzene, one part acetone and 2 parts water; then the column is eluted with acetone to remove the crude product as a dark oil which partly crystallizes on standing. This material is chromatographed again using another 200 g. of the magnesium silicate adsorbent and eluting a colored impurity with 5% acetone-hexane. The column is then eluted with 50% acetone-hexane to collect a tan oil which solidifies on standing. The solid is recrystallized 3 times from ether-hexane to give 0.5 g. of the product of the Example as tan crystals, m.p. 109°-111° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:20][CH2:21][CH3:22])=[CH:5][C:6](=[O:19])[O:7]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]([CH3:34])([CH3:33])[C:31]#[CH:32]>CC(=O)CC.CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Cl-].[Zn+2]>[CH3:33][C:30]1([CH3:34])[O:1][C:2]2[C:3]3[C:4]([CH2:20][CH2:21][CH3:22])=[CH:5][C:6](=[O:19])[O:7][C:8]=3[CH:9]=[C:10]([O:12][C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15])[C:11]=2[CH:32]=[CH:31]1
Reactant: CCCc1cc(=O)oc2cc(OC(=O)C(C)(C)C)cc(O)c12
Reactant: C#CC(C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCCc1cc(=O)oc2cc(OC(=O)C(C)(C)C)c3c(c12)OC(C)(C)C=C3
Temperature: 60 °C
Yield: 72.9 %

Procedure:
To a suspension of compound 7b (304 mg, 1 mmol) in 2-butanone (13 mL) and DMF (1.3 mL) was added potassium carbonate (346 mg, 2.5 mmol), 3-chloro-3-methyl -1-butyne (0.56 mL, 5 mmol) and tetrabutylammonium iodide (360 mg, 1 mmol). The reaction mixture was heated to 60° C. for 1 h, then anhydrous ZnCl2 (1.0 M solution in ether, 1.3 mL) was added. The reaction mixture was heated to 70° C. for 26 h, then cooled to r.t., quenched with saturated aqueous NH4Cl (25 mL), and extracted with ethyl acetate (2×75 mL). The organic solutions were combined, washed with brine, dried (Na2SO4), and concentrated. The crude product obtained was purified by silica gel chromatography (8:1 hexane/ethyl acetate) to obtain 5b as a yellow solid (270 mg, 73%). mp: 65-68 ° C.; Rf: 0.54 (4:1 hexane/ethyl acetate); 1H NMR (CDCl3) 1.04 (3H, d, J=7.2 Hz), 1.39 (9H, s), 1.52 (6H, s), 1.66-1.71 (2H, m), 2.90 (2H, t, J=7.8 Hz), 5.62 (1H, d, J=10.2 Hz), 6.07 (1H, s), 6.30 (1H, d, J=10.2 Hz), 6.62 (1H, s); 13C NMR (CDCl3) 13.8, 22.9, 26.9, 27.8, 38.3, 39.3, 78.1, 103.5, 107.9, 110.9, 113.4, 115.9, 129.1, 148.9, 152.0, 155.1, 157.4, 160.6, 176.2; IR (film): 2967, 1750, 1616, 1364, 1142 cm−1; MS m/e 371 (M+1); Anal. Calcd. for C22H26O5: C, 71.33; H, 7.07. Found: C, 71.08; H, 7.35.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C@H:12]2[CH2:16][N:15]([C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[C:14](=O)[C@H:13]2[F:26])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1([C@H:12]2[CH2:16][N:15]([C@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])[CH2:14][C@H:13]2[F:26])[CH2:10][CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1C[C@H](C2(NC(=O)OC(C)(C)C)CC2)[C@H](F)C1=O
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1C[C@@H](F)[C@@H](C2(NC(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.4 %

Procedure:
Under a nitrogen atmosphere, a 1 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (120 ml) was added dropwise under ice cooling into a solution of 4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone in tetrahydrofuran (120 ml) and the mixture was stirred at room temperature for 5 hours. After evaporating the solvent under reduced pressure, a solvent mixture (200 ml) of ethanol with water (4:1) and triethylamine (20 ml) were added to the residue followed by heating under reflux for 2 hours. Then, the liquid reaction mixture was concentrated under reduced pressure and chloroform (400 ml) was added to the residue. After washing with a saturated aqueous solution of sodium chloride, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was subjected to flash silica gel column chromatography (eluent:n-hexane:ethyl acetate=1:2) to obtain 7.84 g (99.4%) of the title compound as a colorless oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]=1[NH:16]C(=O)C)([O-:3])=[O:2].[OH-].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:5]=1[NH2:16])([O-:3])=[O:2]
Reactant: CC(=O)Nc1c(-c2ccccn2)cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1c(-c2ccccn2)cccc1[N+](=O)[O-]
Yield: 65.9 %

Procedure:
To a solution of N-(2-nitro-6-(pyridin-2-yl)phenyl)acetamide (XCVIII) (4.41 g, 17 mmol, 1 eq) in MeOH (20 mL) was added 2N NaOH aqueous (50 mL) and the mixture was refluxed until the stirring material was consumed completely. The mixture was concentrated in vacuo to remove the MeOH and the precipitate was collected by filtration to afford 2-nitro-6-(pyridin-2-yl)aniline (XCIX) (2.4 g, 11.2 mmol, 65% yield) as a yellow solid. ESIMS found for C11H9N3O2 m/z 216 (M+H).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>O1CCCC1>[CH3:3][N:4]([C:16](=[O:18])[CH3:17])[C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: CN[C@@H](Cc1ccncc1)C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N(C)[C@@H](Cc1ccncc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
Methyl-3-(4-pyridinyl)alanine, dihydrochloride (1.4 g, 0.0053 mol) is stirred in dry tetrahydrofuran (20 mL) with acetic anhydride (0.9 mL, 0.0095 mol) and triethylamine (3.3 mL, 0.0233 mol) at room temperature. After stirring at room temperature overnight the mixture is diluted with 20 mL tetrahydrofuran and filtered and the solids washed with tetrahydrofuran. The filtrate is concentrated to a dark oil, dissolved in dichloromethane (50 mL) and washed with dilute sodium bicarbonate solution (50 mL). The organic layer is dried over magnesium sulfate and concentrated. The residue is triturated with diethyl ether, filtered, and dried to afford 0.83 g of the title compound as a tan solid; mp 86-88° C.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:18])=[N+]=[N-]>C(O)C.[C].[Pd]>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:18]
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Agent: [Pd]
Solvent: CCO
Product: NC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Yield: 55.9 %

Procedure:
5'-azido-2',5'-dideoxyuridine (258 mg, 1 mmole) is dissolved in 50 ml of ethanol and 50 mg of 10% palladium carbon catalyst added. The suspension is maintained at atmospheric pressure in a hydrogenation apparatus for 2.5 hours before filtering through Celite. The solvent is removed in vacuo, the residue dissolved in water and applied to a column of Dowex 50 (H+) resin. After washing the column with 100 ml of water, the 5'-amino-2',5'-dideoxyuridine is eluted with 100 ml of 1M NH4OH. The solution is evaporated to dryness and the residue crystallized from ethanol-ether to provide the desired product, (127 mg, 56%).