Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22](=[O:25])[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22](=[O:25])[CH2:23][CH3:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CCC(=O)CBr
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCC(=O)CN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 25.8 %

Procedure:
Analogously to the general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2 g) is alkylated using 1-bromo-2-butanone (1.7 ml; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at 30° C. for 24 h. After aqueous work-up and purification by RP chromatography the pure material (0.65 g) is de-acetylated in MeOH (70 ml) using DBU (0.6 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-(2-oxo-butyl)-1,3-dihydro-indol-2-one (0.57 g) is obtained and used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:27]5[CH:26]=[CH:25][N:24]=[CH:23][C:22]=5[N:21]=[C:20]4[CH3:28])=[CH:15][CH:14]=3)[CH2:9][C:8](=[O:29])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[C:34](OCC)(OCC)([O:36][CH2:37][CH3:38])[CH3:35]>>[CH2:34]([O:36][CH:37]([N:1]=[C:2]1[C:12]2[C:6]([NH:7][C:8](=[O:29])[CH2:9][CH:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:27]5[CH:26]=[CH:25][N:24]=[CH:23][C:22]=5[N:21]=[C:20]4[CH3:28])=[CH:15][CH:14]=3)[N:11]=2)=[CH:5][CH:4]=[CH:3]1)[CH3:38])[CH3:35]
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1nc2cnccc2n1-c1ccc(C2=Nc3c(N)cccc3NC(=O)C2)cc1
Solvent: CC(=O)O
Product: CCOC(C)N=C1C=CC=C2NC(=O)CC(c3ccc(-n4c(C)nc5cnccc54)cc3)N=C21

Procedure:
A solution of the aniline from Example 14 (0.38 g, 1 mmol) and glacial acetic acid (0.5 ml) in triethyl orthoacetate (5 ml) was stirred at 25° C. for 72 hours. The product was filtered and recrystallised from toluene (60 mg, 13%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(=O)([O-])[O-:11].[K+].[K+].OO.O>CS(C)=O.CC(C)=O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH2:9])=[O:11])=[N:6][CH:7]=1
Reactant: N#Cc1cnc(Br)cn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cnc(Br)cn1
Temperature: 65 °C
Yield: 27.5 %

Procedure:
A suspension of 5-bromo-pyrazine-2-carbonitrile (1.84 g, 10.0 mmol) and potassium carbonate (1.38 g, 10.0 mmol) in DMSO/acetone (16 mL, 1:3) was treated with H2O2 (2.42 mL, 25.0 mmol) at 65° C. over 15 min. The reaction was kept stirring at 65° C. 1 h. Water (2 mL) was added at 40° C. and the suspension was cooled to 0° C. The precipitate was filtered to give the title compound as a yellow solid (556 mg). 1H NMR (300 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.94 (s, 1H), 8.34 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[C:22](=[O:23])([O:9][C:8]([C:7]1[CH:6]=[N:5][CH:4]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:11]=1)=[O:10])[O:24][CH2:25][CH3:26]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)c1cncc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC(=O)c1cncc(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a solution of 5-(trifluoromethyl)nicotinic acid (10.0 g, 52.3 mmol) in THF (250 mL) was added triethyl amine (7.18 mL, 52.3 mmol) at room temperature, then ethyl chloroformate (4.98 mL, 52.3 mmol) was added dropwise at 5° C. slowly. The reaction was stirred for 1 hour to give ethyl [5-(trifluoromethyl)pyridin-3-yl]carbonyl carbonate. NaBH4 (1.702 g, 45.0 mmol) was added to the mixture portionwise at −78° C. followed by addition of MeOH (100 mL) over 30 minutes. The reaction was warmed to 0° C. and stirred overnight. After removal of the solvent, the residue was purified by column chromatography on silica gel eluting with petroleum ether/ethyl acetate=2/1 to give the title compound (5.7 g, 62% yield) as a yellow oil. MS: 178.0 [M+H]+; 1H NMR (400 MHz, CDCl3): δ 8.73 (s, 1H), 8.70 (d, J=1.2 Hz, 1H), 7.92 (d, J=0.4 Hz, 1H), 4.77 (s, 2H), 2.34 (brs, 1H).
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[CH3:15][N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:17].C(O)C.OO>O1CCCC1>[CH3:17][N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:15]
Reactant: CN(C)Cc1ccc(C2CCC(=O)CC2)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)Cc1ccc([C@H]2CC[C@@H](O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
50 ml (0.05 mol) of a 1 molar solution of lithium tri-sec.-butyl-borohydride in absolute tetrahydrofuran are diluted with 100 ml of absolute tetrahydrofuran under a nitrogen atmosphere and then, at -65° C. to -70° C., with stirring and within 10 minutes, a solution of 5.8 g (0.025 mol) of 4-(4-dimethylaminomethylphenyl)-cyclohexanone in 50 ml of absolute tetrahydrofuran is added thereto. The reaction mixture is then left to react for 3 hours at -70° C. and then heated to ambient temperature within 1 hour. It is then hydrolysed with 20 ml of 75% aqueous ethanol and the organoborane is oxidised with alkaline hydrogen peroxide (10 ml of 6M NaOH/15 ml 30% H2O2). The organic phase is separated off, the aqueous phase is saturated with potassium carbonate and extracted with 50 ml of ethyl acetate. The combined organic extracts are dried with sodium sulphate and evaporated down in vacuo. The greasy residue remaining, which consists of a mixture of cis/trans-4-(4-dimethylaminomethylphenyl)cyclohexanol (trans fraction <5%) is purified by column chromatography (aluminium oxide neutral, activity stage III, ICN; petroleum ether/methylethyl ketone=5:1).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15](Cl)[C:16]([CH3:22])=[N:17]2.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1.CCOC(C)=O>[Br:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]([CH3:22])=[N:17]2
Reactant: Nc1ccccc1
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc2cccc(Br)c2nc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
LHMDS (1.0M in THF; 14.37 ml, 14.37 mmol) was added to a solution of 5-bromo-3-chloro-2-methylquinoxaline (126e, 0.74 g, 2.87 mmol) and aniline (1.309 ml, 14.37 mmol, Alfa Aesar, Ward Hill, Mass.) in dioxane (28.7 ml) at RT, and the resulting mixture was stirred at RT for 30 min. The mixture was diluted with EtOAc (200 ml), added to a separatory funnel, and washed with saturated aq. NH4Cl (2×150 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. Purification by silica gel (100% hexanes to 20% EtOAc/hexanes) provided 8-bromo-3-methyl-N-phenylquinoxalin-2-amine (183a, 71% yield) as a brown oil. MS (ESI, pos. ion) m/z: 314.2/316.2 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C@@H:19]([CH2:20][C@@H:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH3:22])[CH2:18][O:17]C1(C)C)=O)(C)(C)C>O.C(#N)C.C(OCC)(=O)C>[NH2:15][C@@H:19]([CH2:20][C@@H:21]([O:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[CH3:22])[CH2:18][OH:17]
Reactant: C[C@@H](C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)Oc1ccc(Cl)cc1
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](C[C@H](N)CO)Oc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
To a solution of trifluoroacetic acid (0.85 ml) in water (18 ml) was added dropwise a solution of (S)-4-[(S)-2-(4-chloro-phenoxy)-propyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.34 g) in acetonitrile (3 ml). The mixture was heated for 4 h at 80° C. with mechanical shaking The mixture was then cooled to room temperature and diluted with ethyl acetate. The mixture was washed with aq. sodium bicarbonate solution and then the organic phse was separated, dried over sodium sulphate and concentrated in vacuo to give (25,45)-2-amino-4-(4-chloro-phenoxy)-pentan-1-ol (0.76 g, 92%) as an off-white solid. MS (ISP): 232.1 ([{37Cl}M+H]+), 230.2 ([{35Cl}M+H]+).
Reaction SMILES: P(Br)(Br)Br.[CH3:5][C:6]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])([CH3:11])[C:7]([NH:9]O)=O.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH3:11][C:6]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])([CH3:5])[C:7]#[N:9]
Reactant: Cc1ccc(-c2nc(CCCCCCOC(C)(C)C(=O)NO)c(C)o2)cc1
Agent: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: Cc1ccc(-c2nc(CCCCCCOC(C)(C)C#N)c(C)o2)cc1
Yield: 74.5 %

Procedure:
Phosphorus tribromide (6.77 g) was added to 94 ml of a solution of 4.90 g of 2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionohydroxamic acid in benzene, and heated to reflux for 4 hours. The reaction solution was cooled, poured into ice-cold water. After addition of saturated aqueous sodium hydrogencarbonate solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1) to provide 3.32 g of the objective compound as a colorless crystals. M.p. 36° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8](=[CH:14][N:15]([CH3:17])C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4](Cl)[CH:3]=1.[CH:21]1(N)[CH2:26][CH2:25]C[CH2:23][CH2:22]1.CC([O-])(C)C.[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:15]2[CH:17]2[CH2:25][CH2:26][CH2:21][CH2:22][CH2:23]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Br)cc1Cl
Reactant: NC1CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
13ad) A solution of 20 g of ethyl 2-(4-bromo-2-chloro-benzoyl)-3-dimethylaminoacrylate (Example 13ac)) in 200 ml of dimethyl sulphoxide is treated with 5.5 g of cyclohexylamine and stirred at room temperature under argon for 45 min. Immediately after the addition the solution begins to decolourize and a colourless, gel-like substance separates. 6.84 g of potassium tert-butylate are added in one portion to this suspension. The resulting suspension is stirred at room temperature for 10 min. and subsequently heated to 50° for 1.5 hrs. The reaction mixture is left to cool to room temperature, poured into 600 ml of ice-water and stirred for a further 30 min. The suspension is suction filtered, the filter residue is washed three times with 100 ml of water each time and three times with 100 ml of hexane each time and dried. Recrystallization of the crude product from ethyl acetate/hexane yields 14.8 g (90%) of ethyl 7-bromo-1-cyclohexyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate as a colourless solid. M.p. 129°-133°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:35]([NH:42][C:11](=[O:13])[CH:10]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C(=CC(=O)O)c2ccc(OC)cc2)cc1
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=CC(=O)NCc2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.84 g (0.01 M) of 3,3-bis(4-methoxyphenyl)acrylic acid was dissolved in 10 ml of dimethylformamide. To the obtained solution, 1.2 g (0.012 M) of triethylamine and 1.2 g of ethyl chlorocarbonate were added under icecooling. After one hour, 1.2 g of benzylamine was added thereto and the mixture was stirred at room temperature for one hour. After the completion of the reaction, the reaction mixture was dissolved in 50 ml of ethyl acetate, washed with 10% hydrochloric acid, a saturated aqueous solution of NaHCO3 and a saline solution successively and dried over magnesium sulfate followed by purifying by silica gel column chromategraphy. Thus 3.3 g of the title compound having the following physicochemical properties was obtained.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH2:30][CH:31]=[CH2:32]>>[CH2:29]([C:28]1[N:2]=[C:1]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]([CH:23]3[CH2:25][CH2:24]3)[C:10](=[O:22])[C:11]3[CH:12]=[CH:13][C:14]([C:17]4[O:21][CH:20]=[N:19][CH:18]=4)=[CH:15][CH:16]=3)[CH2:7][CH2:8]2)[O:26][N:27]=1)[CH2:30][CH:31]=[CH2:32]
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: C=CCCC(=N)NO
Product: C=CCCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-pent-4-enamidine following a procedure analogous to that described in Example 1. LC (method 1): tR=1.19 min; Mass spectrum (ESI+): m/z=434 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[NH:13][C:14]([CH:19]([CH3:21])[CH3:20])([CH3:18])[C:15](=[O:17])[N:16]=1)=[O:5])[CH3:2].[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]([C:25](=[O:26])[NH:24][CH2:22][CH3:23])[C:14]([CH:19]([CH3:20])[CH3:21])([CH3:18])[C:15](=[O:17])[N:16]=1)=[O:5])[CH3:2]
Reactant: CCN=C=O
Reactant: CCOC(=O)c1ccccc1C1=NC(=O)C(C)(C(C)C)N1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)N1C(c2ccccc2C(=O)OCC)=NC(=O)C1(C)C(C)C
Yield: 98.7 %

Procedure:
9 g (0.031 mole) of 2-(2-ethoxycarbonylphenyl)-5-isopropyl-5-methyl-4-oxo-2-imidazoline are dissolved in 30 ml of absolute methylene chloride, and 2.7 g (0.038 mole) of ethyl isocyanate and 0.5 ml of DBU are added at room temperature. After a reaction time of 1 hour, the mixture is poured onto ice and the organic phase is washed twice with water, dried and evaporated. 11.0 g (98% of theory) of 2-(2-ethoxycarbonylphenyl)-1-N-ethylcarbamoyl-5-isopropyl-5-methyl-4-oxo-2-imidazoline are obtained as colorless tablets of melting point 85°-87° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:13]([CH3:14])=[N:12][C:11](SC)=[N:10][C:9]2=[O:17])=CC=1.FC(F)(F)C(O)=O.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C@@H:35]([OH:40])[CH2:36][NH:37][CH2:38][CH:39]=2)=[CH:30][CH:29]=1.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.O.O1CCOCC1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C@@H:35]([OH:40])[CH2:36][N:37]([C:11]3[N:12]=[C:13]([CH3:14])[NH:8][C:9](=[O:17])[N:10]=3)[CH2:38][CH:39]=2)=[CH:30][CH:29]=1
Reactant: O[C@H]1CNCC=C1c1ccc(F)cc1
Reactant: COc1ccc(Cn2c(C)nc(SC)nc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CC=C(c3ccc(F)cc3)[C@@H](O)C2)nc(=O)[nH]1
Yield: 93.3 %

Procedure:
To 1-(4-methoxybenzyl)-6-methyl-4-(methylthio)-1,3,5-triazin-2(1H)-one (1.39 g, 5.0 mmol) synthesized in Reference Synthesis Example 315, trifluoroacetic acid (10 mL) was added and the resultant mixture was stirred for 1 hour under reflux. After completion of the reaction, the reaction solution was concentrated under reduced pressure and 1,4-dioxane (10 mL), (R)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-3-ol (966 mg, 5.00 mmol) synthesized in Reference Synthesis Example 133, and N,N-diisopropylethylamine (1.92 g, 10.0 mmol) were added to the concentrated solution, followed by refluxing the resultant mixture for 2 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1) to obtain the title compound (1.41 g, yield 94%).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]([O:21][C:22](=[O:24])[CH3:23])[CH2:16][O:17][CH2:18][CH2:19][CH3:20])(C1C=CC(C)=CC=1)(=O)=O.[I-:25].[Na+]>CC(C)=O>[C:22]([O:21][CH:15]([CH2:16][O:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][CH2:12][I:25])(=[O:24])[CH3:23]
Reactant: [I-]
Reactant: CCCOCC(CCCOS(=O)(=O)c1ccc(C)cc1)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCOCC(CCCI)OC(C)=O
Reaction time: 18 h

Procedure:
A solution of 4-acetoxy-5-propoxy-1-pentanol tosylate (61.5 g., 0.179 mole) and sodium iodide (79.5 g., 0.53 mole) in acetone (500 ml.) is allowed to stand at 25°-27° C. for 18 hours. The precipitated sodium tosylate is filtered off. Most of the acetone is evaporated from the filtrate and the residue is treated with 300 ml. of water. The oily product is taken up in ether, washed with dilute sodium thiosulfate solution, water, and brine, and dried over sodium sulfate. The solvent is distilled in vacuo to give a quantitative yield of the crude title compound as a yellowish oil which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[CH:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[C:28]([OH:33])[CH:27]=1>CO>[CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[NH:32][C:31]1[CH:26]=[CH:27][C:28]([OH:33])=[CH:29][CH:30]=1)[CH:13]1[NH:23][CH:12]1[CH2:11]3
Reactant: Nc1ccc(O)cc1
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Solvent: CO
Product: CO[C@]12C3NC3CN1C1=C(C(=O)C(Nc3ccc(O)cc3)=C(C)C1=O)[C@H]2COC(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
Mitomycin A (1 g) and p-aminophenol (2 g) are added to methanol (100 ml) and the mixture is stirred for 5 hours at room temperature. After completion of the reaction, the reaction solution is concentrated under reduced pressure and then dried in vacuo. The dried product is then subjected to silica gel column chromatography developed by acetone-chloroform mixture (1:1) and recrystallized from an acetone-ether mixture to obtain a desired product (950 mg) in the form of green needle crystals with a yield of 78%. This product shows a green spot (Rf=0.1) by silica gel thin layer chromatography using acetone-chloroform mixture (1:1) as developer. The product does not show a precise melting point.
Reaction SMILES: [NH2:1][NH2:2].[C:3]([C:5]1[C:10](=S)[NH:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32])#[N:4]>C(O)C>[NH2:4][C:3]1[C:5]2[C:10](=[N:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[NH:2][N:1]=1
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)[nH]c(=S)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Reactant: NN
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)nc2[nH]nc(N)c2c1-c1ccccc1[N+](=O)[O-]
Reaction time: 5 h
Yield: 74 %

Procedure:
0.5 ml of hydrazine is added to a solution of 0.21 g (0.46 mmol) of ethyl 5-cyano-2-(4-methoxyphenyl)-4-(2-nitrophenyl)-6-thioxo-1,6-dihydropyridine-3-carboxylate dissolved in 2 ml of ethanol. The reaction medium is carried at 90° C. for 5 hours. The precipitate obtained is filtered and then recrystallized in a methanol/diethyl ether mixture to yield 0.20 g (74%) of ethyl 3-amino-6-(4-methoxyphenyl)-4-(2-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[Cl:15].[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>ClCCl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[Cl:15]
Reactant: COC(=O)c1cc(I)c(NC(C)=O)cc1Cl
Reactant: C#C[Si](C)(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(NC(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 209.5 %

Procedure:
To a stirred solution of 2-Chloro-4-acetamido-5-iodobenzoic acid methyl ester (2.5 g, 2.8 mmol) in dichloromethane (15.0 mL) were cuprous iodide (0.135 g, 0.71 mmol) and dichloro(bistriphenylphosphine)palladium(II) (0.25 g, 0.31 mmol). The mixture was cooled in an ice bath and added ethynyltrimethylsilane (0.825 g, 8.4 mmol). The resulting mixture was stirred under nitrogen at room temperature for 16 h. The mixture was diluted with dichloromethane (15.0 mL), washed with 5% citric acid, followed by water and dried (MgSO4). After the removal of the solvent, mixture was purified by silica gel flash chromatography using 20% ethyl acetate in heptane to afford the title compound as a light brown powder (1.9 g, 86%), m/z=252 (MH+—SiMe3).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10]C)=O.Cl>C1COCC1>[S:5]1[C:4]2[C:8](=[O:10])[NH:1][CH2:2][C:3]=2[CH:7]=[CH:6]1
Reactant: COC(=O)c1sccc1CN
Agent: Cl
Solvent: C1CCOC1
Product: O=C1NCc2ccsc21
Temperature: 60 °C
Yield: 46 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 116d (5.00 g, 29.2 mmol) and THF (150 mL). Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane complex (10.0 g, 39.1 mmol) was added portionwise. The mixture was heated at 60° C. for 14 h. After this time, the mixture was cooled to 0° C. 4 M hydrochloric acid (60 mL) was added dropwise, and the mixture was filtered. The organic layer was separated, and the aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×150 mL). The filter cake was washed with a 20% (v/v) solution of methanol in methylene chloride (3×150 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride) to afford a 45% yield (1.87 g) of 116e as an off-white solid: mp 104-105° C.; 1H NMR (300 MHz, CDCl3) δ 7.08 (s, 1H), 6.42 (br s, 1H), 4.37 (s, 2H); MS (ESI+) m/z 140.0 (M+H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH:20]1([C:23]2[CH:24]=[C:25]([NH2:34])[N:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:27]=2)[CH2:22][CH2:21]1>>[CH:20]1([C:23]2[CH:24]=[C:25]([NH:34][C:17](=[O:19])[CH2:16][C:13]3[CH:12]=[CH:11][C:10]([N:3]4[C:4]5=[N:5][CH:6]=[CH:7][CH:8]=[C:9]5[N:1]=[CH:2]4)=[CH:15][CH:14]=3)[N:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:27]=2)[CH2:22][CH2:21]1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: Nc1cc(C2CC2)nn1-c1ccccc1
Product: O=C(Cc1ccc(-n2cnc3cccnc32)cc1)Nc1cc(C2CC2)nn1-c1ccccc1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-cyclopropyl-2-phenyl-2H-pyrazol-3-ylamine. Title compound: ES-MS: 435.50 [M+H]+; tR=1.34 min (System 3).