Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[CH2:27][N:28]([CH2:41][C:42]1[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[C:44]([C:52]([F:55])([F:54])[F:53])[CH:43]=1)[C:29]1[N:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:31][N:30]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=O)C.[OH-].[Na+:57]>C(O)C>[Na+:57].[F:51][C:48]([F:49])([F:50])[C:46]1[CH:47]=[C:42]([CH:43]=[C:44]([C:52]([F:53])([F:55])[F:54])[CH:45]=1)[CH2:41][N:28]([CH2:27][C:18]1[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:17]=1[N:7]([CH2:6][CH2:5][OH:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15])[C:29]1[N:34]=[CH:33][C:32]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)=[CH:31][N:30]=1
Reactant: CC(=O)OCCN(CCCCCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CCCCCCN(CCO)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1

Procedure:
Ethyl 7-[(2-acetoxy-ethyl)-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-1-amino]-heptanoate (156 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 4 hours. To the reaction solution are added 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 7-[(2-acetoxy-ethyl)-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-amino]-heptanoic acid (144 mg). The resulting 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-(2-hydroxy-ethyl)-amino]-heptanoic acid (144 mg) is dissolved in ethanol (1 ml), and thereto is added a 1N-aqueous sodium hydroxide solution (172 μl), and concentrated under reduced pressure to give 7-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-(2-hydroxy-ethyl)-amino]-heptanoic acid sodium salt (133 mg). MS (m/z): 750 [M−Na]−
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)=[C:10]1[C:27]([O:29]CC)=[O:28].OC1(C2C=CC=CC=2OC)C2C(=CC=CC=2)C(C2C=CC3OCOC=3C=2)=C1C(OCC)=O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
Ethyl (RS)-1-(2-Methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-hydroxy-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (100 mg, 0.23 mmol) in CH2Cl2 (5 ml) was added triethylsilane (32 mg, 0.28 mmol), followed by boron trifluoride etherate (0.13 ml, 1.05 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 10 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to provide the title compound (91 mg, 96%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:22])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:42][C:43]1[CH:44]=[C:45](I)[CH:46]=[CH:47][C:48]=1[F:49].[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:22])/[C:13](/[C:46]1[CH:45]=[CH:44][C:43]([F:42])=[C:48]([F:49])[CH:47]=1)=[CH:14]/[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Fc1ccc(I)cc1F
Reactant: COC(=O)/C(I)=C\C1CCCCC1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCCC1)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
A mixture of zinc dust (980 mg, 15 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.37 g, 2 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (82 mg, 0.75 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclohexyl-2-iodo-acrylic acid methyl ester (prepared in Example 4, 1.47 g, 5 mmol) in dry tetrahydrofuran (1.5 mL) over 3 min. During the addition, the temperature rose to 45° C. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (5 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) and triphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (10 mL) was stirred at 25° C. under argon for 10 min and then treated with 3,4-difluoro-iodobenzene (960 mg, 4 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 25° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution (50 mL), and the organic compound was extracted into diethyl ether (2×50 mL), The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 5/1 hexanes/diethyl ether) afforded (E)-3-cyclohexyl 2-(3,4-difluoro-phenyl)-acrylic acid methyl ester (1.06 g, 95%) as an oil: EI-HRMS m/e calcd for C16H18F2O2 (M+) 280.1275, found 280.1275.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C:13]([CH3:38])([CH3:37])[C:14]([N:16]([CH3:36])[C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:35][CH2:34]S[CH2:32][CH2:31]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O[O:42][S:43]([O-:45])=O.[K+].S([O-])(O)=O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:38])([CH3:37])[C:14]([N:16]([C:17]2[CH:18]=[N:19][C:20]([N:30]3[CH2:31][CH2:32][S:43](=[O:45])(=[O:42])[CH2:34][CH2:35]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH3:36])=[O:15])[CH:4]=[C:3]([C:2]([F:39])([F:40])[F:1])[CH:8]=1
Reactant: O=S([O-])OO
Reactant: Cc1ccccc1-c1cc(N2CCSCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1-c1cc(N2CCS(=O)(=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.9 %

Procedure:
To a solution of 1.00 g (1.72 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-thiomorpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide in 10 ml methanol were added 1.59 g (2.58 mmol) OXONE®. After stirring for 2 days at room temperature, 5 ml 38% sodium hydrogensulfite solution and 20 ml saturated sodium carbonate solution were added consecutively and methanol was removed in vacuo. The residue was diluted with 25 ml water and extracted with three 25-ml portions of dichloromethane. The combined organic layers were dried (sodium sulfate), purified by flash chromatography and crystallized from ethanol to give 980 mg (93%) of the title compound as white crystals. M.p. 200-201° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=3)=[CH:20][NH:21]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CN(C)C=O.C(OCC)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][O:4][C:5]4[CH:13]=[CH:12][CH:11]=[C:10]5[C:6]=4[CH:7]=[CH:8][NH:9]5)[CH2:28][CH:29]=3)=[CH:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: ClCCOc1cccc2[nH]ccc12
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1ccc2c(C3=CCN(CCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-2-(1H-indole-4-oxy)ethane (0.359 g, 1.85 mmol) and 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole ( 0.500 g, 2.13 mmol) in the presence of 2.0 equivalents of potassium carbonate (0.51 g, 3.7 mmol) in dimethylformamide at 900 C. Yield 0.101 g (14%) of a tan foam. The oxalate salt was prepared by treating the free base with 1.0 equivalent of oxalic acid in diethyl ether and evaporating. mp 120-124° C. (browns) FDMS m/e=391 (M+ of free base).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[NH2:3].[F:10][C:11]([F:18])([CH3:17])[C:12](=O)[CH2:13][C:14]#[N:15]>>[F:10][C:11]([C:12]1[CH:13]=[C:14]([NH2:15])[N:2]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:3]=1)([F:18])[CH3:17]
Reactant: CC(F)(F)C(=O)CC#N
Reactant: NNc1cccnc1
Agent: Cl
Product: CC(F)(F)c1cc(N)n(-c2cccnc2)n1
Yield: 9 %

Procedure:
3-Hydrazinopyridine hydrochloride (435 mg, 3.0 mmol) was treated with 4,4-difluoro-3-oxopentanenitrile (400 mg, 3.0 mmol) (prepared as described in Example 152A Step 1) according to the procedure in Example 161A Step 3 to afford 3-(1,1-difluoroethyl)-1-(pyridin-3-yl)-1H-pyrazol-5-amine (62 mg, 0.27 mmol, 9%). 1H NMR (300 MHz, MeOD) δ 8.86 (s, 1H), 8.60 (d, 1H), 8.12 (d, 1H), 7.62 (t, 1H), 5.82 (s, 1H), 1.92 (t, 3H); LC-MS (ESI) m/z 225 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([C:27]2[N:28]([CH3:36])[C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][C:18]=1[CH:19]=O>>[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([C:27]2[N:28]([CH3:36])[C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][C:18]=1/[CH:19]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH3:14])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CNS(=O)(=O)c1ccc(C(C)=O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Product: CNS(=O)(=O)c1ccc(C(=O)/C=C/c2cc(-c3cc4ccccc4n3C)c(OC)cc2OC)cc1
Yield: 57 %

Procedure:
The title compound was prepared using in an analogous way as Ex-1 using 4-acetyl-N-methyl-benzenesulfonamide (Ex-29A) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A), 57% yield, yellow solid, mp 129–131° C. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=16 Hz, 1H), 8.10 (d, J=9 Hz, 2H), 7.95 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=7 Hz), 1H), 7.47 (d, J=16 Hz, 1H), 7.36 (d, J=8 Hz, 1H), 7.22–7.26 (m, 1H), 7.14–7.16 (m, 1H), 6.59 (s, 1H), 6.51 (s, 1H), 4.42 (br s, 1H) 4.03 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H), 2.69 (d, J=6 Hz, 3H). HRMS (ESI) Calcd. for C27H26N2O5S: 491.1641 (M+H)+; Found: 491.1646.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][CH2:18][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Li+]>CO.O>[NH2:30][C:28](=[O:29])[C:27]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]=1[CH3:26])=[O:31]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1)CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1)CCCC3
Yield: 95.7 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-1-benzyl-2-methyl-6,7,8,9-tetrahydro-1H-benz[g]indol-4-yl]oxy]acetic acid methyl ester (285 mg, 0.671 mmol) in methanol (5 ml) was treated with 1 M lithium hydroxide solution (2.5 mL) at room temperature for 1.5 h. The reaction mixture was diluted with water, concentrated in vacuo, and treated with 1 M hydrochloric acid (1 mL). The resulting precipitate was collected via vacuum filtration and dried to provide 270 mg (96%) of the title compound as a tan powder: mp>300° C. 1H NMR (DMSO-d6) δ 8.00 (bs, 1H), 7.35 (m, 3H), 7.26 (t, J=7.0 Hz, 1H), 6.88 (d, J=7.3 Hz, 2H), 6.21 (s, 1H), 5.64 (s, 2H), 4.38 (s, 2H), 2.88 (m, 2H), 2.71 (m, 2H), 2.35 (s, 3H), 1.60 (m, 4H); MS ES+ m/e 421 (p+1); IR (KBr, cm−1) 1636, 1402.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13].[NH2:19][OH:20]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:19][OH:20])=[O:13]
Reactant: NO
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NO)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-hydroxyisonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.31 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.6 mmol of hydroxylamine. LC/MS [7.37 min; 374 (M+1)]
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29].O>C1COCC1>[CH2:29]([O:14][C@@H:13]1[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 26 g (77 mmol) of benzyl 3-[(tert-butoxycarbonyl)amino]4-hydroxypyrrolidine-1-carboxylate in 120 mL of THF was added 5 g (211 mmol) of sodium hydride at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then 10 mL (115 mmol) of allyl bromide was added. The reaction mixture was warmed up to room temperature and continuously stirred at room temperature overnight. Water (50 mL) was added to quench the reaction. The organic phase was separated, and the aqueous layer was extracted with ethyl acetate twice (100 mL×2). The combined extracts were washed with brine, dried over Na2SO4, evaporated under reduced pressure. Chromatography on silica gel column with 25% EtOAc-hexane provided the title compound (21.3 g, 73%). MS (M+H)+ 377.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:33])[CH:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C@@H:17]([O:30][CH3:31])[C:16]1=[O:32])[C:12](=[CH2:14])[CH3:13]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:33])[C:11]([N:15]1[C@H:18]([S:19][S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)[C@@H:17]([O:30][CH3:31])[C:16]1=[O:32])=[C:12]([CH3:14])[CH3:13]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)[C@H](OC)[C@H]1SSc1nc2ccccc2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](OC)[C@H]1SSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
0.1 ml of triethylamine is added to a solution of 432 mg of 2- [(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2-oxoazetidin-1-yl]-3-methylenebutyric acid methyl ester in 25 ml of methylene chloride and the mixture is stirred at room temperature for 100 minutes. The reaction mixture is diluted with methylene chloride, washed twice with aqueous citric acid solution and water, dried over sodiun sulphate and freed of solvent in vacuo. The residue is purified by chromatography over silica gel with toluene/ethyl acetate (9:1 and 4:1) and yields the title compound in the form of an oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C.C(OCC)C>C(O)C>[N:11]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)CCCCBr
Reactant: C1COCCN1
Solvent: CCOCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCN1CCOCC1
Yield: 86.1 %

Procedure:
A mixture of ethyl 5-bromovalerate (8 g, 38.3 mmole), morpholine (3.67 g, 42 mmole) and triethylamine (4.2 g, 42 mmole) in ethanol (100 mL) was heated to reflux overnight. The solution was concentrated to afford a gummy white solid which was mixed with diethyl ether and filtered to remove the solid. The filtrate was washed with saline (3×50 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 7.1 g (87%) of ethyl 5-morpholin-4-ylpentanoate as a pale brown liquid. MS (m/z, ES+): 217 (M+2, 100%), 216 (M+1, 57%).
Reaction SMILES: [NH2:1][C:2](=[O:23])[CH2:3][N:4]1[C:12]2[C:11](Br)=[CH:10][CH:9]=[CH:8][C:7]=2[C@@H:6]2[CH2:14][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17][C@H:5]12.C(=O)([O-])[O-].[K+].[K+].CNCCNC>>[O:23]=[C:2]1[CH2:3][N:4]2[C@H:5]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@H:6]3[C:7]3[C:12]2=[C:11]([CH:10]=[CH:9][CH:8]=3)[NH:1]1
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc(Br)c1N2CC(N)=O
Agent: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reaction time: 66 h

Procedure:
A suspension of [4aS,9bR]-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (254 mg, 1.34 mmol), cuprous iodide (254 mg, 1.34 mol), potassium carbonate (3.96 g, 28.7 mmol) and N,N′-dimethylethylenediamine (0.31 mL, 2.87 mmol) in dioxiane (20 mL) is heated at reflux for 4.5 hours. Another portion of cuprous iodide (250 mg, 1.32 mmol) and N,N′-dimethylethylenediamine (0.33 mL, 3.05 mmol) is added. The resulting mixture is heated to a reflux for another 3 hours and then at 73° C. for about 66 hours. The reaction mixture is concentrated and passed through a short alumina column using 100:3:3 dichloromethan:triethylamine:methanol. The resulting solvent from the column is evaporated to a solid and redissolved in dichloromethane. The dichloromethane solution is washed with brine, dried with sodium phosphate and concentrated to a solid (3.7 g, 95%, 83% pure by HPLC).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[C:3](=[N:4][O:5][N+:6]=2[O-:10])[CH:2]=1.C1CC[N:19]2[C:14](=[N:15]CCC2)CC1.N#CN.C(O)(=O)C>C(#N)C>[CH:1]1[CH:9]=[CH:8][C:7]2[N+:6]([O-:10])=[N:15][C:14]([NH2:19])=[N+:4]([O-:5])[C:3]=2[CH:2]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: [O-][n+]1onc2ccccc21
Agent: N#CN
Solvent: CC(=O)O
Solvent: CC#N
Product: Nc1n[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 22.5 °C
Reaction time: 48 h
Yield: 38.7 %

Procedure:
To a stirred mixture containing 1.000 kg (7.347 moles) of benzofuroxan and 2.237 kg (14.694 moles) of DBU was added a solution containing 618 g (14.694 moles) of cyanamide in 380 ml of acetonitrile while maintaining the temperature below 25° C. After stirring for 48 hours at 20-25° C. the reaction mixture was dilute with 6.620 liters of acetonitrile and cooled below 15° C. To the cooled mixture was added 882 g (14.694 moles) of acetic acid while maintaining the temperature below 15° C. After stirring overnight at 5-10° C. the precipitated product was collected by filtration and washed with acetonitrile (2×2 liters). The resulting solid was suspended in 2 liters of water, stirred about 30 minutes until a homogeneous suspension was obtained, and then filtered. The collected solid was resuspended in 2 liters of water, stirred for 20-30 minutes and filtered. The solid collected was dried to constant weight under vacuum at 50-55° C. to give 506.6 g of tirapazamine.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[N:44]1([C:50]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[C:58]([F:61])([F:60])[F:59])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>CN(C=O)C.CCCCCC.O>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][C:19](=[O:21])[N:47]1[CH2:48][CH2:49][N:44]([C:50](=[O:51])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[C:58]([F:61])([F:59])[F:60])[CH2:45][CH2:46]1)([CH3:11])([CH3:12])[CH3:13]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
DIPEA (3.5 mL, 20.41 mmol) was added dropwise to tert-butoxycarbonylamino-acetic acid (1.42 g, 8.16 mmol) in DMF (15 mL). EDCI (2.6 g, 13.61 mmol) and HOBT (1.1 g, 8.16 mmol) were added consecutively and, after 10 mins, piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (2 g, 6.80 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water was then added and the product was extracted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 3.3 g of crude product. Purification by column chromatography (using silica gel of mesh size of 60-120 and 60/40 EtOAc:hexane as the eluent) afforded 2.6 g (96% yield) of {2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[CH3:22].Cl.[CH:24]1([CH2:27][O:28][NH2:29])[CH2:26][CH2:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.ClCCl>[CH:24]1([CH2:27][O:28][NH:29][C:11]([C:4]2[C:3]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=3[CH3:22])=[C:2]([F:1])[C:7]3[NH:8][CH:9]=[N:10][C:6]=3[CH:5]=2)=[O:13])[CH2:26][CH2:25]1
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)O)cc2nc[nH]c2c1F
Reactant: NOCC1CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(I)ccc1Nc1c(C(=O)NOCC2CC2)cc2nc[nH]c2c1F
Reaction time: 0.5 h

Procedure:
A solution comprised of 7-fluoro-6-(4-iodo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid, O-cyclopropylmethylhydroxylamine hydrochloride (1.25 equiv.), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (1.25 equiv.), and diisopropylethylamine (3 equiv.) in 1:1 v/v tetrahydrofuran-dichloromethane is stirred for 30 minutes. The reaction mixture is concentrated in vacuo and the residue is taken up into diethyl ether. The ether phase is washed with dilute aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and brine, is dried (MgSO4), and is concentrated in vacuo to afford the desired product. The product may be recrystallized with an appropriate solvent like methanol or chloroform if further purification is necessary.