Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]([CH2:35][CH2:36][CH3:37])[C:10]2[C:15]([C:16]=1[CH2:17][C:18]1[CH:30]=[CH:29][C:21]3[O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:20]=3[CH:19]=1)=[CH:14][C:13]([O:31][CH3:32])=[C:12]([O:33][CH3:34])[CH:11]=2)(=O)=O.C(=O)(OC(C)(C)C)[NH2:41].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>CCOC(C)=O.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1COCC1>[CH:19]1[C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][C:21]=2[CH:29]=[CH:30][C:18]=1[CH2:17][C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:33][CH3:34])=[C:13]([O:31][CH3:32])[CH:14]=2)[C:9]([CH2:35][CH2:36][CH3:37])=[N:8][C:7]=1[NH2:41]
Reactant: CC(C)(C)OC(N)=O
Reactant: CCCc1nc(OS(=O)(=O)C(F)(F)F)c(Cc2ccc3oc4ccccc4c3c2)c2cc(OC)c(OC)cc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc(N)c(Cc2ccc3oc4ccccc4c3c2)c2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 0.75 h

Procedure:
A 2 mL microwave vial equipped with a magnetic stirrer was charged under N2 with 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-yl trifluoromethanesulfonate CCH 42040-1 (13 mg, 23 μmol), t-butyl carbamate (5 mg, 43 μmol), dry powdered cesium carbonate (15 mg, 46 μmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (4 mg, 7 μmol) and tris(dibenzylideneacetone)dipalladium(0) (4 mg, 4 μmol). Dry THF (1.5 mL) was then added and the mixture was stirred for 45 min at 140° C. under microwave irradiation. After cooling to RT, the mixture was diluted with EtOAc (30 mL), then filtered through celite. The solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. The residue was then dissolved in CH2Cl2 (10 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer before addition of TFA (1 mL) and the mixture was stirred overnight at RT then concentrated to dryness under vacuum. The residue was basified with a saturated NaHCO3 solution (10 mL) before extraction with CH2Cl2 (40 mL). The organic phase was isolated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) gave 4 mg of 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-amine. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.5 mL) and the solution was stirred for 5 min at RT, and concentrated at 40° C. under vacuum to afford 4-(dibenzo[b,d]furan-2-ylmethyl)-6,7-dimethoxy-1-propylisoquinolin-3-amine hydrochloride 65 as a pale brown solid (4 mg, 38% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:7]=1.[CH3:28][S:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:6]2[CH:7]=[C:2]([C:34]3[CH:33]=[CH:32][CH:31]=[C:30]([S:29][CH3:28])[CH:35]=3)[CH:3]=[N:4][CH:5]=2)[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:11]1
Reactant: CSc1cccc(B(O)O)c1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cncc(Br)c2)c(F)c1
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CSc1cccc(-c2cncc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)c1
Temperature: 88 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
5-(3-Bromo-pyridin-5-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 4 of Preparation 10, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (12.7 mg, cat.) and a 2N sodium carbonate solution (550.0 uL) were added to a mixed solvent of ethanol (600.0 uL) and 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 20.0 mg of the titled compound as a white liquid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:4](=[O:20])[C:3]=1[C:21]#[N:22].[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([NH2:34])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[H-].[Na+]>CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([NH:34][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4](=[O:20])[C:3]=2[C:21]#[N:22])[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: N#Cc1c(Cl)c2ccccc2n(Cc2ccc(F)cc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Nc2c(C#N)c(=O)n(Cc3ccc(F)cc3)c3ccccc23)C1
Reaction time: 2 h

Procedure:
To a stirred solution of 4-Chloro-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinoline-3-carbonitrile (1 eq, 0.250 g, 0.80 mmole) in N,N′-dimethylformamide was added commercially available 3-Amino-azetidine-1-carboxylic acid tert-butyl ester (1.1 eq 0.151 g, 0.88 mmole) and treated with 60% NaH oil dispersion. (1.5 eq, 0.029 g, 1.2 mmole). After stirring for 2 h, reaction was quenched with 10% HCl aq. (1 ml) then H2O (5 ml). A solid formed that was collected and dried. No further purification was necessary, afforded 3-[3-Cyano-1-(4-fluoro-benzyl)-2-oxo-1,2-dihydro-quinolin-4-ylamino]-azetidine-1-carboxylic acid tert-butyl ester as a pale yellow solid (0.322 g, 90%, calc M+H 449, obs M+H 449).
Reaction SMILES: Cl.O1CCOCC1.C(O[C:13](=O)[N:14](C)[CH2:15][C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)(C)(C)C>ClCCl>[CH3:13][NH:14][CH2:15][C:16]#[C:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=1
Reactant: CN(CC#Cc1ccc(OC(F)(F)F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A 4 M solution of HCl in dioxane (330 μl, 1 mmol) was added at ambient temperature to a solution of methyl-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyl]-carbamic acid tert-butyl ester (50 mg, 0.15 mmol) in dichloromethane (0.5 ml). The reaction mixture was stirred for 3 h at ambient temperature. The solvent was removed under reduced pressure and the residue crystallized from dichloromethane/heptane to yield 20 mg (90 μmol, 57%) of the title compound as brown crystals.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[Cu](C#N)[C:14]#[N:15].O>CN(C=O)C>[CH:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:14]#[N:15])=[N:3][NH:4]2)=[CH:9][CH:8]=1)=[O:12]
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1n[nH]c2cc(C=O)ccc12
Yield: 59.5 %

Procedure:
To a solution of 3-iodo-1H-indazole-6-carbaldehyde (3 g, 10.8 mmol) in DMF (25 mL) was added Copper cyanide (1.9 g, 21 mmol). The solution was heated by microwave irradiation at 185° C. for 10 min Water (100 mL) was added and a white precipitate was collected. The precipitate was dissolved in EtOAc (250 mL), washed with water (2×25 mL), dried over MgSO4 and concentrated to give the title compound as a white solid (1.1 g, 73%). 1H NMR (400 MHz, DMSO-d6) δ 14.92 (bs, 1H), 10.17 (s, 1H), 8.39 (s, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]3[N:17]=[CH:18][C:19]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:20][C:15]3=[N:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)=[O:4].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]([NH2:39])[CH3:38]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]([NH:39][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[C:21]([C:19]2[CH:18]=[N:17][N:16]3[C:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH:7]=4)=[CH:13][N:14]=[C:15]3[CH:20]=2)[CH:22]=1)[CH3:38]
Reactant: CNC(=O)Nc1cccc(-c2cnc3cc(-c4cccc(C(=O)O)c4)cnn23)c1
Reactant: CC(N)c1ccccc1F
Product: CNC(=O)Nc1cccc(-c2cnc3cc(-c4cccc(C(=O)NC(C)c5ccccc5F)c4)cnn23)c1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 96, Step 4 starting from 3-[3-(3-{[(methylamino)carbonyl]amino}phenyl)imidazo[1,2-b]pyridazin-7-yl]benzoic acid and 1-(2-fluorophenyl)ethanamine. LCMS (M+H)+: m/z=509.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[CH:19][CH:18]=2)=[O:15])=[N:11][N:10]=1.CO.[OH-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:19][CH:18]=2)=[O:15])=[N:11][N:10]=1
Reactant: COC(=O)CCCc1ccc(NC(=O)c2nnc(Nc3ccccc3F)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCc1ccc(NC(=O)c2nnc(Nc3ccccc3F)o2)cc1
Reaction time: 8.5 h
Yield: 55.6 %

Procedure:
Methyl 4-{4-[({5-[(2-fluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]phenyl}butanoate (Example 483) (174 mg, 0.44 mmol) was stirred in THF: MeOH (8 mL of a 1:1 mixture) and NaOH (2.5 mL of 2M aqueous solution) was added. The mixture was stirred for 8.5 h then acidified (2M HCl), allowed to stand overnight, then concentrated in vacuo. The precipitate was filtered and washed with water and then Et2O to give the title compound (94 mg, 56%) as a solid; 1H NMR δ 1.77-1.84 (2H, m), 2.22 (2H, t), 2.59 (2H, t), 7.14-7.21 (3H, m), 7.25-7.34 (2H, m), 7.70-7.72 (2H, m), 8.02-8.07 (1H, m), 10.74 (1H, s), 10.94 (1H, s), 11.98 (1H, s); MS m/e MH+ 385.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([NH2:14])[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](=O)[CH2:28][C:29](OCC)=[O:30])=[CH:24][CH:25]=2)[CH:20]=[N:19]1)(=O)C.CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]3[NH:14][C:27]([C:23]4[CH:22]=[C:21]5[C:26](=[CH:25][CH:24]=4)[NH:18][N:19]=[CH:20]5)=[CH:28][C:29](=[O:30])[N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1nc(-c2ccc(Cl)c(Cl)c2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2C(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: O=c1cc(-c2ccc3[nH]ncc3c2)[nH]c2nc(-c3ccc(Cl)c(Cl)c3)nn12
Temperature: 130 °C
Reaction time: 36 h
Yield: 16.6 %

Procedure:
To a solution of 3-(3,4-dichlorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.44 mmol) in n-BuOH (1 ml) was added ethyl 3-(1-acetyl-1H-indazol-5-yl)-3-oxopropanoate (300 mg, 1.00 mmol) and TsOH (5 mg, 0.03 mmol), and the resulting mixture was stirred for 36 h at 130° C. The solids were collected by filtration and washed with methanol (10 ml) to afford 2-(3,4-dichlorophenyl)-5-(1H-indazol-5-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a light yellow solid (29 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[OH:17][CH2:18][CH2:19][NH:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][NH:20][CH2:19][CH2:18][OH:17])[N:3]=1
Reactant: NNCCO
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: OCCNNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[2-hydroxyethylhydrazino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-hydroxyethylhydrazine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8](O)=[S:9])=[N:5][N:4]=[N:3]1.[CH2:11]1[CH2:21][CH2:20][N:19]2[C:14](=NC[CH2:17][CH2:18]2)[CH2:13][CH2:12]1.ClC(OCC(C)C)=O.C(NC1CCCCC1)C>O1CCCC1>[CH2:18]([N:19]([CH:14]1[CH2:13][CH2:12][CH2:11][CH2:21][CH2:20]1)[C:8](=[S:9])[CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1)[CH3:17]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cn1nnnc1CC(O)=S
Agent: CC(C)COC(=O)Cl
Agent: CCNC1CCCCC1
Solvent: C1CCOC1
Product: CCN(C(=S)Cc1nnnn1C)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
2-(1-Methyl-1,2,3,4-tetrazol-5-yl)thio-acetic acid (45 mmole) is dissolved in tetrahydrofuran (50 ml) and thereto is added DBU (50 mmole). To the mixture is added dropwise with stirring isobutyl chloroformate (50 mmole) under ice-cooling and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise N-ethyl-cyclohexylamine under ice-cooling, and the mixture is further stirred at room temperature for 2 hours. After distilling off the solvent under reduced pressure, the resulting residue is extracted with chloroform. The chloroform layer is washed with 5% aqueous hydrochloric acid, an aqueous saturated sodium hydrogen carbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-ethyl-N-cyclohexyl-2-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-acetamide (yield: 52%) which is recrystallized from ether-petroleum ether, white prisms, m.p. 69°-71° C.
Reaction SMILES: [O:1]=[C:2]([CH2:4][N:5]([C:7](=[NH:9])[NH2:8])[CH3:6])[OH:3].[OH-].[NH4+:11]>O>[CH3:6][N:5]([CH2:4][C:2]([O-:3])=[O:1])[C:7]([NH2:9])=[NH:8].[NH4+:11]
Reactant: CN(CC(=O)O)C(=N)N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CN(CC(=O)[O-])C(=N)N

Procedure:
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 7.87 g (60 mmol) of creatine is dissolved in 600 ml of water. To this is added 78 ml of 1M ammonium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, ammonium 2-(1-methylguanidino)acetate, shown below.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[NH:5][CH2:4]1.[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2>>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[N:5]([C:36]([C:31]2[NH:32][C:33]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:26][CH2:25][CH2:24][OH:23])=[CH:35][CH:34]=3)=[O:37])[CH2:4]1
Reactant: NS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Reactant: O=C(O)c1cc2cc(OCCO)ccc2[nH]1
Product: NS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)N(C(=O)c1cc2cc(OCCO)ccc2[nH]1)CC3CCl
Temperature: 0 °C
Yield: 88 %

Procedure:
(Scheme C). The amine 117 was reacted with 5-(2-hydroxyethoxy)-1H-indole-2-carboxylic acid as described in Example 7. The reaction mixture was poured into ice-water and the precipitate was collected to give 28 (88%): mp (EtOAc) 231-234° C.; 1H NMR [(CD3)2SO] δ 11.72 (s, 1H), 9.28 (s, 1H), 8.87 (d, J=1.6 Hz, 1H), 8.44 (d, J=8.9 Hz, 1H), 7.97 (dd, J=8.9, 1.6 Hz, 1H), 7.63 (s, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.22 (d, J=1.7 z, 1H), 7.17 (d, J=2.2 Hz, 1H), 6.97 (dd, J=8.9, 2.4 Hz, 1H), 5.00-4.93 (m, 1H), 4.188-4.81 (m, 1H), 4.74-4.70 (m, 1H), 4.69-4.60 (m, 1H), 4.19-4.12 (m, 2H), 4.05-3.98 (m, 2H), 3.79-3.71 (m, 2H), 2.94 (s, 1H), 2.79 (s, 1H), 1.95 (s, 1H); 13C NMR δ 160.6, 153.2, 147.0, 142.6, 142.5, 132.2, 131.9, 130.4, 129.7, 127.4, 125.6, 124.4, 121.3, 120.5, 116.5, 116.1, 113.2, 106.3, 103.1, 69.8, 59.6, 54.8, 47.6, 41.4. Anal. (C24H21ClN4O7S.⅓H2O) C, H, N.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([C@@H:9]1[NH:14][CH2:13][C:12]2[O:15][CH:16]=[CH:17][C:11]=2[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].[N:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:25][C:26]3[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][C:27]=3[CH:28]=2)=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:2]([O:6][C:7]([C@@H:9]1[N:14]([S:33]([C:30]2[CH:31]=[CH:32][C:26]3[O:25][C:24]([C:21]4[CH:20]=[CH:19][N:18]=[CH:23][CH:22]=4)=[CH:28][C:27]=3[CH:29]=2)(=[O:34])=[O:35])[CH2:13][C:12]2[O:15][CH:16]=[CH:17][C:11]=2[CH2:10]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@H]1Cc2ccoc2CN1
Reactant: O=S(=O)(Cl)c1ccc2oc(-c3ccncc3)cc2c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)[C@H]1Cc2ccoc2CN1S(=O)(=O)c1ccc2oc(-c3ccncc3)cc2c1
Temperature: 60 °C

Procedure:
30 mmol of (5R)-4,5,6,7-tetrahydrofuro[2,3-c]pyridine-5-carboxylic acid tert-butyl ester hydrochloride are placed in 150 ml of pyridine. 30 mmol of 2-(4-pyridyl)-1-benzofuran-5-sulphonyl chloride described in Preparation C are then added at room temperature and the whole is heated at 60° C. overnight.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:11]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].C([O-])([O-])=O.[K+].[K+].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1.O>CN(C=O)C>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:11]=3)=[CH:4][C:3]=2[N+:20]([O-:22])=[O:21])=[CH:32][CH:31]=1
Reactant: CN(C)c1cccc(C(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)c1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1cccc(C(=O)Nc2ccc(Sc3ccc(N)cc3)c([N+](=O)[O-])c2)c1
Temperature: 65 °C

Procedure:
To a solution of Example 239b (5.0 g, 15.6 mmol) in DMF (50 mL) was added K2CO3 (4.3 g, 17.0 mmol) and 4-aminothiophenol (1.9 g, 8.5 mmol). The mixture was heated at 65° C. for 16 h. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The residue was purified by silica gel chromatography eluting with hexanes/ethyl acetate/methanol (50:40:10) to give the desired product (3.4 g, 53%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14](Cl)=[O:15])[CH3:12].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:11]([CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([O:10][C:3]1[C:2]([I:1])=[CH:7][C:6]([I:8])=[CH:5][C:4]=1[I:9])=[O:15])[CH3:12]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CCCCC(CC)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(CC)C(=O)Oc1c(I)cc(I)cc1I
Yield: 119.4 %

Procedure:
A solution of 2,4,6-triiodophenol (20.0 g, 42 mmol), 2-ethylhexanoyl chloride (25 ml, 144 mmol, 3.5 eq.) and 4-dimethylaminopyridine (DMAP; 2 mmol, 250 mg, 0.05 eq.) in 150 ml of pyridine was stirred overnite at room temperature. The solution was poured into 1000 ml of 1N aqueous hydrochloric acid and the aqueous solution was extracted twice with ethyl acetate. The combined organic layers were washed with aqueous hydrochloric acid, water, saturated aqueous sodium chloride and then dried over magnesium sulfate. The ethyl acetate solution was then concentrated under vacuum to give an oil (30 g) which was purified by silica gel chromatography (5% ethyl acetate/hexanes eluent) to give the product. Concentration under high vacuum afforded 21 g (79%) of the desired hexanoate ester as an oil. The product was taken up in hexanes and filtered through a pad of basic alumina. The filtrate was concentrated under high vacuum to give 16.9 g of analytically pure product.
Reaction SMILES: [NH2-].[Na+].[CH2:3]([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=O)[CH:4]=[CH2:5].O1CCC[CH2:18]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:3]([O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=[CH2:18])[CH:4]=[CH2:5]
Reactant: C=CCOc1cc(C=O)ccc1OC
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Product: C=CCOc1cc(C=C)ccc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium amide (39 g) was dispersed in dry tetrahydrofuran (800 Dmls). Methyltriphenylphosphonium bromide (102 g) was added and the mixture stirred at R.T. for 2 hours. 3-allyloxy-4-methoxy-benzaldehyde (50 g) was then added dropwise over ca. 15 mins. and the mixture stirred for a further 3 hours. The mixture was filtered and the solvent removed from the filtrate under reduced pressure. The residue was washed with diethyl ether (1.51) and the solvent removed to yield a brown coloured resin. The washing process was repeated and the residue obtained was distilled under reduced pressure to give 3-allyloxy-4-methoxystyrene (29.5 g), b.p.98-104° C. at 0.8 mbar.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=O)[CH2:29]1)(=[O:27])[CH3:26].CCN(C(C)C)C(C)C.[NH:46]1[C:54]2[C:49](=[C:50]([C:55]3[CH:56]=[C:57]([NH2:64])[C:58]4[CH:59]=[N:60][NH:61][C:62]=4[CH:63]=3)[CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47]1>CN(C=O)C>[C:25]([N:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([NH:64][C:57]2[CH:56]=[C:55]([C:50]3[CH:51]=[CH:52][CH:53]=[C:54]4[C:49]=3[CH:48]=[CH:47][NH:46]4)[CH:63]=[C:62]3[C:58]=2[CH:59]=[N:60][NH:61]3)=[O:36])[CH2:29]1)(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCOC(C(=O)O)C1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCOC(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)C1
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
To a solution of HATU (0.107 g, 0.28 mmol) in dry DMF (3 ml) was added 4-acetyl-2-morpholinecarboxylic acid (0.05 g, 0.282 mmol). DIPEA (0.098 ml, 0.56 mmol) was added and the mixture was left to stand for 10 min. 6-(1H-indol-4-yl)-1H-indazol-4-amine (0.04 g, 0.14 mmol), dissolved in dry DMF (3 ml) was added and the solution was left to stand at room temperature for 20 hr. DMF was removed by blow down under a stream of nitrogen, then the residue was dissolved and purified by Mass Directed AutoPrep Method B. The solvent was removed in vacuo and product dried in a vacuum oven at 50° C. overnight to give the title compound as a brown oil (17 mg).
Reaction SMILES: [CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14](Br)=[C:15]([CH3:21])[C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cu](C#N)[C:24]#[N:25].C(OCC)(=O)C.O>CN1CCCC1=O>[CH2:1]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:24]#[N:25])=[C:15]([CH3:21])[C:16]=2[N+:18]([O-:20])=[O:19])[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1CCc2cc(Br)c(C)c([N+](=O)[O-])c21
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCN1CCc2cc(C#N)c(C)c([N+](=O)[O-])c21
Temperature: 190 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
1-Octyl-5-bromo-6-methyl-7-nitroindoline (4.0 g) was dissolved in N-methylpyrrolidone (40 ml), and copper cyanide (1.9 g) was added, which was followed by stirring at 190° C. for 1 hr. Ethyl acetate (100 ml) and water (100 ml) were added to the reaction mixture. The insoluble matter was filtered off. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5-1/3) to give 2.4 g of oily 1-octyl-5-cyano-6-methyl-7-nitroindoline.