Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Na+].O.O.[Sn](Cl)Cl.[N+:11]([C:14]1[CH:15]=[C:16]([NH:28][C:29](=[O:43])[C:30]#[C:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=2[Cl:42])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])([O-])=O.O>C(OCC)(=O)C>[NH2:11][C:14]1[CH:15]=[C:16]([NH:28][C:29](=[O:43])[C:30]#[C:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:34][C:33]=2[Cl:42])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25]
Reactant: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1N

Procedure:
870 mg (10.3 mmol) of sodium hydrogen carbonate and 1.17 g (5.17 mmol) of tin (II) chloride dihydrate are added at ambient temperature to a solution of 250 mg (0.52 mmol) of 3-(2-chloro-4-trifluoromethylphenyl)propynoic acid-[3-nitro-4-(2-diethylaminoethoxy)phenyl]amide in 50 mL of ethyl acetate. The mixture is refluxed for 12 hours. After cooling, water is added and the organic phase is separated off. The aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is eliminated. The purification of the residue is carried out by column chromatography on Alox (eluant: dichloromethane/methanol (39:1)). Yield: 100 mg (43% of theory); melting point: 127° C.-130° C.; C22H23ClF3N3O2 (M=453.89); calc.: molecular ion peak (M+H)+: 454/456; found: molecular ion peak (M+H)+: 454/456; Rf value: 0.60 (Alox, dichloromethane/methanol (39:1)).
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11].CCN(CC)CC>CCCCCC>[Br:1][CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:11])([F:12])[F:13]
Reactant: FC(F)(F)c1ccccc1C=C(Br)Br
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: FC(F)(F)c1ccccc1C=CBr
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
A solution of 1-(2,2-dibromo-vinyl)-2-trifluoromethyl-benzene (989 mg, 3 mmol), and Et)2POH (0.75 ml, 6 mmol) in Et3N (0.83 ml, 6 mmol) was stirred at 5° for 4 h. Hexane was added, and stirred for further 10 min. The mixture was extracted with hexane, washed with brine and dried over Na2SO4. Evaporation of the solvent and chromatography (hexane) gave 1-(2-bromo-vinyl)-2-trifluoromethyl-benzene (674 mg, 90%) as a colorless liquid. IR (KBr): 1600, 940 cm-1. MS (EI): 251 (M).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C@H:8]1[CH2:12][N:11]([S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C@H:10]([CH2:26][OH:27])[CH2:9]1)([CH3:6])([CH3:5])[CH3:4].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O>[CH2:28]([O:27][CH2:26][C@@H:10]1[CH2:9][C@@H:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:12][N:11]1[S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)(=[O:15])=[O:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](CO)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)O[C@@H]1C[C@@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
R2-ether formation: To a slurry of sodium hydride (60% in mineral oil, 2.75 g) in DMSO (100 ml) were added (2S,4R)-[4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-methanol (11.2 g) in portions within 0.5 h and benzyl bromide (7.2 ml) dropwise within 0.5 h at 20° C. The reaction mixture was stirred at room temperature for 1.5 h, poured onto ice/water and extracted with EtOAc. The organic phases were washed with water and brine, dried over magnesium sulphate and concentrated. The residue was crystallized from acetone/Et2O/hexane to obtain (2S,4R)-2-benzyloxymethyl-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidine (10.05 g) as a colorless solid, mp 101-103° C., MS: 454 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:32][CH:33]([CH3:36])[CH2:34][OH:35].CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[OH:35][CH2:34][CH:33]([NH:32][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=2)[CH:21]=1)[CH3:36]
Reactant: CC(N)CO
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(CO)NC(=O)c1cccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.2 %

Procedure:
A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.121 mmol), 2-aminopropan-1-ol (10 mg, 0.133 mmol), 1-methyl-1H-imidazole (40 mg, 0.484 mmol) and EDCI (92 mg, 0.484 mmol) in dichloromethane (10 mL) and DMF (0.2 mL) was stirred at room temperature for 20 h then extracted with ethyl acetate (50 mL) and washed with water (2×2 mL), then brine (2×2 mL). After drying and concentration, the residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:50) and further purified by Prep-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; gradient conditions: 20% acetonitrile/80% water (0.1% TFA, v/v) initially, proceeding to 45% acetonitrile/55% water (0.1% TFA, v/v) in a linear fashion over 9 min) to afford N-(1-hydroxypropan-2-yl)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (8.7 mg, 14%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.91 (s, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 8.17-8.00 (m, 4 h), 7.65 (t, 1H, J=7.8 Hz), 7.58-7.55 (m, 1H), 6.40 (d, 1H, J=7.5 Hz), 6.28 (d, 1H, J=8.4 Hz), 4.25-4.21 (m, 2H), 3.71-3.58 (m, 3H), 3.54-3.48 (m, 1H), 2.19-2.07 (m, 3H), 1.81 (brs, 1H), 1.29 (d, 3H, J=6.3 Hz), 1.19 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 472, tR=1.654 min, HPLC: 99.36% at 214 nm, 98.85% at 254 nm, tR=5.697 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH2:34](I)[CH3:35]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:34][CH3:35])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC1(c2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3,4-difluorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (200 mg) in DMF (4 mL) was added sodium hydride (60%, 28.4 mg) at room temperature, and the mixture was stirred at 60° C. for 30 min under a nitrogen atmosphere. Ethyl iodide (45.2 μL) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (37.1 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([CH3:22])[CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.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>[CH3:22][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[CH:29]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cccc(B(O)O)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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(C)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
A 100 mL round-bottom flask was charged tert-butyl 4-[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate (1.90 g, 5.14 mmol, 1.00 equiv), (3-methylphenyl)boronic acid (2.12 g, 15.6 mmol, 3.00 equiv), potassium carbonate (2.15 g, 15.6 mmol, 3.00 equiv), Pd(PPh3)4 (0.600 g, 0.520 mmol, 0.10 equiv), dioxane (25 mL), water (2.5 mL) with an inert atmosphere of nitrogen. The resulting solution was stirred overnight at 80° C., diluted with water (50 mL), extracted with dichloromethane (3×40 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide in 2.00 g (95% yield) of tert-butyl 4-[[2-methyl-4-(3-methylphenyl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 381 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH3:16])=[N:4][C:3]=1[O:17][C:18](=[O:24])[N:19]([CH2:22][CH3:23])[CH2:20][CH3:21].[O-:25][C:26]#[N:27].[Na+]>C(O)(=O)C>[CH2:20]([N:19]([CH2:22][CH3:23])[C:18]([O:17][C:3]1[N:4]=[C:5]([CH3:16])[C:6]2[C:11]([C:2]=1[NH:1][C:26]([NH2:27])=[O:25])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:24])[CH3:21]
Reactant: CCN(CC)C(=O)Oc1nc(C)c2cc(OC)c(OC)cc2c1N
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCN(CC)C(=O)Oc1nc(C)c2cc(OC)c(OC)cc2c1NC(N)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 44.3 %

Procedure:
To a solution of 4-amino-3-(diethylcarbamyloxy)-6,7-dimethoxy-1-methylisoquinoline (1.0 g, 3 mmol) in acetic acid (10 mL) was added sodium cyanate (0.23 g, 3.6 mmol) and the mixture was stirred under nitrogen at room temperature for 72 hours. Then the mixture was evaporated to dryness in vacuo and the residue triturated with water to give a gelatinous precipitate which was collected (0.69 g). The filtrate gave additional solids (0.50 g). The combined solids were dissolved in chloroform and purified by low pressure column chromatography on a silica gel column. Elution with 1.8% methanol/chloroform gave purified title compound which was collected from methylene chloride/ether as a colorless crystalline solid (0.865 g, 68.7%), mp 215°-216° C. IR (KBr): 3323, 3316, 3313, 3199, 1712, 1697, 1667, 1428 cm-1 ; NMR (CDCl3): δ 1.23 and 1.28 [each t, J=7 Hz, total 6H, N(CH2CH3)2 ], 2.80 (s, 3H, 1-CH3), 3.20-3.70 [br m, 4H, N(CH2CH3)2 ], 4.98 (s, 2H, NHCONH2), 6.78 and 7.01 (two s, each 1H, 5,8-H), 6.876 (br s, 1H, 4-NH). MS (DCI): 377 (MH)+ ; UV (EtOH) nm: 247 (ε51600), 275 (ε4800), 287 (ε5050), 297 (ε5000).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:35]([OH:55])[C:36]2[N:40](COCC[Si](C)(C)C)[C:39]3[CH:49]=[CH:50][C:51]([C:53]#[N:54])=[CH:52][C:38]=3[N:37]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[C:5]2[C:22]1[N:26](COCC[Si](C)(C)C)[N:25]=[CH:24][CH:23]=1.CC1C(C(O)C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=C2C(=C(C)C=1)N(S(C1C=CC(C)=CC=1)(=O)=O)C=C2C1N(COCC[Si](C)(C)C)N=CC=1>Cl.CO.C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH:35]([OH:55])[C:36]2[NH:40][C:39]3[CH:49]=[CH:50][C:51]([C:53]#[N:54])=[CH:52][C:38]=3[N:37]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[CH:20][CH:21]=1)(=[O:14])=[O:13])[CH:6]=[C:5]2[C:22]1[NH:26][N:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccnn3COCC[Si](C)(C)C)c3c(C(O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ccnn3COCC[Si](C)(C)C)c3c(C(O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn[nH]3)c3c(C(O)c4nc5cc(C#N)ccc5[nH]4)c(C)cc(C)c32)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of a mixture of (±)-2-((5,7-dimethyl-1-tosyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-((5,7-dimethyl-1-tosyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-indol-4-yl)(hydroxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (250 mg, 0.314 mmol) in 1M HCl in MeOH (2 mL) was stirred at 60° C. for 16 h. The reaction mixture was cooled to room temperature, and diluted with CH2Cl2. The layers were separated and the organic layer was washed with 5% aq. NaHCO3, H2O, and brine, dried over Na2SO4, and filtered. After concentration of the filtrate, the resulting residue was purified by silica gel flash column chromatography [CH2Cl2/(2M NH3 in MeOH)=94/6 then 93/7] to give the title compound. MS (ESI+) m/z 537.1 (M+H).
Reaction SMILES: [CH2:1]([O:5][CH:6]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:7][NH:8][CH2:9][CH:10]1[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[CH2:12][O:11]1)[CH2:2][CH2:3][CH3:4].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][CH2:36][C:37](Cl)=[O:38]>O>[CH2:19]([O:18][CH:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:7][N:8]([CH2:9][CH:10]1[O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[CH2:12][O:11]1)[C:37](=[O:38])[CH2:36][Cl:35])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCOC(CNCC1OCC(C)C(C)O1)OCCCC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCOC(CN(CC1OCC(C)C(C)O1)C(=O)CCl)OCCCC

Procedure:
N-(2,2-Dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-dibutoxyethyl)-N-(4,5-dimethyl-1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:12]([O:8][C:6]1[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(I)cc1OCc1ccccc1
Temperature: 65 °C

Procedure:
To a solution of 5-iodo-2-nitrophenol (2.65 g, 10 mmol) (J. Org. Chem. 1998, 63, 4199-4208) in DMF (10 mL) is added benzyl bromide (1.71 g, 10 mmol) and K2CO3 (2.07 g, 15 mmol) and the mixture is heated at 65° C. for 30 min. Then water is added (400 mL) and it is extracted by EtOAc (2×200 mL). The water layer is then acidified and extracted with EtOAc (100 mL). The combined EtOAc layer is then washed with 1N HCl and brine, dried with NaSO4 and concentrated to give the title compound as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:10]([CH2:19]Br)=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14]C)=O.Cl.[C:22]([O:26][C:27](=[O:35])[C@H:28]([CH2:30][CH2:31][C:32](=[O:34])[NH2:33])[NH2:29])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[Br:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:11]2[C:10]=1[CH2:19][N:29]([CH:28]([CH2:30][CH2:31][C:32](=[O:34])[NH2:33])[C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:35])[C:12]2=[O:14]
Reactant: COC(=O)c1cccc(Br)c1CBr
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(CCC(N)=O)N1Cc2c(Br)cccc2C1=O
Temperature: 25 °C
Yield: 47.7 %

Procedure:
Triethylamine (4.66 g, 46.09 mmol) was added to a stirred suspension of methyl 3-bromo-2-bromomethylbenzoate (6.45 g, 20.95 mmol) and L-glutamine t-butyl ester hydrochloride (5.0 g, 20.95 mmol) in THF (100 mL). The mixture was heated to reflux for 18 hours. The mixture was cooled to room temperature and solvent was removed. The residue was dissolved in methylene chloride (100 mL) and washed with water (2×80 mL), brine (80 mL) and dried (MgSO4). Solvent was removed and the residue was purified by chromatography (CH2Cl2:CH3OH 97.5:2.5) to afford tert-butyl 2-(4-bromo-1-oxoisoindolin-2-yl)-4-carbamoylbutanoate (3.97 g, 48%): 1H NMR (CDCl3) δ 7.74 (d, J=7.1 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 6.15 (s, 1H), 5.77 (s, 1H), 5.02-4.96 (m, 1H), 4.58 (d, J=17.4 Hz, 1H), 4.34 (d, J=17.4 Hz, 1H), 2.45-2.10 (m, 4H), 1.46 (s, 9H); 13C NMR (CDCl3) δ 173.83, 169.42, 168.74, 142.28, 134.70, 133.65, 129.80, 122.70, 117.75, 82.66, 54.29, 47.80, 32.27, 27.95, 25.54.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].[N-]=[N+]=[N-].[Na+].[OH2:21]>Cl.CO.CCOC(C)=O>[OH:21][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 90 °C
Yield: 40 %

Procedure:
To a solution of 3-amino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D6) (280 mg, 1.25 mmol, 1 equiv) in a mixture of 2N aqueous HCl solution (2.5 ml) and MeOH (5 ml) at 0° C. was added NaN3 (190 mg, 2.75 mmol, 2.2 equiv) portionwise over 20 min. H2O (5 ml) was added and the resulting mixture was heated at 90° C. for 1 h then cooled to room temperature and diluted with AcOEt. The two layers were separated and the aqueous phase was extracted twice with AcOEt (20 ml). The combined organic layers were washed with brine (20 ml), dried over MgSO4 and concentrated in vacuo to give a crude product which was triturated with Et2O/MeOH to give 3-hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (D36) (110 mg, 40%) as a light tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=O)=[O:12].S(Cl)([Cl:17])=O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([Cl:17])(=[O:14])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
2--Chloro-5-nitro benzene sulphonic acid (484 parts) was charged to a flask then quickly added thionyl chloride (1190 parts) and dimethyl formamide (12 parts). The resultant slurry was heated to 60° C. and stirred at 60°-65° C. for a total of 5 hours. The mixture was cooled to room temperature then poured onto ice/water. The precipitated solid was filtered off and washed with cold water before drying in vac oven to yield the product 2-chloro-5-nitro benzene sulphonylchloride (395 parts).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[I:15].[CH3:19]C([O-])(C)C.[K+].CI.ClC1C=C(C=CC=1)OC1C=C2C(=CC=1)N(C)N=C2I>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:14]=[CH:13][C:12]2[C:8](=[C:9]([I:15])[N:10]([CH3:19])[N:11]=2)[CH:7]=1
Reactant: Clc1cccc(Oc2ccc3[nH]nc(I)c3c2)c1
Reactant: CC(C)(C)[O-]
Agent: Cn1nc(I)c2cc(Oc3cccc(Cl)c3)ccc21
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc2ccc(Oc3cccc(Cl)c3)cc2c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.9 %

Procedure:
To a solution of 5-(3-chlorophenoxy)-3-iodo-1H-indazole (194 mg, 524 μmol) in THF (5 mL) at 0° C. was added KOtBu (82.2 mg, 733 μmol) and the mixture stirred at 0° C. for 30 min. MeI (104 mg, 45.8 μL, 733 μmol) was added. The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane. The combined organics were dried over MgSO4 and concentrated to a clear oil, then purified by chromatography (40 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min) to afford the desired less polar 5-(3-chlorophenoxy)-3-iodo-1-methyl-1H-indazole (154 mg, 400 mmol, 77%) as a clear yellow oil. MS (M+H)+=384.8; 1H NMR (CDCl3) δ: 7.38 (d, J=9.1 Hz, 1H), 7.17-7.29 (m, 2H), 7.11 (d, J=2.3 Hz, 1H), 7.06 (dt, J=7.9, 0.9 Hz, 1H), 6.94 (t, J=2.3 Hz, 1H), 6.86 (dd, J=8.3, 2.3 Hz, 1H), 4.12 (s, 3H). The regioisomer, 5-(3-chlorophenoxy)-3-iodo-2-methyl-2H-indazole, (32 mg, 83.2 μmol, 16%) was also obtained as a clear yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C@@H:17]([C:19]([OH:21])=[O:20])[CH3:18])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:22][C:23]([NH2:25])=[NH:24])=[N:5][CH:4]=1.Cl.N[C:28](N)=N.O>CS(C)=O>[CH3:28][O:20][C:19](=[O:21])[C@@H:17]([CH3:18])[NH:16][S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:22][C:23]([NH2:25])=[NH:24])=[CH:11][CH:10]=1)(=[O:14])=[O:15]
Reactant: N=C(N)N
Reactant: C[C@@H](NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)O
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)[C@@H](C)NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 4.9 %

Procedure:
N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-alanine hydrochloride ##STR33## NaH (35 mg, 80% dispersion by wt in mineral oil, 1.17 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (179 mg, 1.87 mmol) in DMSO (5 mL) and the mixture was heated at 60° C. under N2 for 45 min. 1-{[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]amino}-D-alanine methyl ester (170 mg, 0.47 mmol) was added and the mixture heated at 90° C. for 4 h. The cooled mixture was poured into water and extracted with EtOAc (3×30 mL). The combined organic extracts were dried (MgSO4) and the solvents evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (66:33 to 0:100) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-D-alanine methyl ester (22 mg, 0.057 mmol) as a yellow foam/oil.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C@H:3]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:27](=[O:28])C1.C(N(CC)CC)C>ClCCCl>[CH3:1][C:2]([CH3:24])([CH3:23])[C@H:3]([N:11]1[CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[C:27]1=[O:28])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: Cc1cccc(CNCCN[C@H](C(=O)OC(C)(C)C)C(C)(C)C)n1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
A solution containing the product from Example 10A (1.76 g, 5.25 mmol) in 1,2-dichloroethane (210 mL) was treated with N,N-disuccinimidyl carbonate (1.61 g, 6.28 mmol) and triethylamine (0.75 mL, 5.38 mmol), stirred at 25° C. for 16 hours, and partitioned with 10% Na2CO3. The aqueous phase was extracted with additional dichloromethane. The combined organic phase was dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-25% methyl tert-butyl ether/dichloromethane to give the title compound (1.33 g, 70% yield).