Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:34])=[CH:24][C:25]([O:32][CH3:33])=[C:26]([CH:31]=1)[C:27]([O:29]C)=[O:28].CO.[OH-].[Na+].Cl>O.C1COCC1>[F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:34])=[CH:24][C:25]([O:32][CH3:33])=[C:26]([CH:31]=1)[C:27]([OH:29])=[O:28]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)c(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To the above prepared methyl 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate (assumed 0.211 mmol) in a mixture MeOH (2 mL)/THF (2 mL) at r.t. under N2 was added sodium hydroxide (0.84 mL, 0.84 mmol). The mixture was stirred at r.t. for 24 hours. The mixture was added with 2 ml 1N HCl, and concentrated until off white solids formed. The mixture was added with 5 ml H2O, the solids filtered and washed with 3×2 ml H2O and dried (75.1 mg). 1H NMR (500 MHz, CD3OD) δ 7.95 (m, 2H), 7.73 (s, 1H), 7.51 (d, J=8.24, 1H), 7.30-7.25 (t ovelapping with m, 3H), 7.13 (s, 1H), 3.99 (s, 3H), 2.96 (s, 3H), 2.28 (s, 3H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=452.23, HPLC Rt=1.582.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C@H:24]2[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]2)[C:13]([NH:15][C:16]2[S:17][C:18]([S:21]C#N)=[CH:19][N:20]=2)=[O:14])[CH2:8][CH2:7]1)(=[O:5])[CH2:2][CH2:3][CH3:4].SC[C@@H]([C@@H](CS)O)O.[N:39](=[CH:47][CH2:48]Cl)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]Cl>>[N:39]1([CH2:47][CH2:48][S:21][C:18]2[S:17][C:16]([NH:15][C:13](=[O:14])[N:12]([CH:9]3[CH2:8][CH2:7][N:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:11][CH2:10]3)[C@H:24]3[CH2:29][CH2:28][C@H:27]([CH3:30])[CH2:26][CH2:25]3)=[N:20][CH:19]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: ClCC=NCCCCCCCl
Reactant: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCCC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-butyryl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-(hexamethyleneimino) ethylchloride
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[NH2:8].[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:9][N:4]1[C:3](=[O:10])[C:2]2[N:1]=[C:17]([C:14]3[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=3)[NH:8][C:7]=2[CH:6]=[N:5]1
Reactant: O=Cc1ccncc1
Reactant: Cn1ncc(N)c(N)c1=O
Solvent: O=[N+]([O-])c1ccccc1
Product: Cn1ncc2[nH]c(-c3ccncc3)nc2c1=O
Temperature: 190 °C
Yield: 42 %

Procedure:
0.560 g of 4,5-diamino-2-methyl-2H-pyridazin-3-one and 0.535 g of 4-pyridinecarbaldehyde were added to 10 ml of nitrobenzene, and the mixture was heated at 190° C. under a nitrogen atmosphere for three hours. The reaction solution was cooled down, and the precipitate was collected by filtration to give 0.381 g of the title compound.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11]>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[C:6]1(=[O:11])[C:7]2[C:3](=[CH:2][CH:10]=[CH:9][CH:8]=2)[CH2:4][NH:5]1
Reactant: Nc1cccc2c1CNC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1NCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2,3-dihydro-1H-isoindol-1-one 4 (7 gm, 0.04 mol.) in ethyl acetate and aq. NaHCO3 solution, was treated with mono-methyloctadioic acid chloride at room temperature. The reaction mixture was stirred at room temperature for 30 min. The solid that separated was filtered and dried under vacuum to give 2,3-dihydro-1H-isoindol-1-one 85, which was hydrolyzed by KOH (5 eq) in ethanol at 0° C. to generate acid 59 (5.775 gm).
Reaction SMILES: COC1C=CC(C[N:8]2[C:13](=[O:14])[CH2:12][CH:11]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:10][C:9]2=[O:24])=CC=1>CC#N.O>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([CH:11]2[CH2:10][C:9](=[O:24])[NH:8][C:13](=[O:14])[CH2:12]2)=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: COc1ccc(CN2C(=O)CC(c3ccc([N+](=O)[O-])cc3)CC2=O)cc1
Solvent: O
Solvent: CC#N
Product: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of 22.8 g (64.2 mmol) of 1-(4-methoxy-benzyl)-4-(4-nitro-phenyl)-piperidine-2,6-dione (as prepared in the previous step) in CH3CN (150 mL) was treated with 70.4 g (128 mmol) of ceric ammonium nitrate (CAN) as a solution in water (100 mL). The mixture was stirred at RT for 5 h, diluted with water (100 mL), and extracted with EtOAc (2×150 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (1×100 mL) and water (1×100 mL). The combined aqueous layers were extracted with EtOAc (1×100 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The solid residue was triturated with a minimum amount of CH3CN, filtered, and air-dried. The filtrate was concentrated and triturated again with a minimum amount of CH3CN, filtered, and air-dried as a second batch. The two batches were combined to afford 7.00 g (47%) as an off-white solid: 1H-NMR (CDCl3; 400 MHz): δ 8.26 (d, 2H, J=8.8 Hz), 7.97 (br s, 1H), 7.42 (d, 2H, J=8.8 Hz), 3.62-3.52 (m, 1H), 3.02-2.93 (m, 2H), 2.84-2.74 (m, 2H).
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[N:25]=[C:24]2[O:26][CH2:27][CH2:28][C:23]2=[CH:22][CH:21]=1>ClCCCl.C(Cl)Cl>[Cl:1][C:21]1[CH:22]=[C:23]2[CH2:28][CH2:27][O:26][C:24]2=[N:25][C:20]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Br:13]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Brc1ccccc1-c1ccc2c(n1)OCC2
Solvent: ClCCl
Solvent: ClCCCl
Product: Clc1cc2c(nc1-c1ccccc1Br)OCC2
Reaction time: 8 h
Yield: 206.3 %

Procedure:
Trichloroisocyanuric acid (0.63 g, 2.7 mmol) was added as a solid to a solution of 6-(2-bromophenyl)-2,3-dihydrofuro[2,3-b]pyridine (1.5 g, 5.4 mmol) in 1,2-dichloroethane (30 ml). The mixture was allowed to stir overnight and then a small additional amount of the chlorinating agent was added and the solution refluxed for 1.5 h. The mixture was diluted with methylene chloride and washed with water, brine (sat.), dried (over MgSO4), filtered and concentrated to afford 1.73 grams of the desired product, m.p. 106°-117° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: Oc1cnc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cnc3ccccc3c2)c(Cl)c1
Yield: 99.9 %

Procedure:
To a solution of 3-hydroxyquinoline (1.00 g) and 3-chloro-4-fluoronitrobenzene (1.21 g) in Acetone (20 ml), was added K2CO3 (2.86 g). The mixture was refluxed for 1 hr. After cooling the reaction mixture was filtered through a short celite pad. The filtrate was concentrated to provide compound 198 (2.07 g, quant.) as a brown oil.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])(=[O:5])[C@@H:2]([CH3:4])[OH:3].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.Cl>CN(C)C=O.[Cl-].[Ca+2].[Cl-].[Ag]=O>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[C@@:2]([CH3:4])([OH:3])[C:1]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5]
Reactant: CC(C)COC(=O)[C@@H](C)O
Reactant: C1=COCCC1
Agent: O=[Ag]
Agent: Cl
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CC(C)COC(=O)[C@](C)(O)C1CCCCO1
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of isobutyl (R)-lactate (73 g, 0,5 mol, Merck) and 3,4-dihydro-2H-pyran (70 g, 0,83 mol, Merck) was treated with 5M hydrogen chloride in dimethylformamide (4 ml) and set aside at ambient temperature overnight in calcium chloride protected 250 ml round-bottom flask. Silver oxide (15 g) was added, the mixture stirred magnetically for 2 hours and then filtered. The product was isolated by distillation (13 Pa, b.p. 94-96° C.) to provide isobutyl 2-0-tetrahydropyranyl-(R)-lactate (102.5 g, 89%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31](O)=[O:32])[C:25]=2[O:24][CH2:23][CH2:22]1>>[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([N:17]3[CH2:16][CH:15]4[CH:19]([CH2:20][N:13]([C:9]5[N:8]=[C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)[CH:12]=[CH:11][N:10]=5)[CH2:14]4)[CH2:18]3)=[O:32])[C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1cccc2c1OCCO2
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Product: O=C(c1cccc2c1OCCO2)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid. MS (ESI) mass calcd. for C25H24N4O3, 428.50; m/z found, 429.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH2:9][C:10]([O:12][CH:13]2[CH:17]([OH:18])[CH2:16][O:15][CH2:14]2)=[O:11])=[CH:6][C:5]([N:19]=[C:20]2[N:28]3[N:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])[S:21]2)=[C:4]([F:30])[CH:3]=1.N1C=CC=CC=1.[Cl:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[Cl:1][C:2]1[C:7]([S:8][CH2:9][C:10]([O:12][CH:13]2[CH:17]([O:18][C:39](=[O:40])[CH2:38][Cl:37])[CH2:16][O:15][CH2:14]2)=[O:11])=[CH:6][C:5]([N:19]=[C:20]2[N:28]3[N:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])[S:21]2)=[C:4]([F:30])[CH:3]=1
Reactant: O=C(CSc1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl)OC1COCC1O
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)OC1COCC1OC(=O)CSc1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
In 25 ml of dichloromethane were dissolved 1.19 g of 9-(4-chloro-2-fluoro-5-(4-hydroxytetrahydrofuran-3-yloxycarbonylmethylthio)phenylimino)-8-thia-1,6-diazabicyclo[4.3.0]nonan-7-one and 0.24 g of pyridine, followed by dropwise addition of a solution of 0.34 g of chloroacetyl chloride in dichloromethane. After stirring at room temperature overnight, the reaction mixture was washed with water, and subsequently with aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane =2/3), to obtain 1.02 g of a compound described in Table 1 (No. 32) (74 %).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:34][CH2:35][CH2:36][OH:37])=[N:13][N:14]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[C:8]([Cl:38])[N:7]=1)(=O)C.C[O-].[Na+]>CO.C(Cl)Cl>[Cl:38][C:8]1[N:7]=[C:6]([CH2:5][OH:4])[C:11]2[C:12]([O:34][CH2:35][CH2:36][OH:37])=[N:13][N:14]([C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:10]=2[CH:9]=1
Reactant: CC(=O)OCc1nc(Cl)cc2c1c(OCCO)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCCOc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(CO)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (6-chloro-3-(2-hydroxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (491.9 mg, 0.932 mmol) in MeOH (2 ml) and DCM (2 ml) was charged with sodium methoxide (25 wt % in MeOH, 0.45 ml, 1.968 mmol) and stirred at RT for 2 hr. Quenched with sat aq NH4Cl and extracted 3× with DCM. Washed organics with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide 2-((6-chloro-4-(hydroxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)oxy)ethanol. MS: [M+H]+ m/z 486.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([Br:25])[C:22]([OH:26])=[C:21]([Br:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C@@H:33]([CH2:41][CH3:42])[C:34]([O:36]C(C)(C)C)=[O:35]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Br:27])[C:22]([O:26][C@@H:33]([CH2:41][CH3:42])[C:34]([OH:36])=[O:35])=[C:23]([Br:25])[CH:24]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](O)C(=O)OC(C)(C)C
Reactant: Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br
Product: CC[C@H](Oc1c(Br)cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1Br)C(=O)O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3,5-dibromo-biphenyl-4-ol, and tert-butyl (S)-(−)-hydroxybutyrate, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 79-80° C.; MS m/e 617 (M−H)+;
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH2:17][CH2:16]2)[C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)=[CH:5][CH:6]=1.Cl.[O:28]1CCOCC1>[OH-].[Na+].O=O.[Pt]>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][O:23][CH2:24][C:25]([OH:28])=[O:26])[CH2:19][CH2:20]2)=[CH:13][CH:12]=1
Reactant: OCCOCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: C1COCCO1
Agent: [Pt]
Agent: Cl
Agent: O=O
Product: O=C(O)COCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 58.7 %

Procedure:
To a stirred and heated (80° C.) suspension of hydroxyzine hydrochloride (1.0 g, 2.23 mmol) and 5% Pt/C in dioxane (10 mL) and 1N aqueous NaOH solution (10 mL), O2 was bubbled through for 20 hours. After being cooled down to room temperature, The mixture was filtered through a pad of celite (2.5×2 cm) and washed with water. The filtrate was extracted with dichloromethane (3×25 mL). The combined organic solution was dried (Na2SO4). Evaporation of solvent gave the titled compound as a pale white form (0.51 g, yield 58.7%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)=[CH:22][CH:21]=1
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1
Yield: 21.1 %

Procedure:
The 4-[(phenylmethyl)oxy]-1H-indazole (D1) (543 mg, 1.65 mmol), the [4-(methyloxy)phenyl]boronic acid (500 mg, 3.29 mmol), copper (II) acetate (448 mg, 2.47 mmol), powdered molecular sieves (400 mg) and pyridine (0.27 mL, 3.29 mmol) in DCM (75 mL) were stirred at room temperature in the presence of air. After 4 hours the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM and the combined organics were washed with brine and dried over MgSO4. The crude (880 mg) was purified by flash chromatography (Biotage SP4) with a gradient of Et2O (0 to 30%) in hexane to afford 115 mg of title compound (D32).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[CH:13]=[CH:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a suspension of 5-[(phenylmethyl)oxy]-1H-indole (10 g, 44.78 mmol) in toluene (100 mL) was added benzenesulfonyl chloride (9.1 g, 51.5 mmol), tetrabutylammonium bromide (1.44 g, 4.48 mmol) and a solution of NaOH (23 g, 582 mmol) in 100 mL of water. The mixture was rapidly stirred at rt. After 30 min, additional benzenesulfonyl chloride (0.97 g, 5.5 mmol) was added and stirred for another 30 min. The mixture was partitioned between Et2O and water. The aqueous phase was extracted with Et2O. The combined organic phases were washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-30% EtOAc-hexanes gradient) to afford the title compound (14.2 g, 87% yield): 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=9.0 Hz, 1H), 7.85 (d, J=7.6 Hz, 2H), 7.53-7.50 (m, 2H), 7.44-7.29 (m, 7H), 7.03 (d, J=2.4 Hz, 1H), 7.0 (dd, J=9.0, 2.4 Hz, 1H), 6.57 (d, J=3.7 Hz, 1H), 5.05 (s, 2H); MS (ES) m/z 364 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:44][O:45][C:46]1[C:51]2[N:52]=[C:53]([NH2:55])[S:54][C:50]=2[C:49]([N:56]([CH3:58])[CH3:57])=[CH:48][CH:47]=1>C1COCC1>[CH3:57][N:56]([CH3:58])[C:49]1[C:50]2[S:54][C:53]([NH:55][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:52][C:51]=2[C:46]([O:45][CH3:44])=[CH:47][CH:48]=1
Reactant: COc1ccc(N(C)C)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
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: C1CCOC1
Product: COc1ccc(N(C)C)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
To a stirred solution of 41 mg (0.29 mmol) 4-fluoro-benzoic acid in 1 ml THF were added 128 mg (0.34 mmol) HATU and 0.10 ml (0.56 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 2.5 h. 50 mg (0.22 mmol) 4-methoxy-N7,N7-dimethyl-benzothiazole-2,7-diamine was then added and stirring continued at room temperature for 16 h. The reaction mixture was then concentrated in vactio. Flash chromatography (ethyl acetate/hexane) afforded 64 mg (83%) N-(7-dimethylamino-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide as a white crystalline solid. ES-MS m/e (%): 346 (M+H +, 100).
Reaction SMILES: C[N+]1([O-])CCOCC1.[C:9]([O:13][C:14](=[O:28])[N:15]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][OH:27])[CH:20]=1)[CH3:16])([CH3:12])([CH3:11])[CH3:10].C([N+](CCC)(CCC)CCC)CC>C(Cl)Cl>[C:9]([O:13][C:14](=[O:28])[N:15]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH:26]=[O:27])[CH:20]=1)[CH3:16])([CH3:12])([CH3:10])[CH3:11]
Reactant: CN(CCc1ccc(Cl)c(CO)c1)C(=O)OC(C)(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CN(CCc1ccc(Cl)c(C=O)c1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
NMO (607 mg, 4.35 mmol) was added to a sol. of [2-(4-chloro-3-hydroxymethyl-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (435 mg, 1.45 mmol) in CH2Cl2 (30 mL). The mixture was stirred for 30 min, and tetrapropylammonium perrhutenate (51.0 mg, 0.145 mmol) was added. The mixture was stirred for 1 h, and was filtered over Celite. The filtrate was evaporated under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 19:1) yielded the title compound (330 mg, 76%). LC-MS: tR=1.00 min.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([OH:9])[C:6]([CH3:10])=[CH:5][C:3]=1[OH:4].Cl[C:12]1[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=1.[H-].[Na+]>CN(C)C=O>[OH:4][C:3]1[C:2]([CH3:1])=[CH:8][C:7]([O:9][C:12]2[CH:13]=[CH:14][C:15]([N+:27]([O-:29])=[O:28])=[C:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:17]=2)=[C:6]([CH3:10])[CH:5]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc(O)c(C)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c(C)cc1O
Yield: 44.3 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2,5-dimethylhydroquinone (1.38 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.87 g), sodium hydride (55 wt. %, 0.87 g) and anhydrous N,N-dimethylformamide (20 ml) and the reaction mixture was purified to give the title compound (1.72 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.NC1C([N+]([O-])=O)=C(N2CCN([CH2:51][CH2:52][NH:53][C:54]([NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[O:55])CC2)C(Br)=CN=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([CH2:51][CH2:52][NH:53][C:54]([NH:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[O:55])[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(CCNC(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CCNC(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 1-(2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)ethyl)-3-phenylurea (100 mg, 0.22 mmol), DMF (1.25 mL), 1M Na2S2O4 (3 eq, 0.66 mmol, 0.66 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.05 eq, 0.23 mmol, 34 mg). After filtration, a small sample of the solid product was further purified by semi-preparative hplc to give the pure product as an off-white solid; 1H-NMR (500 MHz, DMSO-d6) 2.50 (2H, obscured by DMSO peak, NCH2), 2.53-2.57 (m, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.27 (q, J=5.7 Hz, 2H, NHCH2), 3.67 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 6.13 (t, br, J=5.0 Hz, 1H, NHCH2), 6.82 (d, J=9.0 Hz, 2H, N,N-dimethylaminophenyl), 6.88 (tt, J=7.4, 1.0 Hz, 1H, phenyl H-4), 7.22 (dd, J=8.4, 7.5 Hz, 2H, phenyl H-3 & H-5), 7.40 (dd, J=8.5, 1.0 Hz, 2H, phenyl H-3 & H-5), 8.01 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.16 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.64 (br s, 1H, PhNH), 13.13 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22]S([O-])=O.[Na+]>Cl.O>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18]([OH:22])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(N2CC3CC2CN3Cc2ccccc2)cc1
Reactant: O=S([O-])O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1ccc(N2CC3CC2CN3Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1.17 g (122) in 17 mL concentrated HCl 0.35 g NaNO2 in 5 mL water were added slowly dropwise, so that the temperature remained below 5° C. The solution was agitated for 2 hours at 60° C., neutralized with NaHSO3 and extracted with ether (4×50 mL). The combined organic phases were dried with Na2SO4, evaporated and distilled in a bulb tube (Kp: 0.05 mbar; 140° C.): 0.1 g (123) (123) as colorless oil. DC: CHCl3/methanol (9:1).