Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([N+:15]([O-])=O)=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=[O:2].[ClH:18]>[Pd].C(O)C>[OH2:2].[ClH:18].[ClH:18].[NH2:1][C:4]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([NH2:15])=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2
Reactant: Cc1c(C)c([N+](=O)[O-])c2[nH]ncc2c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1c(C)c(N)c2[nH]ncc2c1N
Product: O

Procedure:
1.8 g. of 4,7-dinitro-5,6-dimethylindazole, prepared in accordance with the procedure of E. Nelting, Ber. 37, 2556 (1904), were hydrogenated at room temperature in 50 ml. of ethanol and 5 ml. of concentrated hydrochloric acid in the presence of 0.1 g. of catalyst (10% Pd on carbon). After the absorption of H2 ceased, the product was filtered off from the catalyst and reduced. Brown crystals were obtained. Analysis:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[I:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[N:13]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]nc(I)c23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Reaction time: 2 h
Yield: 69.1 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (1 mL, 7.36 mmol) was slowly added to a stirring mixture of tert-butyl 4-(3-iodo-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (3.1 g, 6.134 mmol) and K2CO3 (1.27 g, 9.2 mmol) in DMF (30 mL) at room temperature. After 2 hours, EtOAc (200 mL) and water (100 mL) were added to the mixture, and the phases were separated with warming. The resulting organic suspension was washed with water (3×50 mL) with warming. Final organic phase was concentrated in vacuo without drying over MgSO4 to prevent the loss of the product. The residue was triturated with CH3CN, and the solid formed was filtered, washed with CH3CN (2×10 mL) and dried under high vacuum to provide tert-butyl 4-(3-iodo-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (2.65 g, 69% yield) as a solid. LCMS (APCI+) m/z 626.1 (M+H)+, Retention time=4.96 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:15])[C:5]2[N:9]=[C:8]([N:10]([CH3:12])[CH3:11])[NH:7][C:6]=2[CH:13]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37](Cl)=[O:38]>C1COCC1.C(OCC)(=O)C>[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:36]=1[C:37]([NH:1][C:2]1[CH:3]=[C:4]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:15])[C:5]2[N:9]=[C:8]([N:10]([CH3:11])[CH3:12])[NH:7][C:6]=2[CH:13]=1)=[O:38]
Reactant: O=C(Cl)c1c(F)cccc1Cl
Reactant: Cc1ccc(NC(=O)c2cc(N)cc3[nH]c(N(C)C)nc23)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2cc(NC(=O)c3c(F)cccc3Cl)cc3[nH]c(N(C)C)nc23)cc1Cl

Procedure:
To a solution of 6-amino-N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (50 mg) in THF (1.5 mL), was added N,N-diisopropylethylamine (37 μL) and the mixture was stirred under ice-cooling. To the mixture was added slowly 2-chloro-6-fluorobenzoyl chloride (24 μL), and it was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (30 mg) as pale yellow powder. This was then suspended in MeOH (1 mL), 2N hydrogen chloride/MeOH (1 Eq) was added to obtain a homogeneous solution, and MeOH was removed under reduced pressure. The residue was triturated in n-hexane/ethyl acetate (1:1), and the precipitate was collected by filtration and dried to obtain the titled compound (24 mg) as pale purple powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH2:29][C:30]3[CH:38]=[CH:37][C:33]4[O:34][CH2:35][O:36][C:32]=4[CH:31]=3)[CH2:12][C:13]3[N:14]([CH2:25][CH2:26][CH2:27][CH3:28])[C:15](I)=[N:16][C:17]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1B(O)O>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=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>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]([CH2:29][C:30]3[CH:38]=[CH:37][C:33]4[O:34][CH2:35][O:36][C:32]=4[CH:31]=3)[CH2:12][C:13]3[N:14]([CH2:25][CH2:26][CH2:27][CH3:28])[C:15]([C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=4[CH3:45])=[N:16][C:17]=3[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccccc1B(O)O
Reactant: CCCCn1c(I)nc(-c2ccccc2)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
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: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCn1c(-c2ccccc2C)nc(-c2ccccc2)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-2-iodo-5-phenyl-3H-imidazol-4-ylmethyl)-amine (62 mg, 0.1 mmol) and Pd(PPh3)4 (6 mg) in 1 ml of toluene is added aqueous sodium carbonate (0.4 ml of 2.0 N) and 2-methylphenyl boronic acid (18 mg, 0.13 mmol, 1.3 eq.) in 0.3 ml of ethanol under nitrogen, the resulting mixture is stirred at 100° C. for 8 h. After being cooled to room temperature, the reaction mixture is diluted with 10 ml of ethyl acetate, washed with water and brine and dried over sodium sulfate. Concentration and purification by flash chromatography affords 43 mg of bis-benzo[1,3]dioxol-5-ylmethyl-(3-butyl-5-phenyl-2-o-tolyl-3H-imidazol-4-ylmethyl)-amine 1H NMR (400 MHz, CDCl3) δ 7.70 (2H, d, J=7.2 Hz), 7.43˜7.24 (7H, m), 6.77˜6.67 (6H, m), 5.94 (4H, s), 3.87 (2H, t, J=7.6 Hz), 3.78(2H, s), 3.37 (4H, s), 2.20 (3H,s), 1.17 (2H, m), 0.88 (2H, m), 0.63 (3H, t, J=7.2 Hz); MS (+VE) m/z 588 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Mg].[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[CH:14]=[O:15].Cl>CCOCC.O1CCCC1>[Cl:11][C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[CH:14]([OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: COc1ccccc1Br
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C(O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C

Procedure:
A solution of 2-bromoanisole (50.0 g, 0.267 mol) in ether is added portionwise to a mixture of magnesium (7.10 g, 0.293 mol) in ether. After the addition is complete, the reaction mixture is heated at reflux for one hour, diluted with ether, cooled to 0° C., treated with a solution of 2-chloro-5-nitrobenzaldehyde (39.0 g, 0.210 mol) in tetrahydrofuran, warmed to room temperature, and diluted with an ice-water mixture. After acidifying the aqueous mixture with hydrochloric acid (pH 2--pH 3), the organic phase is separated and the aqueous phase is extracted with ether. The organic extracts are combined, washed sequentially with 10% sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a brown gum.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.C(Cl)Cl.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[C:19]([F:27])[CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:24])=[O:25])=[C:19]([F:27])[CH:18]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 2-aminothiazole (4.51 g, 0.0450 mol) and pyridine (24.26 mL, 0.3000 mol) in methylene chloride (40 mL, 0.6 mol) at 0° C. was added portionwise 4-bromo-2-fluorobenzenesulfonyl chloride (8.2 g, 0.030 mol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc, washed with 1N HCl solution, H2O and brine. The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to give the crude product that was purified via automated flash chromatography (silica gel, 25% EtOAc in hexanes to 100% EtOAc) to give the product as a light brown solid (3.6 g, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:39][O:38][C:36](=[O:37])[C:33]1[CH:32]=[CH:31][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:35][CH:34]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 9.1 %

Procedure:
To a solution of 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (200 mg, 0.48 mmol, Example 56, step 4) in N′N-dimethylformamide (2.0 ml) were added methyl 6-chloropyridine-3-carboxylate (93 mg, 0.53 mmol) and potassium carbonate (199 mg, 1.44 mmol). The mixture was stirred for 4 h at 110° C. After cooling to r.t. water was added and the mixture was extracted twice with AcOEt. The organic phases were washed with water and brine, dried (MgSO4) and concentrated. The product was purified by column chromatography (silica gel, heptane/AcOEt 4:1) to give the title compound (24 mg) as light yellow solid. MS (m/e)=551.2 [M+H+]
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[CH2:17][NH:18][CH3:19].C([O-])(O)=O.[Na+]>Cl.CC(O)C>[Cl:1][C:2]1[N:11]=[C:10]([N:18]([CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][CH3:13])[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNCc1ccccc1OC
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccccc1CN(C)c1nc(Cl)nc2ccccc12
Yield: 39.2 %

Procedure:
A mixture of 2,4-dichloro-quinazoline (88 wt %, 525 mg, 2.3 mmol), (2-methoxy-benzyl)-methyl-amine (300 μL, 2.01 mmol) and 1 drop of concd HCl in i-PrOH (8 mL) was reacted for 5 days then concd in vacuo. Satd NaHCO3 (5 mL) was added then the product extracted into CHCl3 (2×4 mL). The organic portion was washed with water (1×3 mL) then dried (MgSO4), filtered through a plug of silica with an EtOAc wash then purified by MPLC (SiO2/0-20% i-PrOH in CHCl3) yielding the title compound as a white solid (247 mg; 39%). 1H NMR (CDCl3) δ 7.83-7.77 (m, 2H), 7.67 (m, 1H), 7.40-7.32 (m, 2H), 7.26 (m, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 4.96 (s, 2H), 3.81 (s, 3H), 3.31 (s, 3H); LC-MS (ESI+; 314 ([M+H]+)).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[Cl:14][C:15]([Cl:21])([S:19]Cl)[CH:16]([Cl:18])[Cl:17].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1([CH3:13])[N:7]([S:19][C:15]([Cl:21])([Cl:14])[CH:16]([Cl:18])[Cl:17])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Reactant: CC1(C)NC(=O)c2ccccc2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccccc2C(=O)N1SC(Cl)(Cl)C(Cl)Cl
Temperature: 0 °C
Yield: 15.9 %

Procedure:
A 250-ml flask equipped with condenser, stirrer and thermometer and immersed in an ice bath was charged with 150 ml of dichloromethane, 8.3 g (0.047 mol) of 2,2-dimethyl-1,3-benzoxazin-4-one and 10.9 g (0.047 mol) of 1,1,2,2-tetrachloroethylsulfenyl chloride. Then 4.75 g (0.047 mol) of triethylamine dissolved in 10 ml of dichloromethane was added dropwise over a period of 15 minutes. The resulting solution was stirred at 0° C. for 45 more minutes. The crude reaction mixture was washed three times with equal quantities of water. The organic phase was dried and then stripped of solvent. The resulting residue was washed with 200 ml of hexane and filtered. The dried filter cake, 5.1 g, was unreacted 2,2-dimethyl-1,3-benzoxazin-4-one. The filtrate was stripped of hexane and the resulting residue was chromatographed through 300 g of silica gel using 1 liter of hexane, 1 liter of 3% ether-hexane and 3 liters of 5% ether-hexane to give 2.8 g of 2,2-dimethyl-3-(1',1',2',2'-tetrachloroethylthio)-1,3-benzoxazin-4-one. Analysis, calculated for C12H11Cl4NO2S: %C, 37.81; %S, 8.55. Found: %Cl, 40.0; %S, 8.8. NMR spectra confirmed the assigned structure. The infrared spectra had strong adsorption at 1785, 1600, 1460, 1300, 1240 and 740 cm-1. These spectra also had many distinct, medium-strength adsorption bands in the 800-1700 cm-1 region.
Reaction SMILES: C[S:2]([OH:5])(=[O:4])=[O:3].[OH-].[CH3:7][N+:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[N:10][C:9]=1[NH:18][CH:19]([CH3:21])[CH3:20]>O1CCCC1>[S:2]([O-:5])([O-:15])(=[O:4])=[O:3].[CH3:7][N+:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[N:10][C:9]=1[NH:18][CH:19]([CH3:21])[CH3:20].[CH3:7][N+:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[N:10][C:9]=1[NH:18][CH:19]([CH3:21])[CH3:20]
Reactant: CS(=O)(=O)O
Agent: COC(=O)c1cnc(NC(C)C)[n+](C)c1
Agent: [OH-]
Solvent: C1CCOC1
Product: O=S(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.09 mlg [sic] (16.78 mol; 1.61 g) of methanesulfonic acid is added to a solution of 1-methyl-2-isopropylamino-5-methoxycarbonylpyrimidinium hydroxide (3.48 g; 15.35 mol) dissolved in 100 ml of anhydrous tetrahydrofuran. The mixture is stirred under argon at room temperature for one hour. The precipitate which forms is filtered and then rinsed with ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][N:25]([CH3:30])[S:26]([CH3:29])(=[O:28])=[O:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[CH:35][N:34]=1>>[CH3:30][N:25]([CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:36]=[CH:35][N:34]=[C:33]([CH3:32])[CH:38]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCN(C)S(C)(=O)=O)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCN(C)S(C)(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylmethanesulfonamide and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1, m/z=522.1; 1H NMR (CDCl3) 1.23 (m, 1H), 1.48 (d, 3H), 1.68-1.99 (m, 3H), 2.11-2.31 (m, 3H), 2.56 (s, 3H), 2.66 (s, 3H), 2.68 (s, 3H), 2.84-3.08 (m, 3H), 5.68 (m, 1H), 6.92 (d, 1H), 7.15 (d, 1H), 7.25 (m, 4H), 7.31 (m, 4H), 8.43 (d, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=O.[C:19]([C:22]1[CH:23]=[CH:24][C:25]([OH:31])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28])(=[O:21])[CH3:20]>[OH-].[Na+].O.C(O)(=O)C>[OH:31][C:25]1[CH:24]=[CH:23][C:22]([C:19](=[O:21])[CH:20]=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)(=[O:11])=[O:10])=[CH:5][CH:4]=2)=[CH:30][C:26]=1[C:27]([OH:29])=[O:28]
Reactant: O=Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reactant: CC(=O)c1ccc(O)c(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(C=Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1)c1ccc(O)c(C(=O)O)c1

Procedure:
4-Formyl-N-(2-pyridinyl)benzenesulfonamide (5.7 g, 0.022 mol), 5-acetyl-2-hydroxybenzoic acid (6.64 g, 0.044 mol) in 5M sodium hydroxide (20 ml) were stirred for 3 days at room temperature. The solution was diluted with water (100 ml) and acetic acid added dropwise in excess. The precipitate was collected by filtration and washed with water. After drying, the material was recrystallized from acetic acid and dried at 120° C. in vacuo. Yield 6.4 g, 66%.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15]C)[C:9]=3[C:8]([NH:17][C:18]3[CH:19]=[C:20]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([NH:17][C:18]3[CH:19]=[C:20]([S:24]([NH2:27])(=[O:25])=[O:26])[CH:21]=[CH:22][CH:23]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1nccc2c1c(Nc1cccc(S(N)(=O)=O)c1)nn2C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1cccc(Nc2nn(C3CCCC3)c3cc[nH]c(=O)c23)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of 3-((1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)amino)benzenesulfonamide (14.4 mg) in acetonitrile (5 mL) were added sodium iodide (11.1 mg) and chloro(trimethyl)silane (0.038 mL), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was washed with ethyl acetate/diisopropyl ether to give the title compound (10.4 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:26]2[CH:30]=[N:29][N:28]=[N:27]2)=[C:7]([CH:25]=1)[CH2:8][NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11]>CCOC(C)=O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:26]2[CH:30]=[N:29][N:28]=[N:27]2)=[C:7]([CH:25]=1)[CH2:8][NH:9][C:10](=[O:11])[C@@H:12]1[CH2:17][CH2:16][CH2:15][NH:13]1.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:26]2[CH:30]=[N:29][N:28]=[N:27]2)=[C:7]([CH:25]=1)[CH2:8][NH:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCCN1
Product: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
HCl gas was bubbled through a cold (0° C.) solution of tert-butyl (2S)-2-({[5-chloro-2-(1H-tetraazol-1-yl)benzyl]amino}carbonyl)piperidine-1-carboxylate (506 mg, 1.20 mmol) in EtOAc (24 mL) for 5 min. The mixture was stirred at 0° C. for 15 min and the solvent was removed in vacuo. Repeated concentration from Et2O afforded the hydrochloride salt of the title compound as a light yellow foam. 1H NMR (400 MHz, CD3OD): δ 9.58 (s, 1 H), 8.71 (br m, 1 H), 7.67 (d, J=2.4 Hz, 1 H), 7.60–7.51 (m, 2 H), 4.34–4.24 (m, 2 H), 3.78 (br m, 1 H), 3.39–3.36 (m, 1 H), 3.03–2.97 (m, 1 H), 2.16–2.13 (m, 1 H), 2.00–1.85 (m, 2 H), 1.70–1.60 (m, 3 H).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH:7]([C:9]1[S:13][C:12]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[CH3:23])=[CH:11][CH:10]=1)=O.[CH2:24]([NH2:27])[CH:25]=[CH2:26].C(O)(=O)C>C1COCC1>[CH2:24](/[N:27]=[CH:7]/[C:9]1[S:13][C:12]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2[CH3:23])=[CH:11][CH:10]=1)[CH:25]=[CH2:26]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C=O)s2)s1
Reactant: C=CCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CC/N=C/c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anhydrous magnesium sulfate (94 mg; 0.78 mmol; 4.15 eq.) and N-[5-(5-formyl-2-thienyl)-4-methyl-1,3-thiazol-2-yl]acetamide, Compound (1), (50 mg; 0.19 mmol; 1 eq.), are added to a solution of allylamine (17 μl ; 0.23 mmol; 1.20 eq.) and acetic acid (16 μl; 0.28 mmol; 1.50 eq.) in dry THF (5 ml). The reaction is stirred at rt overnight. The mixture is filtered and rinsed with anhydrous THF and DCM, affording N-(5-{5-[(E)-(allylimino)methyl]-2-thienyl}-4-methyl-1,3-thiazol-2-yl)acetamide which is used in the next step without further purification (57.3 mg, quantitative).
Reaction SMILES: [N:1]([O-])=O.[Na+].[F:5][C:6]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:7]=1[NH2:8].Cl.[CH3:15][O:16][CH2:17][C:18](=[O:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21].CC([O-])=O.[Na+]>O.CO>[F:5][C:6]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:7]=1[NH:8][N:1]=[C:19]([C:18](=[O:24])[CH2:17][O:16][CH3:15])[C:20]([O:22][CH3:23])=[O:21]
Reactant: Nc1ccc(I)cc1F
Reactant: COCC(=O)CC(=O)OC
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCC(=O)C(=NNc1ccc(I)cc1F)C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
A solution of NaNO2 (1.66 g, 24 mmol) in H2O (5 mL) was added dropwise at 0° C. to a mixture of 2-fluoro-4-iodoaniline (4.74 g, 20 mmol) and 6 M HCl aqueous solution (20 mL, 120 mmol). After stirring for 15 min, the resulting aqueous solution was added to a suspension of methyl 4-methoxyacetoacetate (2.59 mL, 20 mmol) and NaOAc (9.84 g, 120 mmol) in MeOH (40 mL) pre-cooled at 0° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (6.29 g, 80% yield) as yellow crystals: mp 141-146° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.50 (3H, s), 3.93 (3H, s), 4.64 (2H, s), 7.35 (1H, t, J=8.5 Hz), 7.49-7.55 (2H, m), 12.97 (1H, br s). Anal. Calcd for C12H12FIN2O4: C, 36.57; H, 3.07; N, 7.11. Found: C, 36.74; H, 3.10; N, 7.32.