Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=4)[N:22]=3)=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>O>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([C:23]2[N:22]=[C:21]([C:19]([N:16]3[CH2:15][CH2:14][N:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:12][CH:11]=4)[CH2:18][CH2:17]3)=[O:20])[CH:26]=[CH:25][CH:24]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH3:34]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(N)cc4)CC3)n2)cc1OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(NS(C)(=O)=O)cc4)CC3)n2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a THF (2.5 ml) solution of 211 mg of 1-(4-aminophenyl)-4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazine were added 63.5 mg of methanesulfonyl chloride and 76.8 μl of triethylamine, followed by overnight stirring at room temperature. Further, 79 mg of methanesulfonyl chloride and 103 μl of triethylamine were added in twice thereto, and the whole was stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and then crystallization was carried out from ethyl acetate-diisopropyl ether to obtain 175 mg of 4′-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}methanesulfonanilide as pale purple crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12](=[O:19])[CH:13]=[C:14]([NH2:18])[O:15][CH2:16][CH3:17]>C(O)(C)C>[CH3:10][O:11][C:12]([C:13]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[CH:13]([C:12]([O:11][CH3:10])=[O:19])[C:14]([O:15][CH2:16][CH3:17])=[N:18][C:14]=1[NH2:18])=[O:19]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(N)=CC(=O)OC
Solvent: CC(C)O
Product: CCOC1=NC(N)=C(C(=O)OC)C(c2ccccc2F)C1C(=O)OC
Yield: 59 %

Procedure:
Heating a solution of 6.3 g of 2-fluorobenzaldehyde and 14.5 g of 3-amino-3-ethoxyacrylic acid methyl ester in 50 ml of isopropanol for 8 hours yields 2-amino-4-(2-fluorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid dimethyl ester of melting point 180° C (isopropanol). Yield: 59% of theory.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl.C[N:28](C)CCCN=C=NCC>ClCCl>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]1[CH2:25][CH2:24][N:23]([NH:28][C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:22][CH2:21]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccc(C2CCNCC2)nc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NN1CCC(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.1 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-alanine (1.485 g, 7.847 mmol) and 4-(2-pyridyl)piperidine (0.910 g, 5.60 mmol) in dichloromethane (20 mL) at 0° C., was added N,N-dimethylaminopyridine (DMAP, 2.05 g, 16.8 mmol) and 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (DMAPECD, 2.147 g, 11.2 mmol). The resulting mixture was stirred overnight while warmed up to room temperature. The reaction mixture was quenched with aqueous NH4Cl (30 mL) and extracted with CH2Cl2 (30 mL×2). The combined extracts were dried (K2CO3). concentrated, and purified by flash chromatography on silica gel (100% EtOAc) to obtain 2.09 g (80%) of N-(tert-Butoxycarbonyl)-L-alanine 4-(2-pyridyl)piperidin-1-yl amide.
Reaction SMILES: [CH3:1][C:2]1[S:16][C:5]2=[N:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([OH:10])=[C:4]2[CH:3]=1.[H-].[Na+].[CH2:19](I)[CH3:20]>CN(C)C=O>[CH2:19]([N:6]1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9](=[O:10])[C:4]2[CH:3]=[C:2]([CH3:1])[S:16][C:5]1=2)[CH3:20]
Reactant: CCOC(=O)c1cnc2sc(C)cc2c1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2sc(C)cc2c1=O
Temperature: 70 °C

Procedure:
A mixture of 0.237 part of ethyl 2-methyl-4-hydroxythieno-[2,3-b]pyridine-5-carboxylate, 5 parts by volume of dry dimethyl-formamide and 0.048 part of 50 % sodium hydride in mineral oil is heated at 70°C for 30 minutes, and 0.12 part by volume of ethyl iodide is added thereto. The mixture is heated at 70°C for 2 hours and the solvent is evaporated under reduced pressure. The residue is extracted with chloroform, and the extract is washed with saturated aqueous sodium chloride and dried over sodium sulfate. Evaporation of the solvent gives ethyl 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylate as crystals. Recrystallization from ethyl acetate yields colorless plates melting at 140°-142°C. This product is identical with the product in Example 24.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)cc1Cl
Yield: 58.3 %

Procedure:
To 70 g of diethyl 2-chloro-4,5-difluorobenzoyl-malonate, 90 cc of water was added for emulsification. Then, 0.2 g of p-toluenesulfonic acid was added thereto, and the mixture was refluxed for three hours under vigorous stirring. After cooling, the reaction mixture was extracted three times with 150 cc of methylene chloride, and the extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated and then recrystallized from methylene chloride/n-hexane to obtain 32 g of the desired compound. The physical properties of obtained ethyl 2-chloro-4,5-difluorobenzoylacetate were as follows. From the results of the NMR analysis in chloroform d1, this compound was found to be a mixture of a keto form and an enol-form. ##STR26##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[N:9]([CH2:13][C:14]#[CH:15])[C:8]=2[CH:16]=1)([O-])=O.O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[N:9]([CH2:13][C:14]#[CH:15])[C:8]=2[CH:16]=1
Reactant: C#CCn1c(=O)oc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: C#CCn1c(=O)oc2ccc(N)cc21
Temperature: 80 °C
Yield: 54.5 %

Procedure:
Electrolytic iron (11.39 g) was suspended in 5% aqueous acetic acid solution (22 ml) and heated to 80° C. To the suspension, a solution of 5-nitro-3-(2-propynyl)-3H-benzoxazol-2-one (4.15 g) in acetic acid (20 ml) and ethyl acetate (20 ml) was dropwise added, and the resultant mixture was stirred at 70° C. for 3 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ethyl acetate. The extract was washed with water and sodium bicarbonate solution, dried and concentrated to give 5-amino-3-(2-propynyl)-3H-benzoxazol-2-one (1.95 g). m.p., 102.1° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:24]#[N:25])[CH2:23][CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[S:9][C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3([C:24]#[N:25])[CH2:23][CH2:22][CH2:21]3)[CH:15]=2)=[C:11]([CH3:13])[N:12]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1ccnc(C2(C#N)CCC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)sc1-c1ccnc(C2(C#N)CCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.7 %

Procedure:
A mixture of {5-[2-(1-cyano-cyclobutyl)-pyridin-4-yl]-4-methyl-thiazol-2-yl}-carbamic acid tert-butyl ester (Step 50.2) (300 mg), DCM (5 mL) and TFA (1 mL) is stirred for 4 h at rt, quenched by addition of a saturated solution of NaHCO3, and extracted with DCM. The organic phase is washed with a saturated solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH, 1:0→96:4) to afford 181 mg of the title compound as a yellow solid: ESI-MS: 271.1 [M+H]+; tR=2.48 min (System 1); TLC: Rf=0.45 (DCM/MeOH, 9:1).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12]CC)=O.Cl[CH2:20][C:21]([NH2:23])=[O:22]>C(O)C>[O:12]=[C:10]1[CH:9]([C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH2:20][C:21](=[O:22])[NH:23]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: NC(=O)CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CC(=O)NC1=O
Reaction time: 20 h
Yield: 65.4 %

Procedure:
To a solution of 20% sodium ethoxide•ethanol solution (34.0 g) diluted with ethanol (40 ml) was added a solution of diethyl malonate (16.0 g) in ethanol (40 ml) dropwise over 30 minutes in ice-cooling. After stirring in ice-cooling for additional 30 minutes, thereto was added 2-chloroacetamide (4.7 g) in one portion and the mixture was stirred in ice-cooling for 30 minutes and then at room temperature for 20 hours. The white solid precipitated was collected by filtering and washed with a small amount of ethanol. This white solid was dissolved in water (300 ml) and this resulting aqueous solution was acidified with conc. hydrochloric acid and extracted with dichloromethane (50 ml) three times. The extract was dried over magnesium sulfate, filtered and concentrated to give a yellow oil. This was purified by a flash column chromatography (n-hexane:ethyl acetate=2:1→1:1) to give ethyl 2,5-dioxopyrrolidine-3-carboxylate (5.63 g, 66%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)(Cl)Cl.O>[Cl:22][CH2:23][C:24]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:25]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CCl)Nc1ccccc1Nc1ccccc1
Reaction time: 0.5 h
Yield: 106 %

Procedure:
In 100 ml of chloroform, 10.4 g of N-phenyl-1,2-benzenediamine and 12.1 g of triethylamine were dissolved, and the mixture was cooled to -5° C. to 0° C., and then 13.6 g of chloroacetyl chloride was added dropwise thereto, holding the temperature of the mixture at not higher than 20° C. The reaction nearly went to completion when the addition was finished. After stirring for further 30 minutes, the reaction mixture was diluted with 50 ml of water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and then the solvent is evaporated under reduced pressure. The resulting solid was recrystallized from ethanol to give 15.6 g of crystals having a melting point of 112° C. to 113° C. Yield: 60.0%.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[O:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:7]=1[OH:8].[C:24]([O:33][CH3:34])(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[SH:27].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:4][C:3](=[O:23])[C:2]=1[S:27][C:26]1[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=1[C:24]([O:33][CH3:34])=[O:32]
Reactant: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: COC(=O)c1ccccc1S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COC(=O)c1ccccc1SC1=C(O)CC(CCc2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.9 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in example BBB), 2.2 mmol of methyl thiosalicylate and 2.1 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 91°-92° C.). 1H NMR (DMSO-d6) δ2.25 (m, 2H), 2.38 (m, 1H), 2.62 (m, 1H), 3.44 (q, 2H), 3.82 (s, 3H), 6.06 (bd, 1H), 6.90 (t, 1H), 7.05-7.52 (m, 11H), 7.81 (dd, 1H).
Reaction SMILES: N=C=N.[CH3:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](/[C:14](=[CH:18]\[C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)/[C:15]([OH:17])=O)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C1C=CC2N(O)N=NC=2C=1.[S:34]1[CH:38]=[CH:37][N:36]=[C:35]1[NH2:39]>CN(C=O)C>[CH3:4][S:5]([C:8]1[CH:9]=[CH:10][C:11](/[C:14](=[CH:18]\[C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)/[C:15]([NH:39][C:35]2[S:34][CH:38]=[CH:37][N:36]=2)=[O:17])=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: CS(=O)(=O)c1ccc(/C(=C\c2ccsc2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(/C(=C\c2ccsc2)C(=O)Nc2nccs2)cc1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A suspension of PS-carbodiimide (688 mg, loading 1.34 μmol mg−1, 922 μmol), (E)-2-(4-methanesulfonylphenyl)-3-thiophen-3-ylacrylic acid (Preparation 1, 139 mg, 450 μmol), and HOBt (84 mg, 622 μmol) in anhydrous DMF was stirred for 15 min at 20° C. Thiazol-2-ylamine (32 mg, 320 μmol) was added, then the mixture was stirred for 40 h at 20° C., before being filtered through Celite. The filter cake was washed with DMF (10 mL), EtOAc (20 mL), and CH2Cl2 (20 mL). The solutions were combined, the solvents removed under reduced pressure, and the residue dissolved in EtOAc (50 mL). The EtOAc solution was washed with saturated aqueous Na2CO3 (3×20 mL), H2O (20 mL), and brine (20 mL), before being dried (Na2SO4). Filtration, solvent evaporation, and flash chromatography (IH-EtOAc, 3:1 to 1:3) gave the title compound: RTA=3.43 min; m/z (ES+)=391.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[Br-:20].[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[C:5]([N+:13]2[CH:17]=[CH:16][N:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: FC(F)(F)c1cc(-n2ccnc2)cc(C(F)(F)F)c1
Reactant: CCCCCCCBr
Solvent: C1CCOC1
Product: CCCCCCCn1cc[n+](-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 3.60 mmol (1.00 g) 1-(3,5-bis-trifluoromethylphenyl)imidazole and 4.30 mmol (0.770 g, 0.67 ml) 1-bromoheptane are dissolved in 5 ml THF and heated for 18 h to 90° C.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:21]I>C(Cl)Cl>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
Aqueous KOH (0.3 M, 6 mL) was added to a solution of 14 (0.21 g, 1 mmol) in CH2Cl2 (50 mL). After stirring for 10 min, the precipitate was filtered, washed with cold H2O (10 mL), and dried. The resulting solid was suspended in CH2Cl2 (50 mL) and MeI (150 μL, 2 mmol) was added (see FIG. 25). The mixture was heated for 40 h under reflux and Ar. After cooling to ambient temperature, the mixture was washed with water (20 mL). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography [SiO2: hexanes/CH2Cl2 (1:1)] resulting in 11 (0.10 g, 52%) as an orange solid. mp=151° C.; FABMS: m/z=258 [M+H]+; 1H-NMR (400 MHz, chloroform-d): δ=3.88 (3H, s), 6.99-7.01 (2H, m), 7.93-7.95 (4H, m), 8.30-8.33 (2H, m); 13C-NMR (100 MHz, CDCl3): δ=55.9, 114.7, 123.3, 124.9, 125.8, 147.2, 148.5, 156.2, 163.5.
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C(OC(OCC)OCC)C>C1COCC1.C(Cl)Cl>[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([N:17]2[C:4](=[O:12])[C:5]3[C:6](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:7]=[C:2]2[CH3:1])[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1c(N)cccc1Br
Reactant: Cc1nc2ccccc2c(=O)o1
Solvent: CCOC(OCC)OCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(Br)cccc1-n1c(C)nc2ccccc2c1=O
Temperature: 25 °C
Yield: 19.6 %

Procedure:
A solution of 2-methyl-4H-benzo[d][1,3]oxazin-4-one (300 mg, 1.862 mmol), 3-bromo-2-methylaniline (346 mg, 1.862 mmol), and triethoxymethane (276 mg, 1.862 mmol) in THF (2 mL) was heated overnight in a sealed tube at 100° C. The mixture was cooled to rt and diluted with DCM. The solution was washed with water and NaHCO3 (aq), and dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 to 50:50 hexane-EtOAc) and the crude product was triturated in hexane to give 3-(3-bromo-2-methylphenyl)-2-methylquinazolin-4(3H)-one as an off-white solid (120 mg, 20%). 1H NMR (400 MHz, chloroform-d) δ 8.28 (1H, dd, J=7.92, 1.10 Hz), 7.77-7.82 (1H, m), 7.68-7.73 (2H, m), 7.47-7.52 (1H, m), 7.22-7.25 (1H, m), 7.13-7.17 (1H, m), 2.20 (6H, s). Mass spectrum m/z 329, 331 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1.[CH:25](I)([CH3:27])[CH3:26].O>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([N:9]([CH:25]([CH3:27])[CH3:26])[S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1
Reactant: CC(C)I
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N(C(C)C)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in DMF (2.0 ml), 4′-methoxy-2′-nitro-p-toluenesulfonanilide (0.65 g (2.02 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, isopropyl iodide (1.00 g (5.88 mmol)) was added dropwise. After five hours' heating at 130° C. with stirring, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:2) as eluent, giving 0.21 g (28.5%) of the title compound as pale brown crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: OCCCBr
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCCCO)c1

Procedure:
Alkylation reaction of phenol 58 with 3-bromo-1-propanol gave 2-(3-(3-(3-hydroxypropoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.300 g, 25%): 1H NMR (400 MHz, CDCl3) δ 7.80-7.83 (m, 2H), 7.69-7.71 (m, 2H), 7.12-7.16 (m, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 6.65 (dd, J=8.0, 2.4 Hz, 1H), 4.10 (d, J=6.0 Hz, 2H), 3.84-3.89 (m, 2H), 3.73 (t, J=7.2 Hz, 2H), 2.65 (t, J=8.0 Hz, 2H), 1.98-2.05 (m, 41-1).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.CCN(C(C)C)C(C)C.[C:36]([O:40][C:41]([C:43]1[CH:44]=[CH:45][C:46]([CH3:68])=[C:47]([C:49]2[CH:50]=[C:51]3[C:57]([C:58](O)=[O:59])=[C:56]([C:61]4[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=4)[O:55][C:52]3=[N:53][CH:54]=2)[CH:48]=1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C.CCOC(C)=O>[F:67][C:64]1[CH:65]=[CH:66][C:61]([C:56]2[O:55][C:52]3=[N:53][CH:54]=[C:49]([C:47]4[CH:48]=[C:43]([CH:44]=[CH:45][C:46]=4[CH3:68])[C:41]([O:40][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:42])[CH:50]=[C:51]3[C:57]=2[C:58](=[O:59])[NH:2][CH3:1])=[CH:62][CH:63]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1-c1cnc2oc(-c3ccc(F)cc3)c(C(=O)O)c2c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ncc(-c3cc(C(=O)OC(C)(C)C)ccc3C)cc12
Reaction time: 1 h
Yield: 90.2 %

Procedure:
HATU (209 mg, 0.550 mmol) was added to a stirring solution of methanamine (1.2 mL, 2.4 mmol, 2M in THF), DIEA (240 μL, 1.37 mmol) and 5-(5-(tert-butoxycarbonyl)-2-methylphenyl)-2-(4-fluorophenyl)furo[2,3-b]pyridine-3-carboxylic acid (205 mg, 0.458 mmol) in DMF (4.5 mL) at rt. It was allowed to stir for 1 hour. The mixture was diluted with EtOAc and washed with sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (190 mg, 0.413 mmol, 90% yield) consistent by LCMS and NMR. 1H NMR (400 MHz, MeOD) δ ppm 8.28 (1H, d, J=2.26 Hz), 8.08 (1H, d, J=2.01 Hz), 7.99-8.06 (2H, m), 7.92 (1H, dd, J=8.03, 1.76 Hz), 7.86 (1H, d, J=1.51 Hz), 7.45 (1H, d, J=8.03 Hz), 7.30 (2H, t, J=8.78 Hz), 2.95 (3H, s), 2.34 (3H, s), 1.60 (9H, s). LC-MS retention time: 2.70 min; m/z (MH+): 461. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[C:28]1=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:32]([N:29]3[CH2:30][CH2:31][N:27]([CH2:26][CH2:25][O:24][CH3:23])[C:28]3=[O:35])=[O:33])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(N)ccc1Oc1ccnc(Cl)c1
Reactant: COCCN1CCN(C(=O)Cl)C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCN1CCN(C(=O)Nc2ccc(Oc3ccnc(Cl)c3)c(C)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A 0° C. mixture of Example A7 (0.350 g, 1.485 mmol) and pyridine (0.251 mL, 3.12 mmol) in DCM (10 mL) was treated with a solution of Example B4 (0.368 g, 1.782 mmol) in DCM (5 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with DCM (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM) to afford N-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide (487 mg, 81%) as a yellow oil. MS (ESI) m/z: 406.1 (M+H+).