Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][NH:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])[CH:2]([CH3:4])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>CCO.O.COCCOC>[OH:13][CH2:12][CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:15][NH:16][C:17](=[O:18])[O:19][CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)COC(=O)NCC(CCC(=O)O)NC(=O)OCC(C)C
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: COCCOC
Product: CC(C)COC(=O)NC[C@H](CCCO)NC(=O)OCC(C)C
Temperature: -25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A round bottom flask was charged with crude S)-4,5-bis((isobutoxycarbonyl)amino)pentanoic acid (14.22 g, 42.84 mmol) and 1,2-dimethoxyethane (70 mL). N-methyl morpholine (5.24 mL, 47.1 mmol) was added with stirring and the resulting solution was cooled to −25° C. Then isobutyl chloroformate (6.8 mL, 51.4 mmol) was added slowly and a white precipitate formed. The cold bath was removed, and the mixture was allowed to warm to room temperature. The precipitate was collected by filtration and washed with 1,2-dimethoxyethane (2×30 mL). The combined filtrate and washings were deoxygenated with a stream of nitrogen, and a solution of NaBH4 (2.43 g, 64.3 mmol) in EtOH (150 mL) was added dropwise at 0° C. After 2 h, water (10 mL) was cautiously added. The mixture was stirred overnight and the 0° C. bath was allowed to warm to room temperature. The solvent was removed by rotary evaporation. The resulting solid was dissolved in EtOAc (300 mL) and water (200 mL) was added. The aqueous phase was extracted with EtOAc (2×100 mL) and the combined organic phases were dried on anhydrous Na2SO4. The solvent was removed by rotary evaporation and the crude product was purified on a silica gel column (1:1 v/v EtOAc/Hexane). The solvent was removed and dried in vacuum to give (S)-diisobutyl (5-hydroxypentane-1,2-diyl)dicarbamate as a white solid (11.13 g, 35 mmol, 82%).
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[F:7][C:8]1[C:9]([CH:18]=[O:19])=[CH:10][C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1>O>[F:7][C:8]1[C:9]([C:18]([OH:1])=[O:19])=[CH:10][C:11]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:17]=1
Reactant: O=Cc1cc2c(cc1F)OCCO2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc2c(cc1F)OCCO2
Temperature: 100 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
To a solution of KMnO4 (0.35 g, 2.2 mmol) in H2O (11 mL) at 80° C. was added 7-fluoro-2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.20 g, 1.1 mmol). The resulting suspension was stirred at 100° C. for 24 h. The reaction mixture was filtered and the solids were washed with H2O (30 mL). The filtrate was acidified with concentrated HCl, which led to the formation of a white precipitate, which was collected, washed with H2O and dried in vacuo to provide 0.12 g (57%) of the title compound as a white solid. MS (ESI): exact mass calculated for C9H7FO4, 198.03; m/z not found. 1H NMR (400 MHz, DMSO-d6): 12.95 (s, 1H), 7.29 (d, J=7.2, 1H), 6.87 (d, J=11.6, 1H), 4.34-4.31 (m, 2H), 4.27-4.24 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[N:7][N:6]=1)[CH3:4].[I:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:3]([C:5]1[S:9][C:8](=[N:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[N:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([I:17])=[CH:19][CH:20]=2)[N:6]=1)[CH3:4]
Reactant: BrCc1ccc(I)cc1
Reactant: CCc1nnc(NC(=O)C(F)(F)F)s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2ccc(I)cc2)c(=NC(=O)C(F)(F)F)s1
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a suspension of sodium hydride (0.44 g) in N,N-dimethylformamide (10 ml) was added 5-ethyl-2-trifluoroacetylamino-1,3,4-thiadiazole (2.25 g) in three portions on ice. After the resulting mixture was stirred at the same temperature for 30 minutes, to the mixture was added 4-iodobenzyl bromide (2.97 g), and the mixture was stirred at room temperature for two hours. To the reaction mixture, ethyl acetate (50 ml) was added. The resulting mixture was washed successively with 10% aqueous citric acid solution and water and dried over anhydrous magnesium sulfate, followed by the removal through distillation. The residue so obtained was crystallized from n-hexane, collected by filtration and then dried, whereby 2.2 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH2:13](I)[CH:14]=[CH2:15]>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:15][CH:14]=[CH2:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCn1ccc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.3 g: 8.5 mmol) in dry THF (30 ml) was added sodium hydride (1.0 g, 0.25 mmol, 60% dispersion in mineral oil). After stirring at ambient temperature for 1 hour, allyl iodide (0.93 ml, 10 mmol) was added and stirring continued for 48 hours. The mixture was concentrated in vacuo, triturated in hot ethyl acetate, and filtered. The filtrate was concentrated in vacuo to give an orange solid residue. The solid was triturated in CH2Cl2 and filtered to afford 4-chloro-7-allyl-pyrrolo[2,3-d]pyrimidine as a light yellow powder (0.58 g, 36%): TS-MS: 194 (MH+).
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19][CH3:20])=[O:18])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH2:4][CH2:3]1.CCO>[Pd].C1COCC1>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][C:2]([CH3:1])([C:17]([O:19][CH3:20])=[O:18])[CH2:3][CH2:4]2)=[N:9][CH:10]=1
Reactant: COC(=O)C1(C)CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(c2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of methyl 4-methyl-1-(5-nitropyridin-2-yl)piperidine-4-carboxylate (3.32 g, 11.89 mmol) in abs EtOH (200 mL) and THF (200 mL) was added 10% Pd/C (400 mg) and then the reaction mixture was evacuated with hydrogen (5 cycles) and allowed to stir at ambient temperature overnight. The reaction mixture was filtered and then concentrated and the black residue purified on a 120 g silica Crawford silicyle cartridge loading in 40% EtOAc/isohexane with some DCM and eluting a gradient of 40-80% EtOAc using an Isco companion to provide the title compound (2.96 g, 11.89 mmol, 100%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([NH:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])=O.[O-]CC.[K+].S([O-])(O)(=O)=O.[Na+]>C(O)C.O>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]1[NH:12][C:10](=[O:11])[C:9]2[CH:13]=[CH:14][CH:15]=[N:16][C:8]=2[N:7]=1
Reactant: NC(=O)c1cccnc1NC(=O)c1ccccc1C(F)(F)F
Agent: CC[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)nc2ncccc12

Procedure:
2-(2-Trifluoromethyl-benzoylamino)-nicotinamide (800 mg, 2.6 mmol) is dissolved in 10 ml of ethanol. Potassium ethoxide (435 mg, 5.2 mmol) is added to the solution which is heated to reflux for 16 h. The reaction mixture is evaporated in vacuo to afford a gummy residue that is dissolved in water and acidified with 10% sodium hydrogen sulfate to pH 7. The resulting precipitate is filtered and dried under vacuum at 50 C to give 2-(2-trifluoromethyl-phenyl)-3H-pyrido[2,3-d]pyrimidin-4-one.
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C@H:18]1[CH2:27][CH2:26][C:25]2[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=2[CH2:19]1)=O)C.C(O[C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54](O)=O)=[CH:50][CH:49]=2)[CH2:44][CH2:43]1)=O)(C)(C)C>>[OH:3][CH2:4][CH2:6][N:7]([CH2:54][C:51]1[CH:50]=[CH:49][C:48]([CH:45]2[CH2:44][CH2:43][N:42]([CH3:40])[CH2:47][CH2:46]2)=[CH:53][CH:52]=1)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C@H:18]1[CH2:27][CH2:26][C:25]2[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=2[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CNc1cc(OC)c(OC)cc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1cc([C@H]2CCc3cc(O)ccc3C2)c(N(CCO)Cc2ccc(C3CCN(C)CC3)cc2)cc1OC
Yield: 36.4 %

Procedure:
Synthesized from pivalic acid (S)-6-[2-(ethoxycarbonylmethylamino)-4,5-dimethoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (90 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (88 mg) according to an analogous synthetic method to the above-mentioned Preparation Example 86 and Example 337, the title compound (37 mg) was obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]([C:26]([OH:28])=O)[N:20]=[N:19]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C[C:32]2N(O)N=[N:35][C:33]=2[CH:34]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:33]1([NH:35][C:26]([C:21]2[N:20]=[N:19][N:18]([C:15]3[CH:14]=[CH:13][C:12]([C:10]([NH:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:11])=[CH:17][CH:16]=3)[C:22]=2[CH2:23][CH2:24][CH3:25])=[O:28])[CH2:34][CH2:32]1
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCN2CCCCC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 61 h
Yield: 126.6 %

Procedure:
1-(4-{[(2-Piperidin-1-ylethyl)amino]carbonyl}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (650 mg, 1.52 mmol) obtained in Example 62b), HOBt (104 mg, 0.759 mmol, 0.5 eq.) and cyclopropylamine (0.152 ml, 2.12 mmol, 1.4 eq.) were dissolved in acetonitrile-DMF (1:1, 10 ml), WSC (386 mg, 1.97 mmol, 1.3 eq.) was added, and the mixture was stirred at room temperature for 61 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed sequentially with 2% aqueous sodium carbonate solution-saturated brine (1:1, 40 ml×2, 1:4, 40 ml×1). The aqueous layers were each extracted with ethyl acetate (30 ml). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated, the residue was dissolved in toluene, and the solution was subjected to column chromatography on NH silica gel (Fuji Silysia Chemical Ltd., 100-200 mesh, DM1020, 6 g). The flow-through solution and the fraction obtained by elution with ethyl acetate-hexane (1:1-2:1) were concentrated, and ethyl acetate and diethyl ether were added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (408 mg, 0.961 mmol, 63.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH:14]2[CH2:16][O:15]2)[CH2:8][CH2:7]1.[NH3:21]>CO>[NH2:21][CH2:16][CH:14]([OH:15])[CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:4]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:2]([Cl:1])[CH:3]=2)[CH2:7][CH2:8]1
Reactant: Clc1ccc(OC2CCN(CCC3CO3)CC2)cc1Cl
Reactant: N
Solvent: CO
Product: NCC(O)CCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1

Procedure:
In a sealed metal tube, a solution of 4-(3,4-dichlorophenoxy)-1-(2-oxiran-2-ylethyl)piperidine (1.00 g) in 7N ammonia in methanol (25 ml) was heated at 70° C. for 12 h. The solvent was removed under vacuum and the residue purified on silicagel (0 to 10% 7N ammonia in methanol/dichloromethane) to afford the title compound as a yellow oil (0.55 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:3]=1.[O:19]1[CH2:23][CH:20]1[CH2:21][OH:22].[OH-].[Na+]>ClCCl>[Cl:8][C:6]1[N:7]=[C:2]([O:22][CH2:21][CH:20]2[O:19][CH2:23]2)[N:3]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=1
Reactant: OCC1CO1
Reactant: Cc1cc(C)c(Oc2nc(Cl)nc(Cl)n2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(C)c(Oc2nc(Cl)nc(OCC3CO3)n2)c(C)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a mechanically stirred solution of 50 g (0.155 mol) 2,4-dichloro-6-(2,4,6-trimethylphenoxy)-1,3,5-triazine in 170 ml dichloromethane, cooled to 0°.varies.10° C., was added 26.38 g (0.356 mol) 2,3-epoxy-1-propanol in one portion. Aqueous sodium hydroxide (50% solution; 14.26 g) was added to the mixture dropwise with stirring over about 25 minutes maintaining the reaction temperature between 0° and 10° C. and preferably around 0°-5° C. After stirring an additional 30 minutes, the reaction mixture was allowed to warm slowly to room temperature. The dichloromethane layer was washed with distilled water until neutral and dried over magnesium sulfate. The reaction product was found by proton nuclear magnetic resonance to be 2-chloro-4-glycidoxy-6-(2,4,6-trimethylphenoxy)-1,3,5-triazine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[C:13](=[O:27])[NH:14][C:15](=[O:26])[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=2)=[CH:3]1>[Pd].CC(O)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[C:13](=[O:27])[NH:14][C:15](=[O:26])[C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc([N+](=O)[O-])c3)C(=O)NC2=O)c2cc(Cl)ccc21
Agent: [Pd]
Solvent: CC(=O)O
Product: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2cc(Cl)ccc21
Temperature: 0 °C
Yield: 62.1 %

Procedure:
A mixture of 3-(1-methyl-5-chloroindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (865 mg), 10% palladium on carbon (90 mg), and glacial HOAc (35 mL) was stirred and hydrogenated at atmospheric pressure using a balloon (2 h). The reaction mixture was filtered through a pad of celite, cooled to 0° C. and KOH pellets were added until pH 8. The solution was extracted with ETOAc, dried (magnesium sulfate), and stripped. The crude was flash chromatographed with 10% through 20% ETOAc-Hexane to provide 3-(1-methyl-5-chloroindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (495 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:18]=[C:11]2[N:12]=[C:13]([CH3:17])[CH:14]=[C:15](O)[N:10]2[N:9]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:28].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:28][C:15]1[N:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:18]=[C:11]2[N:12]=[C:13]([CH3:17])[CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(-c3ccccc3Cl)cc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)n2nc(-c3ccccc3Cl)cc2n1
Temperature: 95 °C
Yield: 85.6 %

Procedure:
To a slurry of 2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol (I-1A-3f; 700 mg, 2.70 mmol) and triethylamine (0.57 ml, 4.0 mmol) in toluene (30 ml) at room temperature was added POCl3 (1.3 ml, 14 mmol), dropwise. The mixture was heated at 95° C. for 21 hours, cooled to room temperature, then slowly added to a stirred mixture of ice, saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo, to afford the crude product (0.79 g). Purification on a Biotage™ Flash 40S column using 0–20% ethyl acetate in hexanes as eluant afforded I-1A-3g as an off-white solid (643 mg, 86%): +ESI MS (M+1) 278.12; 1H NMR (400 MHz, CD2Cl2) δ 7.96–7.93 (m, 1H), 7.54–7.51 (m, 1H), 7.50–7.35 (m, 2H), 7.15 (s, 1H), 6.90 (s, 1H), 2.59 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=2)[CH2:9]1)=O)(C)(C)C>CO.Cl.O1CCOCC1>[Br:21][C:19]1[CH:18]=[N:17][CH:16]=[C:15]([O:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Br)c2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Brc1cncc(O[C@@H]2CCCNC2)c1
Yield: 120.1 %

Procedure:
A solution of (R)-3-(5-bromo-pyridin-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (596 mg, 1.7 mmol) in MeOH (5 mL) and HCl solution in 1,4-dioxane (4N; 1.5 mL) is stirred at room temperature for 16 h. The mixture is concentrated to provide 525 mg 3-bromo-5-((R)-piperidin-3-yloxy)-pyridine as the hydrochloride salt.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:9].[CH:10]1([CH2:13][O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26]C2C(Cl)=CN=CC=2Cl)[CH2:12][CH2:11]1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:10]1([CH2:13][O:14][C:15]2[C:16]([O:35][CH3:36])=[CH:17][CH:18]=[C:19]3[C:24]=2[NH:23][C:22](=[O:25])[CH:21]=[C:20]3[NH:26][C:2]2[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][C:3]=2[CH3:9])[CH2:11][CH2:12]1
Reactant: Cc1cncc(C)c1Br
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCC1CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(Nc3c(C)cncc3C)cc(=O)[nH]c2c1OCC1CC1
Temperature: 110 °C

Procedure:
A solution of 4-bromo-3,5-dimethylpyridine (1.16 g, 6.21 mmol) and degassed toluene (5 mL) was added to a mixture of 4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one (1.94 g, 7.45 mmol, intermediate for Example 3), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), (0.28 g, 0.31 mmol), 2,2-dicyclohexylphosphorane triisopropylbiphenyl (0.59 g, 1.24 mmol), sodium tert-butoxide (1.20 g, 12.4 mmol), and degassed toluene (20 mL) under N2. The mixture was heated at 110° C. for 2 h, allowed to cool to room temperature, sonicated until the solids broke up, and then filtered through Celite with ethyl acetate (500 mL). The filtrate was concentrated, purified by silica gel chromatography (0→8% methanol/dichloromethane), and then re-purified by reverse-phase HPLC (25→100% acetonitrile/H2O) to give 8-(cyclopropylmethoxy)-4-(3,5-dimethylpyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1H), 8.43 (s, 1H), 8.42 (s, 2H), 7.89 (d, 1H), 7.03 (d, 1H), 4.54 (s, 1H), 3.91 (s, 3H), 3.85 (d, 2H), 2.15 (s, 6H), 1.28 (m, 1H), 0.47 (m, 2H), 0.28 (m, 2H); MS (ESI): 365.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([NH:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[N:21]=[C:20]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[O:19][N:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:16][C:17]1[N:21]=[C:20]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24]([N:11]2[C@H:10]3[C@H:13]([CH2:14][CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)[CH2:12]2)=[O:25])[O:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1noc(-c2ccccc2C(=O)N2C[C@H]3CCN(C(=O)OC(C)(C)C)C[C@H]32)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64.4 %

Procedure:
To a solution of 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (550 mg, 2.59 mmol) in CH2Cl2 (9 mL) was added 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (545 mg, 2.59 mmol) followed by EDCl (745 mg, 3.89 mmol), HOBt (525 mg, 3.89 mmol) and TEA (0.72 mL, 5.18 mmol). The mixture was stirred for 14 h at room temperature and then washed (2×) with saturated aqueous NH4Cl solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hex to 100% EtOAc/Hex) afforded the desired product as a colorless foam (665 mg, 61%). MS (ESI): mass calculated for C21H26N4O4, 398.20, m/z found 399.0 [M+1]+. 1H NMR (500 MHz, CDCl3): 8.14-8.05 (m, 1H), 7.67-7.52 (m, 2H), 7.45-7.36 (m, 1H), 4.39-4.21 (m, 2H), 4.04-3.96 (m, 1H), 3.90-3.83 (m, 0H), 3.77-3.43 (m, 3H), 2.96-2.76 (m, 2H), 2.47 (s, 3H), 2.03-1.72 (m, 2H), 1.54-1.36 (m, 9H).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[N+:13]([O-])([OH:15])=[O:14]>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:13]([C:11]1[CH:10]=[CH:9][C:3]2[C:4]([C:6]([OH:8])=[O:7])=[CH:5][S:1][C:2]=2[CH:12]=1)([O-:15])=[O:14]
Reactant: O=C(O)c1csc2ccccc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1csc2cc([N+](=O)[O-])ccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
2 g benzo[b]thiophene-3-carboxylic acid are dissolved in 11 ml acetic anhydride and cooled to 0° C. A solution of 4.4 ml concentrated nitric acid in 10 ml acetic acid is added dropwise, while not allowing the temperature to rise above 5° C. Then the mixture is stirred for 1.5 hours and then combined with 200 ml ice water. The solid is suction filtered and dried in vacuo. Then it is dissolved in hot ethanol. After cooling to ambient temperature the solid (5-nitro-benzo[b]thiophene-3-carboxylic acid, approximately 80%) is suction filtered. By elimination of the solvent in vacuo, 6-nitro-benzo[b]thiophene-3-carboxylic acid (approx. 66%) is obtained from the mother liquor.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][CH3:20])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:19][CH3:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCCCCBr
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCCCC[C@@H](O)[C@H](CC)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 6 (610 mg, 2.28 mmol) and 1-bromoheptadecane (1.82 g, 5.70 mmol), alcohol 62 was obtained as a colorless oil (620 mg, 54% yield).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10](Cl)=[O:11].C1(C)C=CC=CC=1.[NH2:25][C:26]1[CH:38]=[C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>O>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([NH:25][C:26]1[CH:38]=[C:37]([O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[O:11]
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
0.089 mL of pyridine and 0.11 mL of 2,6-dichlorobenzoyl chloride were added to 3.0 mL of toluene solution containing 0.15 g of tert-butyl 2-amino-4-phenoxybenzoate at room temperature sequentially, and the resulting mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and 0.021 mL of pyridine and 0.037 mL of 2,6-dichlorobenzoyl chloride were added sequentially and heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and water was added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 2-(2,6-dichlorobenzamido)-4-phenoxybenzoate.