Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>CCC(C)=O>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][O:12][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[C:2](=[O:3])[CH3:1])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(O)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(OC)cc1C(C)=O

Procedure:
A mixture of 16.6 g (100.0 mmol) of 2-hydroxi-5-methoxyacetophenone, 20 g (208 mmol) of potassium carbonate, 16.7 g (100.0 mmol) of ethyl bromoacetate and 200 ml of MEK is stirred at reflux temperature for 10 hr. The solids are filtered and the filtrate concentrated. The residue is suspended in water and the solid is filtered and dried. Yield: 10.2 g (40%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.Cl.[CH3:32][NH:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH3:32][N:33]([CH3:34])[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
In a 1 dram vial, (S)-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzoic acid (100 mg, 0.245 mmol) was suspended in DMF (Volume: 1.227 mL) then added dimethylamine hydrochloride (24.02 mg, 0.295 mmol), HATU (140 mg, 0.368 mmol) and N-methylmorpholine (0.108 mL, 0.982 mmol). The reaction was stirred at RT overnight. The mixture was purified by prep HPLC-MS (acidic mode, 15-35%). The pH of the combined fractions was adjusted to pH=8-9 and extracted with EtOAc (3×30 ml), washed with brine, dried with MgSO4, filtered and concentrated to dryness. The residue was taken up with water/ACN (1:1), and concentrated in vacuo to provide the title compound as a fluffy white solid (21 mg, 19% yield). m.p.=99.2° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.85-2.04 (m, 3 H) 2.12-2.21 (m, 1 H) 2.43-2.49 (m, 4 H) 2.94 (s, 6 H) 3.14-3.23 (m, 4 H) 3.35-3.43 (m, 3 H) 3.54-3.64 (m, 1 H) 3.94-4.03 (m, 1 H) 6.92 (d, J=9.09 Hz, 2 H) 6.99 (d, J=1.77 Hz, 1 H) 7.29 (d, J=8.84 Hz, 2 H) 7.62 (d, J=1.52 Hz, 1 H) 10.44 (s, 1 H). [M+H] calc'd for C24H30N6O2, 435; found, 435.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][C:31]([OH:33])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]1(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.[CH:56]([NH:59][CH3:60])([CH3:58])[CH3:57]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:29][CH2:30][C:31]([N:59]([CH:56]([CH3:58])[CH3:57])[CH3:60])=[O:33])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[S:16]1(=[O:28])=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCC(=O)O)cc2OCc2ccccc2)S1(=O)=O
Reactant: CNC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C)C(=O)CCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid (0.10 g, 0.2 mmol), EDCl (0.38 g, 0.20 mmol) and HOAt (0.027 g, 0.20 mmol) in DMF (1 mL) is added N-isopropyl-N-methylamine (0.15 g, 0.2 mmol). The mixture is stirred at RT for 18 h, then poured into water. The mixture is extracted into EtOAc and the organic phase washed with water (3×) and sat. NaCl (1×). The organic solution is dried over Na2SO4 and the solvent removed under reduced pressure to afford the title compound. This is used directly in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[S:20][CH:21]=[CH:22][C:15]=12>CN(C)C=O>[CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[S:20][CH:21]=[CH:22][C:15]=23)[CH2:5][CH2:4]1
Reactant: Clc1ccnc2sccc12
Reactant: CN(C)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1CCC(Oc2ccnc3sccc23)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-(dimethylamino)cyclohexan-1-ol (127 mg, 0.89 mmol, 1.50 equiv) in N,N-dimethylformamide (15 mL). This was followed by the addition of sodium hydride (71 mg, 1.77 mmol, 3.00 equiv, 60%). The resulting solution was stirred for 30 minutes at 80° C. in an oil bath. 4-chlorothieno[2,3-b]pyridine (100 mg, 0.59 mmol, 1.00 equiv) was added to the mixture. The resulting solution was stirred for 3 h at 120° C. in an oil bath. The reaction was then quenched by the addition of 10 mL of ethanol. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with dichloromethane/methanol (10:1). The resulting product (50 mg) was further purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, CH3CN and water with 0.05% NH4HCO3 (3.0% water with 0.05% NH4HCO3 up to 3.0% in 1 min, up to 4.7.0% in 13 min, up to 100.0% in 2 min); Detector, uv 254/220 nm. This resulted in 9.6 mg (6%) of N,N-dimethyl-4-[thieno[2,3-b]pyridin-4-yloxy]cyclohexan-1-amine as a white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[H-].[Na+].Cl[C:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][C:12]=1[CH:27]=O>C1COCC1>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([N:14]2[CH2:15][CH2:16][C:11]3[O:3][C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:27][C:12]=3[CH2:13]2)(=[O:18])=[O:19])=[CH:21][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Cl)=C(C=O)C2)cc1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(o1)CCN(S(=O)(=O)c1ccc(C)cc1)C2

Procedure:
To a solution of ethyl glycolate (1 eq) in THF was added sodium hydride (2.5 eq) at 0° C. and the reaction mixture was stirred for 1 h 4-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,5,6-tetrahydropyridine-3-carbaldehyde (1 eq) obtained in step II of example 200 in THF was added at 0° C. and was refluxed for 2 h. Reaction was quenched with water and extracted with ethyl acetate, organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the ethyl 5-[(4-methylphenyl)sulfonyl]-4,5,6,7-tetrahydrofuro[3,2-c]pyridine-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[C:15]([CH:19]([CH:26]2[CH2:28][CH2:27]2)[NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:16]=[N:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:26]1([CH:19]([C:15]2[CH:16]=[N:17][CH:18]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[CH:14]=2)[NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH2:28][CH2:27]1
Reactant: COc1cccc(B(O)O)c1
Reactant: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(c1cncc(-c2ccccc2OC)c1)C1CC1
Temperature: 100 °C
Yield: 35.4 %

Procedure:
A mixture of 3-methoxyphenylboronic acid (48 mg, 0.31 mmol), N-((5-bromopyridin-3-yl)(cyclopropyl)methyl)ethanesulfonamide (100 mg, 0.31 mmol), PdCl2(PPh3)2 (18 mg, 0.02 mmol) and Na2CO3 (2 M in water, 0.39 mL, 0.78 mmol) in DMF (2 mL) was heated at 100° C. for 2 h. After concentration, the resulting residue was dissolved in DCM and filtered. The filtrates were concentrated and purified by flash column (EtOAc/Heptane, v/v, 0-40%) to give the title compound (38 mg, 35%); ESI-MS m/z: 347 [M+1]+. 1H-NMR (MeOD, 400 MHz) δ 8.75 (1H, bs), 8.61 (1H, bs), 8.17 (1H, bs), 7.46 (1H, t, J=8.0 Hz), 7.27 (1H, dd, J=8.0, 2.4 Hz), 7.24 (1H, t, J=2.4 Hz), 7.05 (1H, dd, J=8.0, 2.4 Hz), 3.94 (1H, d, J=9.2 Hz), 3.91 (3H, s), 3.03-2.89 (2H, m), 1.35-1.29 (1H, m), 1.29 (3H, t, J=7.2 Hz), 0.81-0.75 (1H, m), 0.676-0.60 (2H, m), 0.53-0.48 (1H, m)
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[F:21])[C:13]1=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[F:21])[C:13]2=[O:22])[C:3]([OH:23])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester (311 mg, 0.97 mmol) in tetrahydrofuran (6 mL) at room temperature was treated with a mixture of lithium hydroxide monohydrate (82 mg, 1.95 mL) in water (6 mL). The reaction mixture was then stirred at room temperature until the reaction was complete by TLC (˜2 h). After this time, the reaction mixture was treated with 1N aqueous hydrochloric acid solution until the pH=2. The reaction mixture was then extracted with ethyl acetate (3×20 mL). The combined organic layers were then dried over magnesium sulfate, filtered to remove the drying agent and the filtrate was concentrated in vacuo to afford (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (230 mg, 78%) as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1([CH3:18])[CH2:17][CH2:16]1)[CH:9]=[CH:8]2)=[O:4].[OH-].[Na+]>CO>[CH3:18][C:15]1([C:10]2[CH:9]=[CH:8][C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[N:11]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1ccc2nc(C3(C)CC3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(c2ccc3cc(C(=O)O)ccc3n2)CC1
Yield: 83.7 %

Procedure:
A solution of Methyl-2-(1-methylcyclopropyl)quinoline-6-carboxylate (225 mg, 0.93 mmol) and 2M sodium hydroxide solution (2 ml. 4 mmol) in methanol (10 ml) was heated at 60° C. for 2 hours. After the solvent was evaporated in vacuo, the residue was dissolved in water. The aqueous solution was neutralized with 2M hydrochloric acid solution (2 ml) and the precipitated white solid was extracted with ethyl acetate (×3). The combined solution was washed with brine, dried over sodium sulfate and concentrated in vacuo to give crude white solid, which was recrystallized from ethyl acetate and hexane to furnish the title compound (177 mg, 84%) as a white solid. MS (ESI): m/z 228.15 [M+H]+, 226.13 [M−H]−.
Reaction SMILES: CO[C:3]([C:5]1[C:9]([CH3:10])=[CH:8][N:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=1)=[O:4].[NH2:17][C:18]([NH2:20])=[NH:19]>CN1C(=O)CCC1.O>[CH3:10][C:9]1[C:5]([C:3]([NH:19][C:18]([NH2:20])=[NH:17])=[O:4])=[CH:6][N:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=1
Reactant: N=C(N)N
Reactant: COC(=O)c1cn(-c2ncccn2)cc1C
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cn(-c2ncccn2)cc1C(=O)NC(=N)N
Temperature: 25 °C
Yield: 53.4 %

Procedure:
250 mg 4-methyl-1-pyrimidin-2-yl-1H-pyrrole-3-carboxylic acid methyl ester was dissolved in 0.3 mL of NMP. After addition of 1 g guanidine (preparation according to known literature) the mixture was heated under argon for 1 h to 90° C. Completion of the reaction was checked by LCMS. The mixture was cooled to room temperature and then diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water (twice), dried over anhydrous sodium sulfate. After filtration the solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column flash chromatography (eluent: dichloromethane/methanol=5/1) to obtain 150 mg of N-(4-methyl-1-pyrimidin-2-yl-1H-pyrrole-3-carbonyl)-guanidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20]C)=[O:19])[NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[K+].Cl>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([OH:20])=[O:19])[NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2ccc(OCc3ccccc3)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2ccc(OCc3ccccc3)cc2[nH]1
Reaction time: 72 h

Procedure:
Methyl 6-benzyloxyindole-2-carboxylate (EXAMPLE 247, 3.77 g) is dissolved in 33.5 ml of dioxane and 3.35 ml of water is added. Then solid potassium hydroxide (0.9 g) is added and the reaction is heated to 50° for 6 hr. Then a further 0.9 g of potassium hydroxide is added and the reaction is stirred at 20°-25° for 72 hr and heated at 50° a further 4 hr. Then it is cooled to 20°-25° and acidified to pH 4-5 with 2N hydrochloric acid. The reaction is extracted with methanol/chloroform (10/90, 3 times) and the extracts are dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)(=[O:4])[CH2:2][CH3:3].[BrH:17].C(O)(=O)C.Br.[NH+]1C=CC=CC=1.O>C(O)(=O)C>[Br:17][CH:2]([CH3:3])[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=[O:4]
Reactant: Br
Reactant: CCC(=O)c1ccc2c(c1)NC(=O)C(C)O2
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Reaction time: 2 h

Procedure:
To a solution of 6-propionyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.4 g) and 30% hydrogen bromide-acetic acid (10 ml) in acetic acid (50 ml) was added pyridinium hydrobromide perbromide (5.12 g) at ambient temperature and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water. The resultant precipitate was collected by filtration and dissolved in a mixture of ethyl acetate and tetrahydrofuran. The organic solution was washed with a saturated aqueous solution of sodium bicarbonate and brine. The solvent was dried over magnesium sulfate and removed in vacuo to afford a crystalline residue, which was washed with diisopropyl ether to give 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (3.8 g).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C@@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C1CCN2C(=NCCC2)CC1>>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:17]([CH3:16])[CH2:22]2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Prepared according to Procedure G using 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.00 g, 4.10 mmol) and (R)-tert-butyl 2-methylpiperazine-1-carboxylate and using DBU as a base to give (R)-tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-2-methylpiperazine-1-carboxylate. Mass Spectrum (ESI) m/e=412.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([Cl:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[CH:37]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:4]1[CH:3]=[C:2]([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[CH:37]3)[CH:7]=[CH:6][C:5]=1[N:8]1[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)=[N:11][NH:10][C:9]1=[O:24]
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2Cl)C1
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4[nH]ccc4c3)cc2Cl)C1
Temperature: 120 °C
Yield: 48 %

Procedure:
A mixture of 4-(4-bromo-2-chlorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (140 mg, 0.329 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (80 mg, 0.329 mmol), potassium carbonate (182 mg, 1.315 mmol), and tetrakis(triphenylphosphine)palladium(0) (19.0 mg, 0.016 mmol) in 1,4-dioxane (5 mL) and water (2 mL) was heated at 120° C. for 3.5 hr. The reaction mixture was cooled and loaded onto a silica gel pre-column and purified by flash chromatography (dichloromethane to 6% methanol in dichloromethane) to afford the title product (73 mg, 0.158 mmol, 48% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.96-8.78 (m, 1H), 8.37 (br. s, 1H), 7.92-7.82 (m, 2H), 7.76-7.64 (m, 1H), 7.56-7.47 (m, 1H), 7.47-7.39 (m, 2H), 7.36-7.30 (m, 1H), 6.76-6.61 (m, 1H), 4.04-3.02 (m, 4H), 2.80-2.39 (m, 3H), 2.34-2.03 (m, 1H), 1.84-1.60 (m, 1H), 1.07-0.94 (m, 2H), 0.76 (dd, J=3.3, 7.8 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl[CH2:20][CH:21]([OH:30])[CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>O>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][CH2:22][CH:21]([OH:30])[CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:6][CH:7]=2)[CH:25]=1
Reactant: OC(CCl)CCc1cccnc1
Reactant: Oc1ccc(-c2cccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc(-c2cccnc2)cc1
Yield: 38.2 %

Procedure:
Prepared according to the method as described in Example 24b) from 3-(4-hydroxyphenyl)pyridine (1.68 g), ethanol (30 ml), sodium hydroxide (0.393 g), water (10 ml) and (±)-α-(chloromethyl)-3-pyridinepropanol (0.91 g, Example 24a)) to give the title compound as a pale yellow solid (0.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17](=[O:20])[CH2:18]Br.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:18][C:17]([O:16][CH3:15])=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CNc1cccc(Cl)c1
Temperature: 60 °C

Procedure:
To a solution of 3-chloroaniline and potassium carbonate (3 equiv.) in DMF is added methylbromoacetate (1.1 equiv.), and the reaction is stirred at 60° C. After complete reaction, the solution is poured into EtOAc and washed with water, sat. aq. NaHCO3 soln., and brine. The solution is dried (Na2SO4), filtered, and concentrated in vacuo. The resulting material is purified by silica gel chromatography to provide the titled compound.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[NH2:19][CH:20]([CH3:23])[C:21]#[CH:22]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:19][CH:20]([C:21]#[CH:22])[CH3:23])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: C#CC(C)N
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Solvent: CC#N
Product: C#CC(C)NC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C

Procedure:
A mixture of 1-nitro-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene (3.13 g, 10.9 mmole) and 3-amino-1-butyne (4.5 g, 65.1 mmole) in acetonitrile (45 ml) was stirred at reflux temperature under a positive pressure of nitrogen for 17 hours. The reaction mixture was evaporated under reduced pressure then the residue placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. Recrystallization yielded the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])(=[O:3])[CH3:2].[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>O1CCOCC1>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c(Cl)c(C(C)=O)cnc12
Solvent: C1COCCO1
Product: COc1cccc2c(Nc3ccccc3C)c(C(C)=O)cnc12
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A mixture of crude 3-acetyl-4-chloro-8-methoxyquinoline (7.9 g) and o-toluidine (2 ml, 19 mmol) in dioxan (150 ml) was heated under reflux with stirring for 2 hours, then cooled and evaporated. Aqueous sodium bicarbonate was added, the mixture extracted with chloroform, and the organic extract dried and evaporated. Recrystallisation from ethyl acetate and then from ethanol gave 3-acetyl-4-(2-methylphenylamino)-8-methoxyquinoline (2.65 g, 44% from 3-acetyl-8-methoxy-4(1H)-quinolone), m.p. 171°-173°.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([N:2]1[CH2:3][CH:4]2[CH:5]([CH2:6][N:7]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=3)[CH2:8]2)[CH2:1]1)=[O:10]
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: FC(F)(F)c1cccc(Cl)n1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3cccc(C(F)(F)F)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-6-trifluoromethyl-pyridine. MS (ESI): mass calculated for C23H20F3N3OS, 443.49; m/z found 444.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.62-7.33 (m, 5H), 7.29-7.05 (m, 2H), 7.04-6.80 (m, 2H), 6.37 (s, 1H), 4.01-2.47 (m, 10H).