Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)([OH:14])[C:6]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:5]=2[CH:4]=1.OS(O)(=O)=O.[OH-].[Na+]>CO>[Cl:26][C:24]1[CH:23]=[CH:22][C:6]2[C:7]([OH:14])([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:3](=[O:2])[CH2:4][C:5]=2[CH:25]=1.[ClH:26]
Reactant: COC1=Cc2cc(Cl)ccc2C(O)(C2CCN(C)CC2)c2ncccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCC(C2(O)c3ccc(Cl)cc3CC(=O)c3cccnc32)CC1
Product: Cl
Temperature: 25 °C

Procedure:
Dissolve 5-Methoxy-8-chloro-11-(1-methyl-4-piperidinyl)-11 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol (4.26 g) in CH3OH (6 mL) at 0° C. under an argon atmosphere. Add slowly a cooled solution of 92% aqueous H2SO4 (54 mL). Allow the mixture to warm to room temperature for 35 minutes. Pour the solution onto ice, basify with aqueous NaOH (25%), and extract with methylene chloride (3×). Combine the organic portions, wash with brine and dry over sodium sulfate. Filter and concentrate in vacuo. Triturate the residue with ispropyl ether to give an intermediate, 8-chloro-11-hydroxy-11-(1-methyl-4-piperidinyl)-6,11-dihydro-5 H-benzo[5,6]cyclohepta[1,2-b]pyridin-5-one as a white solid (3.58 g., 92%, m.p. 170° to 174° C. as HCl salt).
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[C:16](N1C=CN=C1)([N:18]1C=CN=[CH:19]1)=O.C(N(CC)CC)C.Cl.CNC>CN(C=O)C>[Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([N:18]([CH3:19])[CH3:16])=[O:15]
Reactant: O=C(O)c1cnn(-c2ccccc2)c1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cnn(-c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.3 %

Procedure:
Three grams of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid and 2.6 g of carbonyldiimidazole was dissolved in 50 ml of DMF. The solution was stirred for 20 minutes and 2.3 g of triethylamine and 1.8 g of dimethylamine hydrochloride were added to the reaction mixture. The mixture was stirred at room temperature for 3 hours and was poured into ice water. The precipitated solid was collected by filtration and recrystallized from ethanol/water to afford 1.2 g of 5-bromo-1-phenyl-N,N-dimethyl-1H-pyrazole-4-carboxamide. Yield 37%. mp=79°-81° C.
Reaction SMILES: CS[C:3]([S:12][CH3:13])=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([NH2:17])(=O)[CH3:15].[H-].[Na+].C1(C)C=CC=CC=1.C(OCC)(=[O:29])C>>[CH3:15][C:14]1[NH:11][C:10](=[O:29])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([S:12][CH3:13])[N:17]=1
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Reactant: CCOC(C)=O
Reactant: CC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(SC)nc(C)[nH]c1=O
Yield: 39 %

Procedure:
A solution of ethyl 3,3-bis(methylthio)-2-cyanoacrylate (10.0 g, 45.6 mmol), acetamide (3.0 g, 50.2 mmol), sodium hydride (70% oil, 2.0 g, 58.3 mmol) in ethyl acetate (250 mL)-toluene (250 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added ethanol (200 mL), and the mixture was stirred with heating under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether to give the title compound (4.1 g, 39%) as a pale-yellow powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:24][C:22](=[O:23])[CH:21]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)[CH3:27])[CH3:26]
Reactant: CCOC(=O)C(C)Br
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C

Procedure:
To a mixture of NaH (60%, 4.92 g, 0.205 mol) in DMF (60 mL) is added 5-benzoxyindole at 0˜5° C., then stirred 30 min. ethyl 2-bromopropionate is added dropwise, the mixture is allowed to warm to room temperature and heated at 70° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate. Concentration and column chromatography on silica gel eluted with hexanes and ethyl acetate yields the title compound (29 g).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]=[CH2:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Cl:12][C:13]([Cl:18])(Cl)[C:14](Cl)=[O:15]>C(OCC)C>[CH2:1]([C@H:4]1[CH2:5][CH2:6][C@H:7]([CH:10]2[CH2:11][C:14](=[O:15])[C:13]2([Cl:18])[Cl:12])[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C[C@H]1CC[C@H](CCC)CC1
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H](C2CC(=O)C2(Cl)Cl)CC1

Procedure:
A mixture of 0.25 mol of trans-4-propyl-1-vinylcyclohexane (prepared according to WO 88/02357) and 800 ml of diethyl ether is reacted with trichloroacetyl chloride in accordance with Example 1B.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17]OS(C)(=O)=O)=[CH:11][CH:10]=2)[CH2:4][O:3]1.[Br-:24].[Li+]>CC(C)=O>[Br:24][CH2:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C@@H:5]2[CH2:4][O:3][C:2]([CH3:23])([CH3:1])[O:6]2)=[CH:10][CH:11]=1
Reactant: [Br-]
Reactant: CC1(C)OC[C@@H](COc2ccc(CCCOS(C)(=O)=O)cc2)O1
Agent: [Li+]
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H](COc2ccc(CCCBr)cc2)O1
Temperature: 25 °C

Procedure:
Methanesulfonic acid 3-[4-((R)-2,2-dimethyl[1,3]dioxolan-4-ylmethoxy)-phenyl]-propylester (11.8 g, 34.2 mmol) in acetone (200 mL) is treated with lithium bromide (8.9 g, 100 mmol) and then heated to reflux for 5 h. After cooling to RT the mixture is concentrated in vacuo. The resulting residue is dissolved in EtOAc (150 mL), washed with water (2×50 mL), brine then dried (MgSO4), filtered and concentrated in vacuo to give an oil. Purification by flash chromatography (SiO2, iso-hexane:EtOAc, 4:1) gives the title compound as colourless oil that solidifies upon standing.
Reaction SMILES: C1[C:6]([OH:7])=CC=CC=1C.C1([OH:17])C=C(C)C=C(C)C=1.C1(=O)OC(=O)C=C1.C[O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32]C>>[OH:17][CH:30]1[O:29][CH2:28][C@@H:27]([OH:26])[C@H:6]([OH:7])[C@H:31]1[OH:32]
Reactant: COCCOCCOC
Reactant: Cc1cccc(O)c1
Reactant: Cc1cc(C)cc(O)c1
Agent: O=C1C=CC(=O)O1
Product: OC1OC[C@@H](O)[C@H](O)[C@H]1O
Temperature: 95 °C
Reaction time: 4 h

Procedure:
M-cresol (114 g), 3,5-xylenol (42.8 g), diglyme (50.0), and maleic anhydride (3.13 g) were combined in a flask and heated to 95° C. The solution was purged with nitrogen for 3 minutes. Formaldehyde (37.2% in water, 83.7 g) was added slowly over 75 minutes. Heating at 95° C. was continued for four hours. The volatile components were distilled away from the reaction mixture until the residue was at 200° C. Vacuum was applied slowly to the distillation until 35 mmHg and 220° C. were both reached. The novolak resin in the reaction flask was then cooled to room temperature. RMW=9.2; DR=10.4.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[CH2:29]([OH:32])[C:30]#[CH:31].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1.[Cu]I.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>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:31]#[C:30][CH2:29][OH:32])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CCO)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
A solution of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1 mmol) and propargyl alcohol (84 mg, 1.5 mmol) in toluene (6 mL) was treated with copper(I) iodide (19.2 mg, 0.10 mmol), dichlorobis(triphenylphosphine)palladium(II) (36 mg, 0.05 mmol), and N,N-diisopropylethylamine (2 ml). The resulting mixture was stirred at 25° C. for 1 h and was then heated to 60° C. for 1 h. At this time, the reaction was concentrated in vacuo. The residue was extracted into ethyl acetate from a 1N aqueous hydrochloric acid solution. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxy-prop-1-ynyl)-pyrazin-2-yl]-propionamide (275 mg, 57%) as a pale yellow solid: (ES)+-HRMS m/e calcd for C22H24ClN3O4S (M+H)+ 462.1249, found 462.1252.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=O)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[H-].[Na+].O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][CH2:16][C:17]2=[O:19])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCCNc1ccc(CC(=O)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1ccc(N2CCCC2=O)cc1
Yield: 58.5 %

Procedure:
A mixture in tetrahydrofuran (50 ml) of ethyl 4-[4-(ethoxycarbonylmethyl)phenyl]aminobutanoate (2.4 g. 8.3 mmols) and sodium hydride (oily) (0.5 g, 12 mmols) was stirred, while heated under reflux, for 18 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with brine, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give a solid of ethyl[4-(2-oxopyrrolidin-1-yl)phenyl]acetate (1.2 g, 59%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.CCN(CC)CC>C(Cl)Cl>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:8][CH:9]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
A solution of acryloyl chloride (29.5 mL, 363 mmol) in CH2Cl2 (50 mL) was added dropwise (30 min) to an ice-cold solution of 4′-aminoacetophenone (49.0 g, 363 mmol) and Et3N (50.6 mL, 363 mmol) in CH2Cl2 (300 mL). The reaction mixture was stirred at 0° for 15 min and then was concentrated under reduced pressure. The residue was dissolved with EtOAc. The solution was washed successively with 10% aqueous HCl, saturated aqueous NaHCO3 and H2O. The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford the desired N-(4-acetylphenyl)-2-propenamide (52 g, 76% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ8.17 (broad s, 1H), 7.93 (d, J=8.9 Hz, 2H), 7.72 (d, J=8.9 Hz, 2H), 6.47 (dd, J=1.0, 16.9 Hz, 1H), 6.33 (dd, J=10.2, 16.9 Hz, 1H), 5.80 (dd, J=1.0, 10.2 Hz, 1 H), 2.58 (s, 3H); MS (FAB) m/z 190 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12](OCC)(=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:6][C:4]2=[O:5]
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1cc(Cl)ccc1N
Product: CCOC(=O)c1nc2ccc(Cl)cc2c(=O)[nH]1
Yield: 58 %

Procedure:
2-Amino-5-chlorobenzamide (2.387 g) and diethyl oxalate were stirred at 175° C. for 6 hr. The mixture was allowed to cool, and the obtained crude crystals were washed with hot ethanol to give the title compound (2.051 g, 58%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([CH:6]([C:11]2[CH:12]=[C:13]([N:18]3[CH:22]=[N:21][N:20]=[CH:19]3)[CH:14]=[C:15]([F:17])[CH:16]=2)[C:7]([F:10])([CH3:9])[CH3:8])[CH2:3]1.Br[CH:24]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].C(N(C(C)C)CC)(C)C>CC#N>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([CH:24]([N:2]2[CH2:3][CH:4]([CH:6]([C:11]3[CH:12]=[C:13]([N:18]4[CH:19]=[N:20][N:21]=[CH:22]4)[CH:14]=[C:15]([F:17])[CH:16]=3)[C:7]([F:10])([CH3:9])[CH3:8])[CH2:5]2)[C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[CH:38][CH:37]=1
Reactant: CC(C)(F)C(c1cc(F)cc(-n2cnnc2)c1)C1CNC1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(F)C(c1cc(F)cc(-n2cnnc2)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
A sample of 135 mg (0.41 mmole) of 4-[3-(1-Azetidin-3-yl-2-fluoro-2-methylpropyl)-5-fluorophenyl]-4H-1,2,4-triazole hydrochloride, 211 mg (0.62 mmole) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile and 181 uL (1.025 mmole) of diisopropylethylamine in 5 mL of dry CH3CN was heated at reflux for 3 h. The solution was concentrated and the residue was dissolved in 20 mL of CH2Cl2 and 5 mL of NaHCO3. The layers were separated and the organic phase was dried over Na2SO4 and concentrated. The residue was purified on silica gel using CH2Cl2-EtOAc—NH3 (2M in MeOH), 200:50:4 to afford the title compound as a mixture of 4 diastereomers: Mass Spectrum: m/e=518 (M+1).
Reaction SMILES: CO[C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=2)[C:3]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(SC)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(SC)cc1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
3-Cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid methyl ester (400 mg, 1.44 mmol) and methyl urea (267 mg, 3.60 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 5.6 mL, 3.89 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C., filtered through celite, and the celite was thoroughly washed with ethyl acetate. The ethyl acetate filtrate was washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-propionyl]-3-methyl urea (141 mg, 31%) as a white solid: mp 185-186° C.; EI-HRMS m/e calcd for C17H24N2O2S (M+) 320.1559, found 320.1559.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:17]=[C:18]([NH2:29])[CH:19]=[CH:20][C:21]=1[S:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:19]=[CH:20][C:21]=1[S:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1
Reactant: N#Cc1cnc2cc(F)ccc2c1Cl
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(F)ccc23)cc1Cl

Procedure:
Following the procedure of Example 1, a mixture of 1.2 g (5.81 mmol) 4-chloro-7-fluoro-3-quinolinecarbonitrile, 1.53 g (6.39 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine and 0.671 g (5.81 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (12 mL) at 120° C. for 45 minutes to yield 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-fluoroquinoline-3-carbonitrile as an off-white solid, mp 268-272° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=3)[C:14]([NH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([CH3:19])[CH3:18])=[O:15])[CH:9]=2)[O:4][C:3]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.[CH3:36]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.CCOC(C)=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>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:3]2[O:4][C:5]3=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([CH:26]=[CH:27][CH:28]=4)[C:14]([NH:16][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)([CH3:19])[CH3:18])=[O:15])[CH:9]=[C:10]3[C:2]=2[CH3:36])=[CH:30][CH:31]=1
Reactant: CC(C)(NC(=O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1)c1ccccc1
Reactant: CB1OB(C)OB(C)O1
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: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
Pd(Ph3P)4 (4.4 mg, 3.8 μmol) was added to a stirring solution of 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (20 mg, 0.038 mmol), trimethylboroxine (11 μL, 0.076 mmol), and Na2CO3 (12.0 mg, 0.11 mmol) in DMF (1.4 mL) and Water (0.14 mL) at room temperature. It was subjected to microwave irradiation: 180° C. for 30 min. The mixture was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(2-phenylpropan-2-yl)benzamide (15 mg, 0.032 mmol, 85% yield) by LCMS. LC-MS retention time: 1.87 min; m/z (MH+): 465. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 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 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[O:38][CH:37]=[N:36][C:35]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:42][C:39]5([C:35]6[N:36]=[CH:37][O:38][C:34]=6[CH3:33])[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1ocnc1C1(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncoc5C)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(5-methyloxazol-4-yl)cyclopropanamine (0.06 g, 0.46 mmol, 1.0 eq), HOBT (0.062 g, 0.46 mmol, 1.0 eq), EDC.HCl (0.08, 0.46 mmol, 1.0 eq), in DCM at ambient temperature and under a nitrogen atmosphere was added diisopropylehtylamine (0.19 ml, 1.3 mmol, 3.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by Combiflash column chromatography (4 g flash column, CV 4.8 ml, 18 ml/min, max pressure 200 psi) using 0.5% Methanol/DCM. Yield: 0.045 g (17.6%) 1H NMR (400 MHz, DMSO-d6): δ 1.11-1.14 (m, 2H), 1.20-1.23 (m, 2H), 2.29 (s, 3H), 2.31 (s, 3H), 2.82 (d, 3H, J=4.4 Hz), 3.95 (s, 3H), 7.12 (s, 1H), 7.33 (dd, 1H, J=1.6, 8.4 Hz), 7.40 (apparent t, 2H, J=8.8 Hz), 7.49 (d, 1H, J=1.2 Hz), 7.60 (s, 1H), 7.72 (d, 1H, J=8.4 Hz), 7.97-8.01 (m, 2H), 8.04 (s, 1H), 8.46-8.48 (m, 1H), 8.67 (s, 1H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)C(=O)C2=CC=CC=C12.O.NN>CO>[NH2:12][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:6]#[N:5])=[CH:8][CH:9]=1
Reactant: N#Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CO
Solvent: O
Product: N#Cc1ccc(CN)cc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
Next, 26.0 g (99 mmols) of 4-phthalimidomethylbenzonitrile prepared in the same manner as above was admixed with 6.32 ml (0.129 mol) of hydrazine hydrate and 300 ml of methanol. The mixture was refluxed for 1 hour, cooled to room temperature and concentrated. The residue was dissolved in 300 ml of 1 mol dm-3NaOH, followed by extraction with ether. The ethereal layer was washed with saturated aqueous solution of sodium chloride, dryed over MgSO4 and concentrated, affording 11.8 g (yield 90%) of 4-aminomethylbenzonitrile.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Temperature: 25 °C
Yield: 93.8 %

Procedure:
To a 1M solution of BBr3 (1.1 L, 1.6 equiv.), cooled at 0° C. with an ice-water bath, add 6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (187 g, 0.684 mol) in DCM (200 mL) over 1 h., while maintaining the temperature between 0° C. and 10° C. Warm the reaction mixture to ambient temperature and stir until HPLC indicates completion of the reaction (about 2 h.). Cool the solution to 0° C. and transfer it via cannula into an ice/water solution (1.2 L), thereby precipitating the product as a white solid. Add EtOAc (2 L) to dissolve most of the precipitate, separate the layers and concentrate the organic layer in vacuo. Extract the aqueous layer three times with EtOAc (2×2 L, 1×1 L). Wash the combined organic layers with water (2 L), and then brine (2 L), dry over Na2SO4, filter and concentrate in vacuo to give the desired intermediate as a light yellow solid (166.3 g, 94%). Use the product for the next step without further purification. Prepare an analytical sample by chromatography on silica gel eluting with 40% diethyl ether in hexane: mp 183.0-185.2° C. 1H NMR (300 MHz, DMSO-d6), δ 9.39 (s, 1H), 6.94-6.88 (m, 1H), 6.72-6.68 (m, 1H), 6.61-6.57 (m, 1H), 3.67-3.32 (m, 4H), 2.99-2.86 (m, 4H); 13C NMR (300 MHz, DMSO-d6), δ 154.50, 141.47, 141.18, 126.77, 126.64, 125.77, 125.33, 120.38, 120.32, 118.49, 114.67, 113.64, 113.47, 47.31, 47.27, 47.00, 46.96, 45.83, 45.49, 36.17, 34.93, 26.46, 25.18, 20.66, 14.00; MS (ES+) m/z 260 (M+H)+; Anal. Calc'd. for C12H12F3NO2: C, 55.60; H, 4.67; N, 5.40. Found: C, 55.51, H, 4.71; N, 5.29.