Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]1(=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCc2ccccc21
Solvent: CCOCC
Product: Fc1ccc(C2=CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of solution of 4-fluorophenylmagnesium bromide (prepared from 6.43 ml of 4-fluorobromobenzene and 1.71 g of Mg in 50 ml of ether) at room temperature under argon was added dropwise over 40 minutes a solution of 1-indanone (6.61 g, 50 mmole) in dry ether (20 ml). After stirring at room temperature for 1 hour, the reaction was quenched by the dropwise addition of saturated NH4Cl solution (15 ml). The mixture was diluted with Et2O, washed with saturated NaCl solution, dried (MgSO4) and evaporated.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)=[CH:15][CH:14]=1)([CH3:12])[CH3:11].O.[OH-].[Na+]>C1COCC1.CCOCC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:16]1[CH:17]=[CH:18][C:13]([C:10]([CH3:12])([CH3:11])[CH2:9][OH:8])=[CH:14][CH:15]=1
Reactant: COC(=O)C(C)(C)c1ccc(-c2ccco2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)c1ccc(-c2ccco2)cc1
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
To a cooled solution (0° C.) of (1M)lithium aluminum hydride (13.3 mL, 13.3 mmol) in THF (27 mL) is added a solution of 2-(4-furan-2-yl-phenyl)-2-propionic acid methyl ester (3.1 g, 12.7 mmol) (reference example 30a) in THF (11 mL). The resulting solution is stirred for 15 min then added slowly H2O (0.5 mL), 15% NaOH (0.5 mL) and H2O (1.5 mL). The resulting slurry is diluted with ether, filtered through a pad of celite and the filtrate concentrated to give 2.7 g of title compound as a white crystalline solid. 1H NMR (CDCl3) δ 1.34 (s, 6H), 3.62 (m, 3H), 6.46 (m, 1H), 6.62 (d, J=3 Hz, 1H), 7.40 (d, J=8 Hz, 2H), 7.46 (bs, 1H), 7.64 (d, J=8 Hz, 2H). MS (EI) m/z 216 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([CH2:14]C)[C:6]=2[CH:16]=1.CI>>[Br:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:10][C:9]([CH3:11])([CH3:12])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[CH:16]=1
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(Br)cc21
Solvent: CI
Product: Cc1cc2c(cc1Br)N(C)C(=O)C(C)(C)O2

Procedure:
This was prepared using a procedure similar to that described to make Compound 1C, except using methyl iodide in Step 1C. MS (electrospray): mass calculated for C12H14BrNO2, 283.02; m/z found 284 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[NH:9][C:10]=1[CH2:11][CH:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH:12]1([CH2:11][C:10]2[NH:9][C:8]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)=[N:7][C:6]=2[C:4]([OH:5])=[O:3])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)c1nc(-c2ccc3ccccc3c2)[nH]c1CC1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc(-c2ccc3ccccc3c2)[nH]c1CC1CCCCCC1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a suspension of the product of step b (1.73 g, 4.62 mmol) in ethanol (25 ml) was added the solution of sodium hydroxide (1.29 g, 32.3 mmol) in water (5 ml). The reaction mixture was heated under reflux for 48 h, allowed to cool to room temperature and concentrated under reduced pressure. The aqueous solution was diluted with water (30 ml) and acidified to pH=2 with 1M hydrochloric acid. The precipitate was collected by filtration, washed with water, and dried to afford the product as an off-white solid (1.53 g, 96%). 1H NMR (300 MHz, d6-DMSO) 8.77 (1H, s), 8.24-7.98 (4H, m), 7.64 (2H, m), 2.91 and 2.64 (2H, 2×d), 2.03 (1H, m), 1.69-1.24 (12H, m).
Reaction SMILES: [NH2:1][C:2](=C)/[CH:3]=[CH:4]/[C:5](/[NH:8][C:9]1[C:18]2[CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:15](=[O:28])[NH:14][C:13]=2[N:12]=[CH:11][CH:10]=1)=[CH:6]/[CH3:7].[F:30][C:31]1[CH:32]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[CH:34]=[CH:35][C:36]=1[F:37]>>[F:30][C:31]1[CH:32]=[C:33]([S:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[C:18]4[CH2:17][N:16]([CH2:19][C:20]5[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=5)[C:15](=[O:28])[NH:14][C:13]=4[N:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)(=[O:40])=[O:39])[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: C=C(N)/C=C/C(=C/C)Nc1ccnc2c1CN(Cc1ccc(OC)cc1)C(=O)N2
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Product: COc1ccc(CN2Cc3c(Nc4ccc(NS(=O)(=O)c5ccc(F)c(F)c5)cc4)ccnc3NC2=O)cc1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 62 using 5-[(Z)-4-amino-1-eth-(E)-ylidene-penta-2,4-dienylamino]-3-(4-methoxy-benzyl)-3,4-dihydro-1 H-pyrido[2,3-d]pyrimidin-2-one and 3,4-difluoro-benzenesulfonyl chloride. LC-MS (M+H=552, obsd.=552).
Reaction SMILES: [Na+:1].[CH3:2][C:3]1[C:11]([CH3:19])([CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]=1[CH2:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24]>C(O)(=O)C.C(OC(=O)C)(=O)C>[Na+:1].[CH3:19][C:11]1([CH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:16])=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N+:4]([CH2:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:24])=[O:25])=[C:3]1/[CH:2]=[CH:12]/[CH:11]=[CH:3]/[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC1=[N+](CCCS(=O)(=O)O)c2ccccc2C1(C)CCCS(=O)(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(CCCS(=O)(=O)O)C(/C=C/C=C/Nc2ccccc2)=[N+](CCCS(=O)(=O)O)c2ccccc21
Temperature: 120 °C
Reaction time: 4 h

Procedure:
0.822 g (2 mmol) 2,3-dimethyl-1,3-bis-(3-sulfo-propyl)-3H-indolium sodium salt 7 and 0.65 g (2.5 mmol) malonaldehyde-bisphenylimine-hydrochloride are dissolved in a mixture of 10 ml acetic acid and 20 ml acetic anhydride and stirred at 120° C. for four hours. The solvent is removed in vacuum after cooling to room temperature. The residue is washed carefully with ethyl acetate. A dark brown solid is obtained which is processed without further purification.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[N:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1ccnc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(COc3cc(C(CC(=O)O)C4CC4)ccn3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(2-((5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methoxy)pyridin-4-yl)propanoate (218 mg) in THF (3.0 mL) and methanol (1.5 mL) was added 1N aqueous sodium hydroxide solution (3.0 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (3.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (175 mg) as a white amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[N:3]1.Cl.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH:19]([N:23]2[CH:27]=[C:26]([C:28]3[C:29]4[CH:36]=[CH:35][N:34](COCC[Si](C)(C)C)[C:30]=4[N:31]=[CH:32][N:33]=3)[CH:25]=[N:24]2)[CH2:20][C:21]#[N:22])[CH2:14][CH2:13]1.C(N(CC)CC)C.FC(F)(F)C(O)=O.C(N)CN>C(#N)C.CO.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH:19]([N:23]3[CH:27]=[C:26]([C:28]4[C:29]5[CH:36]=[CH:35][NH:34][C:30]=5[N:31]=[CH:32][N:33]=4)[CH:25]=[N:24]3)[CH2:20][C:21]#[N:22])[CH2:14][CH2:13]2)(=[O:9])=[O:8])=[N:3]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CC4CCNCC4)c3)ncnc21
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(S(=O)(=O)N2CCC(CC(CC#N)n3cc(-c4ncnc5[nH]ccc45)cn3)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
1-Methyl-1H-pyrazole-3-sulfonyl chloride (108 mg, 0.597 mmol), 4-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilypethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (from example 5, step 4; 250 mg, 0.498 mmol), and triethylamine (208 μL, 0.00149 mol) were dissolved in acetonitrile (2.5 mL). The mixture was stirred at RT for 1 h. Solvents were evaporated. The crude product was treated with DCM (4 mL) and trifluoroacetic acid (4 mL, 0.05 mol) for 30 min, evaporated under reduced pressure. To the resultant residue was added methanol (5 mL) and ethylenediamine (0.5 mL, 0.007 mol). The resulting mixture was stirred at RT for 30 min, and concentrated under reduced pressure. The residue was purified on RP-HPLC (XBridge C-18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH, at flow rate 60 mL/min) to give the desired product (183 mg, 76.6%). LCMS calculated for C22H26N9O2S(M+H)+: m/z=480.2; Found: 480.0. 1H NMR (300 MHz, CD3OD): δ 8.92 (1H, s), 8.86 (1H, s), 8.49 (1H, s), 7.83 (1H, d, J=3.6 Hz), 7.69 (1H, d, J=2.1 Hz), 7.23 (1H, d, J=3.6 Hz), 6.59 (1H, d, J=2.1 Hz), 4.94 (1H, m), 3.89 (3H, s), 3.70 (2H, m), 3.12 (2H, m), 2.33 (2H, m), 2.19 (1H, m), 1.94 (1H, m), 1.82 (1H, m), 1.58 (1H, m), 1.32 (2H, m), 1.05 (1H, m) ppm.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=2)[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].O.C1(C)C=CC=CC=1>[F:38][C:33]1[CH:32]=[C:31]([C:29]2[CH:28]=[CH:27][N:26]=[C:25]([C:14]3[C:9]4[O:8][C:6]5[C:5]([C:10]=4[CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=5)[CH:30]=2)[CH:36]=[CH:35][C:34]=1[F:37]
Reactant: Cc1ccc2c(n1)oc1c(B3OC(C)(C)C(C)(C)O3)cccc12
Reactant: Fc1ccc(-c2ccnc(Cl)c2)cc1F
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccc(F)c(F)c4)ccn3)cccc12
Yield: 65.4 %

Procedure:
A mixture of 2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuro[2,3-b]pyridine (3.0 g, 9.70 mmol), 2-chloro-4-(3,4-difluorophenyl)pyridine (2.41 g, 10.67 mmol), Pd2(dba)3 (0.178 g 0.194 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.319 g, 0.776 mmol), potassium phosphate (7.21 g, 34.0 mmol), toluene (70 mL) and water (7 mL) was degassed with nitrogen and then refluxed overnight. The mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was dried on Na2SO4 and then further purified by column chromatography using ethyl acetate in dichloromethane to give 8-(4-(3,4-difluorophenyl)pyridin-2-yl)-2-methylbenzofuro[2,3-b]pyridine (2.36 g, 6.34 mmol, 65.3% yield).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:57])=[N:50][C:51]([CH3:56])=[CH:52][C:53]=1[O:54][CH3:55]>ClCCl.O>[OH:57][C:49]1[C:48]([CH2:47][NH:46][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[C:53]([O:54][CH3:55])[CH:52]=[C:51]([CH3:56])[N:50]=1
Reactant: COc1cc(C)nc(O)c1CN
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)nc(O)c1CNC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a solution of 4-phenoxybenzoic acid (60 mg, 0.28 mmol) in dichloromethane (15 mL) were added 1-Hydroxybenzotriazole (49 mg, 0.36 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) and triethylamine (73 mg, 0.72 mmol). The resulting solution was stirred at room temperature for 30 minutes. Then 3-(aminomethyl)-4-methoxy-6-methylpyridin-2-ol (40 mg, 0.24 mmol) was added to the solution, and it was stirred at room temperature for 16 hours. Water (20 mL) was added to the mixture. It was extracted with dichloromethane (50 mL). The organic layer was concentrated in vacuo to provide crude product which was purified by silica gel column chromatography dichloromethane/methanol=10:1 to afford N-((2-hydroxy-4-methoxy-6-methylpyridin-3-yl)methyl)-4-phenoxy benzamide (32 mg, 37%) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][CH:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][C:21]3[CH:22]=[C:23]([CH2:31][OH:32])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=3)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:32][CH2:31][C:23]1[CH:22]=[C:21]([CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=1)[CH2:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[CH:11]([NH:10][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])[CH2:12][CH2:13]2
Reactant: NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21
Reactant: O=S(=O)(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CCc2cc(Cc3cc(CO)cc(C(F)(F)F)c3)ccc21)c1cccs1
Yield: 35.9 %

Procedure:
2-thiophenesulfonyl chloride (23 mg, 0.126 mmol) was added to a solution of (3-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)phenyl)methanol (40 mg, 0.124 mmol) and triethylamine (34 μL, 0.244 mmol) in DCM (2 mL). The reaction was stirred at rt for 24 h before aq. sat. NaHCO3 (2 mL) was added to the mixture and the whole was filtered over a phase separator. The organic filtrate was evaporated to dryness in a Genevac. The crude material was purified by prep. LCMS to afford the title compound (20.8 mg, 35.7%). MS (ESI): m/z [M−H]− 466.0.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:9]1[C:10]([CH:13]=[O:14])=[CH:11][NH:12][C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1c[nH]c(-c2cccnc2F)c1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1c[nH]c(-c2cccnc2F)c1Cl
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 44.4 %

Procedure:
5-(2-Fluoropyridin-3-yl)-1H-pyrrole-3-carbaldehyde (610 mg) was dissolved in N,N-dimethylformamide (20 mL), N-chlorosuccinimide (641 mg) was added and the mixture was stirred at 80° C. for 40 min. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:2→1:1) to give the title compound as a colorless powder (yield 320 mg, 44%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH:12]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13]1)[CH2:7]2.[F:19][C:20]1[C:21]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=2[CH3:34])[NH2:30])=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O1CCOCC1>[F:19][C:20]1[C:21]([C:27]2[CH:28]=[C:29]([NH:30][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][N:6]([CH:12]3[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13]3)[CH2:7]4)[CH:31]=[CH:32][C:33]=2[CH3:34])=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Cc1ccc(N)cc1-c1ncc(F)cc1F
Reactant: O=S1(=O)CCC(N2CCc3c(Br)cccc3C2)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(Nc2cccc3c2CCN(C2CCS(=O)(=O)C2)C3)cc1-c1ncc(F)cc1F
Temperature: 100 °C
Yield: 63.9 %

Procedure:
To the reaction vessel containing 5-bromo-2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinoline (50 mg, 0.15 mmol), 3-(3,5-difluoropyridin-2-yl)-4-methylaniline (33 mg, 0.15 mmol), Pd2(dba)3 (13 mg, 0.014 mmol), Xantphos (16 mg, 0.028 mmol) and K3PO4 (74 mg, 0.35 mmol) is added anhydrous dioxane (1 mL). The vessel is flushed with nitrogen, sealed and heated to 100° C. for 15 hours. The reaction is then cooled to ambient temperature, filtered through a celite pad to remove salt. The filtrate is concentrated and purified by silica gel flash chromatography to afford [3-(3,5-difluoro-pyridin-2-yl)-4-methyl-phenyl]-[2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-amine as an off-white solid (45 mg, 65%). MS m/z 470.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ8.67 (d, 1H, J=2.4 Hz), 7.39 (s, 1H), 7.22 (d, 1H, J=8.4 Hz), 7.12 (m, 2H), 7.00 (dd, 1H, J1=8.0 Hz, J2=2.4 Hz), 6.91 (d, 1H, J=2.4 Hz), 6.75 (d, 1H, J=7.2 Hz), 3.79 (d, 1H, J=19.2 Hz), 3.71 (d, 1H, J=19.2 Hz), 3.47 (m, 2H), 3.34 (m, 1H), 3.18 (m, 2H), 2.82 (m, 2H), 2.72 (m, 2H), 2.47 (m, 1H), 2.17 (m, 1H), 2.11 (s, 3H).
Reaction SMILES: C(OC([N:11]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:12][C:13]([NH:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1)=[O:14])=O)C1C=CC=CC=1>[Pd].CO>[F:40][C:37]([F:38])([F:39])[C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[C:27]2[NH:11][CH2:12][C:13]([NH:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:17]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN(C(=O)OCc2ccccc2)c2ccnc3ccc(C(F)(F)F)cc23)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2ccnc3ccc(C(F)(F)F)cc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To flask containing tert-butyl 3-(2-(((benzyloxy)carbonyl)(6-(trifluoromethyl)quinolin-4-yl)amino)acetamido)azetidine-1-carboxylate (306 mg, 0.309 mmol), prepared in Step G, and Palladium on Carbon (98 mg, 0.092 mmol, 5%, “Degussa, wet”) was carefully added methanol (40 mL). The reaction flask was evacuated, backfilled with hydrogen via balloon and stirred at room temperature overnight. The catalyst was removed by filtration and the filtrate concentrated in vacuo to afford the product.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=2[O:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:18][C:16]1[CH:15]=[CH:14][C:5]2[O:6][C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=3[CH:2]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[CH2:3][C:4]=2[CH:17]=1
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(C)ccc1O2
Reactant: O=C1OCCN1CCN1CCNCC1
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(C)ccc1O2

Procedure:
In a manner analogous to that described in the preceding paragraph, by reacting 10-chloro-10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin with 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone there is obtained 3-[2-{4-[10,11-dihydro-2,8-dimethyl-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone having a melting point of 175°-176° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:9][CH:8]1[C:10]#[N:11])(=O)=O.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>CO>[CH2:12]([N:14]([CH2:6][CH:7]1[CH2:9][CH:8]1[C:10]#[N:11])[CH2:15][CH3:16])[CH3:13]
Reactant: CS(=O)(=O)OCC1CC1C#N
Reactant: CCNCC
Solvent: CO
Product: CCN(CC)CC1CC1C#N

Procedure:
To 10 mL of methanol add 1.75 g (2.10 mmol) of 2-[[(methylsulfonyl)oxy]methyl]cyclopropanecarbonitrile and 2.0 g (27 mmol) of diethylamine. Reflux the reaction and monitor by thin-layer chromatography. Upon completion remove the solvent in vacuo and add 50 mL methylene chloride and 50 mL sat. sodium carbonate. Separate the organic layer and dry over Na2SO4. Filter the drying agent and remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][C@@H:13]3[C@H:8]([CH2:9][CH2:10][CH2:11][N:12]3[C:15](=[O:18])[CH2:16][CH3:17])[CH2:7][C:6]=2[CH:19]=1.[CH:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])[CH3:21].Cl.C(OCC)C>N1C=CC=CC=1>[CH:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:14][C@@H:13]4[C@H:8]([CH2:9][CH2:10][CH2:11][N:12]4[C:15](=[O:18])[CH2:16][CH3:17])[CH2:7][C:6]=3[CH:19]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(=O)N1CCC[C@@H]2Cc3cc(N)ccc3C[C@H]21
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC(=O)N1CCC[C@@H]2Cc3cc(NS(=O)(=O)c4ccc(C(C)C)cc4)ccc3C[C@H]21
Reaction time: 1 h
Yield: 70.5 %

Procedure:
1.21 g of trans-1-(7-amino-3,4,4a,5,10,10a-hexahydro-2H-benzo[g]quinolin-1-yl)propan-1-one (0.38 mmol) were dissolved in 2 ml of pyridine. At 0-4° C., 0.08 g of 4-isopropyl-benzene sulfonylchloride (0.4 mmol) were added, and the reaction stirred for 1 h under cooling. 40 ml of aqueous 1 N hydrochloride acid and diethyl ether were added, the phases separated, and the aqueous layer extracted twice with diethyl ether. The organic phases were combined, washed three times with water acidified with 1 N aqueous hydrochloric acid, dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 0.118 g of the product.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[C:8]([O:15][CH3:16])=[N:9][CH:10]=[C:11]([Cl:14])[C:12]=1[CH3:13].[Cu]C#N.[Cl-].[Li+].[CH3:22][O:23][C:24]1[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=[C:29]([CH3:37])[C:25]=1[C:26](Cl)=[O:27].COC1C(OC)=C(OC)C=C(C)C=1C(O)=O.S(Cl)(Cl)=O>>[CH3:22][O:23][C:24]1[C:32]([O:33][CH3:34])=[C:31]([O:35][CH3:36])[CH:30]=[C:29]([CH3:37])[C:25]=1[C:26]([C:7]1[C:8]([O:15][CH3:16])=[N:9][CH:10]=[C:11]([Cl:14])[C:12]=1[CH3:13])=[O:27]
Reactant: COc1cc(C)c(C(=O)Cl)c(OC)c1OC
Reactant: COc1ncc(Cl)c(C)c1Br
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Agent: COc1cc(C)c(C(=O)O)c(OC)c1OC
Solvent: O=S(Cl)Cl
Product: COc1cc(C)c(C(=O)c2c(OC)ncc(Cl)c2C)c(OC)c1OC
Reaction time: 15 h
Yield: 43 %

Procedure:
(b-2) The same reaction as in Step (b-1) was carried out that 11 ml (11.0 mmol) of an isopropylmagnesium chloride 1M tetrahydrofuran solution and 2.5 g (10.6 mmol) of 3-bromo-5-chloro-2-methoxy-4-methylpyridine were used, except that 1.25 g (1.1 mmol) of tetrakistriphenylphosphine palladium was used instead of the tetrahydrofuran solution of copper(I) cyanide and lithium chloride, and that 2,3,4-trimethoxy-6-methylbenzoyl chloride prepared from 2.4 g (10.6 mmol) of 2,3,4-trimethoxy-6-methylbenzoic acid and 5 ml of thionyl chloride was dropwise added at 0° C. over a period of 2 hours, followed by stirring at the same temperature for 15 hours to obtain 1.7 g (yield: 43%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-5-chloro-2-methoxy-4-methylpyridine, and the compound was identified by 1HNMR.