Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[C:5]([C:12]([NH2:14])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].[OH:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1>>[C:1]([C:3]1[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[C:5]([C:12]([NH2:14])=[O:13])[S:6][C:7]=1[N:27]1[CH2:28][CH2:29][O:30][CH:25]([CH2:24][OH:23])[CH2:26]1)#[N:2]
Reactant: CS(=O)(=O)c1sc(C(N)=O)c(-c2ccc(Cl)cc2Cl)c1C#N
Reactant: OCC1CNCCO1
Product: N#Cc1c(N2CCOC(CO)C2)sc(C(N)=O)c1-c1ccc(Cl)cc1Cl
Temperature: 60 °C
Yield: 70.3 %

Procedure:
4-cyano-3-(2,4-dichlorophenyl)-5-(methylsulfonyl)thiophene-2-carboxamide (0.026 g, 0.069 mmol) was dissolved in 2-hydroxymethylmorpholine (0.300 g, 2.56 mmol) and the solution was heated at 60° C. overnight. The residue was concentrated in vacuo and column chromatography was performed and yielded 4-cyano-3-(2,4-dichlorophenyl)-5-[2-(hydroxymethyl)morpholin-4-yl]thiophene-2-carboxamide (0.020 g, 66%) as a white solid. LCMS: (FA) ES+ 412. 1H NMR (400 MHz, d4-methanol) δ: 7.76 (s, 1H), 7.49 (d, 1H), 7.40 (d, 1H), 4.08-3.92 (m, 3H), 3.84-3.72 (m, 2H), 3.69-3.59 (m, 2H), 3.15-3.08 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([C@@H:9](O)[CH3:10])=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([C@H:9]([N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: C[C@H](O)c1nc2cc(Cl)ccc2n1CCC(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](c1nc2cc(Cl)ccc2n1CCC(F)(F)F)n1nc(S(C)(=O)=O)c2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a mixture of (1S)-1-[5-chloro-1-(3,3,3-trifluoropropyl)-1H-benzimidazol-2-yl]ethanol (145 mg, 0.50 mmol) and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine (140 mg, 0.70 mmol) in DCM (15 mL) was added PPh3 (262 mg, 1.0 mmol) and DEAD (170 mg, 1.0 mmol). The mixture was then stirred at room temperature overnight. After the reaction was complete, the mixture was washed by 2 N aqueous solution of NaOH and the organic layer was concentrated in vacuo. The residue was purified by preparative HPLC to afford 1-{(1R)-1-[5-Chloro-1-(3,3,3-trifluoropropyl)-1H-benzimidazol-2-yl]ethyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (56.6 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].ClOC(C)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:31][C:32]([NH2:34])=[O:33])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.O1CCCC1>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:12][C:13]([Cl:16])=[CH:14][C:15]=1[CH:31]([S:30][C:27]1[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=1)[C:32]([NH2:34])=[O:33]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: NC(=O)CSc1ccc(Cl)cc1
Agent: CC(C)(C)OCl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)C(Sc1ccc(Cl)cc1)c1cc(Cl)cc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold (-70° C.) solution of 20 g (0.0863 mole) of 2-amino-5-chlorobenzophenone in 500 ml of methylene chloride under nitrogen atmosphere was added a solution of 9.48 g (0.088 mole) of t-butyl hypochlorite in 50 ml of methylene chloride. After an additional 15 min stirring, a solution of 17.35 g (0.0863 mole) of α-(4-chlorophenylthio)acetamide in 500 ml of a 50/50 mixture of tetrahydrofuran and methylene chloride was added. The mixture was stirred at -70° C. for 2 hr, 8.72 g (0.0863 mole) of triethylamine was added, and the stirred solution was allowed to warm to room temperature over a period of 2 hr. The reaction mixture was extracted with several portions of water and the organic layer dried over magensium sulfate. The volume of liquid was reduced to about 500 ml. Methylene chloride, 500 ml, was added to precipitate the product which after filtration and drying weighed 16.62 g (44.7%). The yellow solid melted at 198°-200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[S:8][C:7]1=[O:16].Cl[C:21]([OH:23])=[O:22].[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.ClCCl>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[S:8][C:7](=[O:16])[N:6]([CH2:5][C:4]3[CH:3]=[C:2]([NH:1][C:21](=[O:22])[O:23][CH2:33][CH2:32][CH2:31][N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)[CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:11]=1
Reactant: O=C(O)Cl
Reactant: CCCN1CCN(C)CC1
Reactant: Nc1cccc(Cn2c(=O)sc3ccc(Cl)cc32)c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCCOC(=O)Nc2cccc(Cn3c(=O)sc4ccc(Cl)cc43)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
173 mg (0.36 mmol) of 3-(3-aminobenzyl)-5-chloro-3H-benzothiazol-2-one and 198 mg (0.67 mmol) of 3-(4-methylpiperazin-1-yl)propane 1-chloroformate are suspended in 3 ml of THF, and 253 μl (1.46 mmol) of DIPEA are added. The reaction mixture is stirred overnight at room temperature. 50 ml of dichloromethane are added to the suspension, which is subsequently washed with 10 ml of 2N NaOH, dried and evaporated. The crude product is purified by means of preparative HPLC. The product “A13” is in the form of the trifluoroacetate.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:10][Si:11]([CH3:19])([CH3:18])[O:12][Si:13]([CH2:16]I)([CH3:15])[CH3:14].C(#N)C.CCCCC>O>[CH2:1]([N:8]1[CH2:14][Si:13]([CH3:16])([CH3:15])[O:12][Si:11]([CH3:19])([CH3:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(CI)O[Si](C)(C)CI
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCCCC
Solvent: CC#N
Product: C[Si]1(C)CN(Cc2ccccc2)C[Si](C)(C)O1
Reaction time: 1 h

Procedure:
An amount of 33.6 g. (0.315 mole) of benzylamine is added over a period of approximately 5 minutes to 41.4 g. (0.1 mole) of 1,3-bis-iodomethyl-1,1,3,3-tetramethyl-disiloxane with stirring in a bath at room temperature. Stirring is continued at room temperature for one hour. (A slurry resulted). Addition of 50 ml. of acetonitrile gives a clear solution which is then heated to reflux for 2 hours. The cooled solution is distributed between approximately 0.5 l. of pentane and 1.5 l. of water. The aqueous layer is then extracted with one more approximately 200 ml. portion of pentane, and the combined organic layer is washed twice with approximately 300 ml. of water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to provide a clear yellow mobile liquid. This product is then vacuum distilled to give 4-benzyl-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6-disilacyclohexane; b.p. 134° to 135° C., at 13 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([OH:20])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:23](OC)([CH3:25])[CH3:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]2[O:20][C:23]([CH3:25])([CH3:24])[O:18][C:17]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H](O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)O1
Yield: 87.7 %

Procedure:
(S)-3-(4-Benzyloxy-phenyl)-2-hydroxy-propionic acid (2.0 g, 7.34 mmol), 2,2-dimethoxypropane (18.63 g, 0.179 mol) and pyridinium p-toluene sulfonate (0.92 g, 3.66 mmol) in chloroform (80 mL) was heated to reflux for 40 minutes under N2. The mixture was cooled, diluted with water, and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated in vacuo to give crude product that was purified by flash chromatography using 10:1 hexanes:acetone to afford the title compound (2.01 g, 88%). 1H-NMR (400 MHz, CDCl3) δ 7.43–7.29 (m, 5H), 7.17 (d, 2H, J=8.80 Hz), 6.91 (d, 2H, J=8.80 Hz), 5.04 (s, 2H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.12 (dd, 1H, J=14.617 Hz, J=4.40 Hz), 2.99 (dd, 1H, J=14.67 Hz, J=6.36 Hz), 1.49 (s, 3H), 1.36 (s, 3H). MS (ES+) m/z calc'd for C19H20O4 (M+NH4) 330. Found m/z 330.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][C:10]([NH:16][C@H:17]2[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]2)=[N:11]3)=O)[CH2:3][CH2:2]1.Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH:1]1([C:4]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][C:10]([NH:16][C@H:17]2[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]2)=[N:11]3)=[N:27][OH:28])[CH2:3][CH2:2]1
Reactant: O=C(c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)C1CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)C1CC1
Reaction time: 2 h
Yield: 45.6 %

Procedure:
A stirred suspension of cyclopropyl-[2-((R)-indan-1-ylamino)-quinolin-5-yl]-methanone (example 30) (150 mg, 0.46 mmol), hydroxylamine hydrochloride (95 mg, 1.37 mmol) and sodium carbonate (145 mg, 1.37 mmol) in ethanol (5 ml) was heated under reflux conditions for 18 h, the reaction mixture was poured into water (5 ml) and the mixture was stirred for 2 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (heptane/ethyl acetate) to yield the title compound as off-white solid (72 mg, 46%). M.p. 151° C.; MS: m/e=344.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Li]CCCC.CN([CH:18]=[O:19])C.S(=O)(=O)(O)O>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Cc1cc(F)cc(F)c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(F)c(C=O)c(F)c1
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
To a solution of 1,3-difluoro-5-methylbenzene (10.2 g, 80 mmol) in anhydrous ether (80 mL) was added n-BuLi (2.5 M solution in hexane, 48 ml, 120 mmol) over a 20 min period while the internal temperature was maintained at around −50° C. After stirring at that temperature for 1.5 hr, DMF (14.6 g, 200 mmol) was added over a 20 min period. After stirring at the same temperature for an additional 1.5 h, the reaction mixture was slowly poured into 1N aqueous sulfuric acid (300 mL) and extracted with ether three times. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated to give the title compound (11.2 g, 90%). 1H-NMR (500 MHz, CDCl3): δ 10.25 (s, 1H), 6.75 (d, 2H, J=9.9 Hz), 2.39 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:14]3[CH:15]=C[C:17](F)=[C:18]([CH:21]=3)C#N)=[N:9][N:10]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:5]=[CH:4][N:3]=1.[OH:23][NH:24][C:25](=O)[CH3:26].CC([O-])(C)C.[K+].C[N:35](C=O)C>>[NH2:1][C:2]1[C:7]2[C:8]([C:14]3[CH:21]=[CH:18][C:17]4[O:23][N:24]=[C:25]([NH2:35])[C:26]=4[CH:15]=3)=[N:9][N:10]([CH:11]([CH3:12])[CH3:13])[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: CC(=O)NO
Reactant: CC(C)n1nc(-c2ccc(F)c(C#N)c2)c2c(N)nccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)n1nc(-c2ccc3onc(N)c3c2)c2c(N)nccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 5-(4-amino-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-fluorobenzonitrile (304) (49 mg, 0.166 mmol), N-hydroxyacetamide (compound 305) (18.7 mg, 1.5 eq, 0.249 mmol) and t-BuOK (27.9 mg, 1.5 eq, 0.249 mmol) in DMF (4 mL) was stirred at 25° C. overnight. The mixture was concentrated in vacuo, brine (10 mL) was added and then extracted with ethyl acetate (3×30 mL). The combined organic layer was washed with brine (10 mL), dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography eluting with a mixture of methanol in dichloromethane to afford the desired product, 5-(4-amino-1-isopropyl-1H-pyrazolo[4,3-c]pyridin-3-yl)benzo[d]isoxazol-3-amine (7) (28 mg, 55% yield) (compound 306) as a white solid. ESI-MS m/z: 309.35 [M+1]+.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:16]#[N:17])[CH:6]=[CH:5][C:4]=2[NH:3]1.[H-].[Na+].[H][H].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O>[CH2:22]([N:3]1[C:2](=[O:1])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:16]#[N:17])[CH:6]=[CH:5][C:4]1=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: [H][H]
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc2[nH]c(=O)c3ccccc3c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)c1ccccc1c(=O)n2Cc1ccccc1
Yield: 48 %

Procedure:
6-Oxo-5,6-dihydrophenanthridine-2-carbonitrile (1 g) was suspended in DMF (20 ml), 60% sodium hydride (0.2 g) was added under ice cooling, and stirring was carried out until the generation of hydrogen stopped. Benzyl bromide (0.59 ml) was added, followed by stirring at room temperature for 1 hour. Water was added, and the produced solid was collected by filtration and purified by silica gel chromatography (dichloromethane:n-hexane=1:1) to thereby obtain 0.68 g (yield: 48%) of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[O:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[CH:39][C:40]3[N:44]=[C:43]([C:45]4[C:53]5[C:48](=[CH:49][CH:50]=[C:51]([NH2:54])[CH:52]=5)[N:47]([CH:55]5[CH2:60][CH2:59][CH2:58][CH2:57][O:56]5)[N:46]=4)[NH:42][C:41]=3[CH:61]=2)[CH2:33][CH2:32]1>CN(C=O)C>[F:11][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]([NH:54][C:51]2[CH:52]=[C:53]3[C:48](=[CH:49][CH:50]=2)[N:47]([CH:55]2[CH2:60][CH2:59][CH2:58][CH2:57][O:56]2)[N:46]=[C:45]3[C:43]2[NH:44][C:40]3[CH:39]=[CH:38][C:37]([N:34]4[CH2:35][CH2:36][O:31][CH2:32][CH2:33]4)=[CH:61][C:41]=3[N:42]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CCC(F)(F)CC1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccc(N4CCOCC4)cc3[nH]1)nn2C1CCCCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2c(c1)c(-c1nc3cc(N4CCOCC4)ccc3[nH]1)nn2C1CCCCO1)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.3 %

Procedure:
4,4-Difluorocyclohexanecarboxylic acid (3.92 mg, 0.024 mmol), HOBt (4.84 mg, 0.036 mmol), EDC (6.87 mg, 0.036 mmol) and sodium bicarbonate (2.007 mg, 0.024 mmol) was added to a solution of 3-(6-morpholino-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (10 mg, 0.024 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 24 h after and then the solvent was removed in vacuo. Purification by flash column chromatography (6% CH3OH/CH2Cl2) afforded the title compound (6 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.49 (s, 1H), 7.76-7.70 (m, 2H), 7.57 (d, 1H, J=8.8 Hz), 7.17 (m, 1H), 7.07 (dd, 1H, J=2.0 & 8.8 Hz), 5.90 (dd, 1H, J=2.0 and 9.6 Hz), 4.01 (m, 1H), 3.86 (m, 4H), 3.81 (m, 1H), 3.17 (m, 4H), 2.65 (m, 1H), 2.53 (m, 1H), 2.43 (m, 1H), 2.18-2.10 (m, 2H), 1.99 (m, 3H), 1.92-1.82 (m, 4H), 1.75 (m, 3H); ESI-MS [M+H]+: 565.17.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:20])=[O:19]>C1COCC1>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:18]([OH:19])([CH3:20])[CH3:17])=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)=O
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.75 h

Procedure:
To magnesium turnings (30.2 g, 1.24 mol) in THF (30 mL) is added 1,2-dibromoethane (0.7 mL) followed by dropwise addition, over 1 h, of 4-bromotrifluoromethylbenzene (200 g, 0.89 mol) dissolved in THF (700 mL). The reaction is heated occasionally to maintain a gentle reflux and is stirred 45 min after the addition is complete. The dark reaction mixture is then cooled in an ice bath and acetone (103 g, 1.78 mol) added dropwise. After stirring an additional 1.5 h the reaction is carefully quenched with aqueous saturated NaHSO4, ethyl acetate added, the organics dried over MgSO4, concentrated and purified by silica gel chromatography (9:1 to 3:2, hexane to ethyl acetate) to give 4-trifluoromethyl-α,α-dimethylbenzyl alcohol of sufficient purity to carry to the next step; yield: 114 g (63%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:3]=1.[ClH:20].[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[ClH:20].[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=1[O:10][CH2:11][C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: [H][H]
Reactant: N#Cc1ccc(F)cc1OCC(=O)N1CCOCC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCc1ccc(F)cc1OCC(=O)N1CCOCC1
Reaction time: 7 h
Yield: 29.2 %

Procedure:
A solution of 4-fluoro-2-(2-morpholino-2-oxoethoxy)benzonitrile, (500 mg, 1.89 mmol) in warm ethanol (30 mL) and ethyl acetate (30 mL) was mixed with conc.HCl (0.32 mL, 3.78 mmol, 2 eq.). To this was added 10% Pd—C (100 mg; Aldrich), and the mixture was hydrogenated at 1 atm of hydrogen for 20 hrs at room temperature. To this mixture was added an additional amount of 10% Pd—C (50 mg) and stirring continued for another 7 hrs. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to dryness. The residue was triturated with ethyl acetate, then with ethanol to obtain the title compound (168 mg, Yield 29%) as an off-white powder: 1H NMR (CD3OD, 500 MHz) δ ppm: 3.55 (2H, t, J=5 Hz, NCH2), 3.62 (2H, t, J=5 Hz, NCH2), 3.70 (2H, t, J=5 Hz, OCH2), 3.75 (2H, t, J=5 Hz, OCH2), 4.17 (2H, s, NCH2), 5.17 (2H, s, OCH2), 6.82 (1H, dt, J=2.5, 8.5 Hz, Ar—H), 7.05 (1H, dd, J=2.5, 10.5 Hz, Ar—H), 7.43 (1H, dd, J=6.5, 8.5 Hz, Ar—H); 13C NMR (CD3OD, 125.77 Hz) δ ppm: 39.40, 42.49, 44.97, 66.11, 66.46, 66.59, 101.38, 101.59, 108.40, 108.57, 118.40, 132.53, 132.62, 158.43, 158.52, 63.87, 165.83, 168.27. HRMS (ESI) calcd for C13H18N2O3F (M+H) 269.1301, found 269.1301.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>CN(C)C=O>[CH2:32]([O:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH:5][CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:33]
Reactant: CCI
Reactant: COc1ccc(N)cc1O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ccc(OC)c(OCC)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-Hydroxy-4-methoxyaniline (0.64 g) and diethyl ethoxymethylenemalonate (1.20 g) were stirred at 115° for 30 minutes. Dimethylformamide (9.6 ml), potassium carbonate (960 mg) and ethyl iodide (0.44 ml) were added to the mixture, and the whole mixture was stirred at room temperature for 20 hours. The precipitate was removed by filtration, and the filtrate was concentrated and purified by silica gel column chromatography (Wako Gel C-200, 25 g) to give diethyl (3-ethoxy-4-methoxyanilino)methylenemalonate (1.5 g). The product was suspended in diphenyl ether (19.5 ml), and the suspension was stirred at 250°-260° for 6 hours. After the reaction mixture was left to cool down to room temperature, ether was added to the mixture and the precipitate was collected by filtration. It was purified by silica gel column chromatography (Wako Gel C-200, 35 g) to give 7-ethoxy-6-methoxy-4(1H)-quinolone (compound 62, 280 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([CH:21]=[CH2:22])[CH:11]=1)[CH3:9])(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:30])([F:29])[C:26]([O-:28])=[O:27].[CH3:20][S:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:8]([NH3+:7])[CH3:9])=[CH:11][C:12]=1[CH:21]=[CH2:22])(=[O:19])=[O:18]
Reactant: O=C(O)C(F)(F)F
Reactant: C=Cc1cc(C(C)NC(=O)OC(C)(C)C)ccc1NS(C)(=O)=O
Solvent: ClCCl
Product: C=Cc1cc([C@@H](C)[NH3+])ccc1NS(C)(=O)=O
Product: O=C([O-])C(F)(F)F
Yield: 143.7 %

Procedure:
[1-(4-methanesulfonylamino-3-vinylphenyl)ethyl]carbamic acid t-butyl ester (158.4 mg, 0.465 mmol, 1 eq.) was put into 100 ml round-bottom flask and dissolved in methylenechloride. To the solution was added trifluoroacetic acid (179.2 μl, 2.326 mmol, 5 eq.) and stirred for one night. After confirming the completion of the reaction with TLC, the reaction solution was concentrated under reduced pressure to yield brown crude liquid (236.7 mg).
Reaction SMILES: [N:1]([OH:4])=[N+]=[N-].[C:5]([O:9][C:10](OC([O-])=O)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.[OH-].[OH-].[Pd+2]>[C:10]([NH:1][OH:4])([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: [N-]=[N+]=NO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NO
Yield: 39.2 %

Procedure:
A solution of 15a (9.85 g, 69.8 mmol) and t-butyldicarbonate (18.3 g, 83.8 mmol) in 50 mL of MeOH was placed in a Parr bottle with 20% Pd(OH)2 (2.0 g) and hydrogenated under 50 psi of H2 overnight. The reaction mixture was filtered through a sintered glass funnel and concentrated on a rotary evaporator. The residue was triturated with ether and the solid was collected and dried to give 3.64 g (24% yield) of Boc-amino alcohol 15b.
Reaction SMILES: C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[C:30](=[CH2:38])[CH:31]3[CH2:37][NH:36][CH2:35][CH:32]3[C:33]=2[CH:34]=1>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[CH:30]([CH3:38])[CH:31]3[CH2:37][NH:36][CH2:35][CH:32]3[C:33]=2[CH:34]=1
Reactant: C=C1c2ccc(Cl)cc2C2CNCC12
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1c2ccc(Cl)cc2C2CNCC12
Reaction time: 2 h

Procedure:
Di-tert-butyl dicarbonate (0.43 g, 2.00 mmol) and DIEA (1.0 mL, 6.0 mmol) were added to a solution of 5-chloro-8-methylene-1,2,3,3a,8,8a-hexahydro-2-aza-cyclopenta[a]indene (2.0 mmol) in CH2Cl2 (10 mL) at 0° C. The reaction mixture was stirred for 2 hours at from 0° C. to room temperature, then quenched with aqueous HCl (10 mL, 0.1 M). The organic extracts were washed with brine, dried over MgSO4, and concentrated to afford the subtitle compound in quantitative yield. MS calculated for C17H20ClNO2+H: 306, observed: 306.
Reaction SMILES: [C:1]1(=[N:7]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].CS(C)=O.[CH:15]#[CH:16].N1C=CC=[CH:19][CH:18]=1>>[CH:15]([N:7]1[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=2[CH:19]=[CH:18]1)=[CH2:16]
Reactant: C#C
Reactant: c1ccncc1
Reactant: ON=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: C=Cn1ccc2c1CCCC2
Yield: 90 %

Procedure:
5 g of cyclohexanone oxime, 2.5 g of sodium hydroxide, 100 ml of dimethylsulfoxide and 5 ml of pyridine are heated for 3 hours at a temperature of 90° C in a one-liter rotary autoclave in the presence of a 5-fold excess of acetylene (with respect to the stoichiometric amount thereof). Maximal pressure is 27 atm. The reaction mixture is extracted with diethyl ether and distilled to give 5.3 g (90%) of 1-vinyl-4,5,6,7-tetrahydroindole.