Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[C:14]2[CH:13]=[C:12]([C:15](N(OC)C)=[O:16])[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.O.Cl>O1CCCC1>[Cl:5][C:6]1[C:14]2[CH:13]=[C:12]([C:15](=[O:16])[CH2:1][CH3:2])[S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1cc2c(Cl)cccc2s1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1cc2c(Cl)cccc2s1
Reaction time: 0.5 h

Procedure:
Ethylmagnesium bromide (1M solution in tetrahydrofuran; 17.2 ml) was added under nitrogen to a stirred solution of 4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (4 g; prepared in a manner similar to that described in Example 18) in tetrahydrofuran (120 ml) then the mixture was allowed to stand at ambient temperature for 30 minutes, heated under reflux for 30 minutes and allowed to stand at ambient temperature for 30 minutes. Further ethylmagnesium bromide (1M solution in tetrahydrofuran; 7.0 ml) was added and the mixture was allowed to stand at ambient temperature for 2 hours. Water (200 ml) and 5M hydrochloric acid (15 ml) were added, and the product was extracted into dichloromethane (2×90 ml). The combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 1-(4-chlorobenzo[b]thiophen-2-yl)propan-1-one (1.88 g) as a pale yellow solid, m.p. 96-98° C.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:30])[CH2:2][CH3:3].[CH:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44](=[O:45])[CH2:43][CH:42]([CH2:46]OS(C)(=O)=O)[CH2:41]2)=[CH:36][CH:35]=1)([CH3:33])[CH3:32].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH:31]([C:34]1[CH:39]=[CH:38][C:37]([N:40]2[C:44](=[O:45])[CH2:43][CH:42]([CH2:46][N:25]3[CH:26]=[C:22]([C:9]4[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:11]5[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:30])[N:6]([CH2:27][CH2:28][CH3:29])[C:7]=5[N:8]=4)[CH:23]=[N:24]3)[CH2:41]2)=[CH:36][CH:35]=1)([CH3:33])[CH3:32]
Reactant: CC(C)c1ccc(N2CC(COS(C)(=O)=O)CC2=O)cc1
Reactant: CCCn1c(=O)c2c(nc(-c3cn[nH]c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC4CC(=O)N(c5ccc(C(C)C)cc5)C4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 77.5 °C
Yield: 80.5 %

Procedure:
A mixture of 1,3-dipropyl-8-(1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.100 g, 0.23 mmol), methanesulfonic acid 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl ester (0.107 g, 0.34 mmol), K2CO3 (0.048 g, 0.34 mmol) and DMF (1 ml) were heated at 75-80° C. for 16 hrs. Reaction mixture was cooled to 20-25° C. and water was added (10 ml). The aqueous layer was extracted with ethyl acetate, washed with saturated brine solution. The organic layer was dried over Na2SO4 and evaporated to obtain crude product (0.2 g). The crude product was purified by preparative TLC to obtain pure 8-{1-[1-(4-isopropyl-phenyl)-5-oxo-pyrrolidin-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.12 g, 80%) as a light yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH2:13])=[N:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21](O)=[O:22])[CH:16]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:21](=[O:22])[C:17]2[CH:16]=[C:15]([Cl:14])[CH:20]=[CH:19][N:18]=2)=[N:2]1
Reactant: NCCNc1nsc2ccccc12
Reactant: O=C(O)c1cc(Cl)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCNc1nsc2ccccc12)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
A mixture of N1-(benzo[d]isothiazol-3-yl)ethane-1,2-diamine (100 mg, 0.52 mmol), 4-chloropicolinic acid (90 mg, 0.57 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg, 0.57 mmol) and triethylamine (174 μL, 1.1 mmol) in dichloromethane (5 mL) was allowed to stir at room temperature overnight. The reaction mixture was washed successively with 1N aqueous hydrochloric acid, saturated sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by flash column chromatography, on silica gel, eluting with a mixture of 1% methanol in dichloromethane and selected fractions were combined and concentrated under reduced pressure to give N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)-4-chloropicolinamide (50 mg) as a white solid. 1H NMR (300 MHz, CDCl3): 8.66 (broad s, 1H), 8.41 (d, 1H), 8.20 (s, 1H), 7.78 (t, 2H), 7.65-7.38 (m, 3H), 5.95 (broad s, 1H), 3.84 ppm (m, 4H). MW=333 confirmed by LC-MS, tr=12.38 min (Method Y) MH+=334.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[CH3:19][S:20]([NH:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:21]>>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:26]3[CH:25]=[C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])[CH:29]=[CH:28][CH:27]=3)[C:9]=2[CH:10]=1
Reactant: Fc1ccc2c(c1)C(=CBr)c1ccccc1CC2
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccc(F)cc32)c1

Procedure:
Following the procedures essentially as described in Example 219, below, and using 5-bromomethylene-3-fluoro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (200 mg, 0.660 mmol) and 3-methanesulfonylaminophenylboronic acid (156 mg, 0.726 mmol), affords 212 mg (82%) of a mixture of geometric isomers of the title compound as a yellow solid. MS (ES) 411 (M+NH4), 392 (M−H); HPLC shows 98% purity.
Reaction SMILES: [N:1]#[C:2]Br.[CH:4]1([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:16]=3)=[C:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:12]=[CH:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(O)C>[CH2:23]([N:22]1[C:17]2[CH:16]=[C:15]([C:14]3[N:10]([CH:4]4[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]4)[CH:11]=[N:12][C:13]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:20]=[CH:19][C:18]=2[N:21]=[C:2]1[NH2:1])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CNc1cc(-c2c(-c3ccccc3)ncn2C2CCCCC2)ccc1N
Reactant: N#CBr
Solvent: CCO
Product: CC(C)Cn1c(N)nc2ccc(-c3c(-c4ccccc4)ncn3C3CCCCC3)cc21
Temperature: 25 °C
Yield: 52 %

Procedure:
Add cyanogen bromide (101 mg, 0.96 mmol) to a solution of 1-(cyclohexyl)-4-phenyl-5-(3-(isobutylamino)-4-aminophenyl)-1H-imidazole (250 mg, 0.64 mmol) in 6 mL ethanol. Stir over night at room temperature. Add saturated aqueous sodium carbonate and extract well with 9:1 ethyl acetate:methanol. Combine the organic phases, dry over magnesium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with a gradient of 5-8% methanol in dichloromethane to provide the title compound (52%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:21]=[C:20](Cl)[N:19]=1>CN(C=O)C.CO>[Cl:17][C:18]1[N:19]=[C:20]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[C:22]([CH2:24][N:25]([CH3:27])[CH3:26])[CH:23]=1
Reactant: CN(C)Cc1cc(Cl)nc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)Cc1cc(Cl)nc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (44.2 mg, 0.219 mmol) in DMF (0.7 mL) was added sodium hydride (13.2 mg, 0.329 mmol). After stirring for 30 minutes, 1-(2,6-dichloropyridin-4-yl)-N,N-dimethylmethanamine (45 mg, 0.22 mmol) was added to the reaction vial. The reaction solution was heated at 100° C. overnight. The reaction solution was diluted with methanol and purified with preparative LCMS to give the desired product. LCMS (M+H)+: 370.1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[C:26]([F:27])=[C:25](F)[C:11]([C:12]([C:14](=[CH:20][NH:21][CH:22]2[CH2:24][CH2:23]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[C:10]([F:29])[C:9]=1[F:30].O>CN(C)C=O>[Br:7][C:8]1[C:26]([F:27])=[C:25]2[C:11]([C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][N:21]2[CH:22]2[CH2:24][CH2:23]2)=[C:10]([F:29])[C:9]=1[F:30]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)c(Br)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(Br)c(F)c(F)c2c1=O
Temperature: 150 °C
Yield: 64.1 %

Procedure:
Potassium carbonate (30 g) was added to a stirred solution/suspension of 31.65 g ethyl 2-(4-bromo-2,3,5,6-tetrafluorobenzoyl)-3-cyclopropylaminopropenoate in 300 ml dimethylformamide. The mixture was heated at 150° C. for 1.5 hours, then cooled, poured into water and extracted with methylene dichloride. The extract was washed with water and sodium chloride solution, dried (magnesium sulfate) and concentrated. The residue was recrystallized from acetonitrile to give 19.3 g (64%) ethyl 7-bromo-1-cyclopropyl-5,6,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, m.p. 187°-189° C.
Reaction SMILES: CN(C)C=O.BrCCBr.Cl[Si](C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]Br.[C:25]([C:27]1[C:28](I)=[C:29]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[S:30][C:31]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)#[N:26]>[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:24][C:23]1[CH:22]=[CH:21][C:18]([CH2:19][C:28]2[C:27]([C:25]#[N:26])=[C:31]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[S:30][C:29]=2[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:17][C:16]=1[F:15]
Reactant: Fc1cc(CBr)ccc1Cl
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1Cc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame-dried scintillation vial, to a suspension of zinc (0.0998 g, 1.53 mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) were added 1,2-dibromoethane (0.003279 mL, 0.03805 mmol) and chlorotrimethylsilane (0.004830 mL, 0.03805 mmol). Stirred at room temperature for 15 min, at which point a solution of 3-fluoro-4-chlorobenzylbromide (0.341 g, 1.53 mmol) in N,N-dimethylformamide (1.36 mL, 17.6 mmol) was added. The resulting suspension was stirred at room temperature for 16 hours. A scintillation vial containing ethyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (199 mg, 0.507 mmol and bis(tri-t-butylphosphine)palladium(0) (12.96 mg, 0.02537 mmol) was purged via vacuum/backfilling with argon. To this was added the organozinc solution from above, and the resulting solution was stirred at 45° C. for 6 hours, at which point LC/MS showed complete conversion to a single new peak with mass representing desired product. The reaction mixture was transferred to a separatory funnel containing saturated NaHCO3 (aq., 10 mL) and water (10 mL), and then diluted with EtOAc (40 mL). The layers were separated, and the aqueous layer was extracted 2×30 mL with EtOAc. The combined organic layers were washed 1× brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford crude ethyl 3-(4-chloro-3-fluorobenzyl)-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate as a brown oil that was used without further purification. LCMS: (FA) ES+ 409, 411
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[C:26]4[N:25]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:33]([F:36])([F:35])[F:34])[NH:23][C:22]=4[CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH2:4][O:3]1.Cl>C1COCC1.CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]([C:18]2[C:26]3[N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:35])([F:36])[F:34])[NH:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CC1(C)OC[C@@H](COc2cccc(NC(=O)c3cccc4[nH]c(-c5ccccc5C(F)(F)F)nc34)c2)O1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cccc(OC[C@@H](O)CO)c1)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (R)-N-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide (134; 51.5 mg, 0.1 mmol) in 3 mL of THF was added 4 N HCl dropwise until observe color change, solution darkens, at which point an additional 1 mL of HCL is added and the solution is allowed to stir at room temperature for 18 h. The reaction mixture was diluted with MeOH and then concentrated under reduced pressure. The resulting yellowish suspension is purified by preparatory HPLC. The desired product (Compound 725) was obtained as a white solid (32.5 mg, 64%). MS (ESI) calcd for C24H20F3N3O4: 471.14; found: 472 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7]>O1CCCC1.[Pt]>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([O:14][CH3:15])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: COc1ccc(C=CC(=O)O)c(Cl)c1Cl
Agent: [Pt]
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)O)c(Cl)c1Cl
Reaction time: 0.79 h

Procedure:
2,3-Dichloro-4-methoxycinnamic acid (200.8 g., 0.813 mole) is dissolved in tetrahydrofuran (1600 ml.) and 5% platinum on charcoal (16.3 gm.) is added. The mixture is divided into 8 separate units and each is placed in a Parr hydrogenation apparatus in an atmosphere of hydrogen at an initial pressure of 50 p.s.i. Upon shaking, the time required for the reduction of each batch is 35 to 60 minutes.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH3:21][S:22][C:23]1[N:28]=[C:27]([CH:29]=[O:30])[CH:26]=[CH:25][N:24]=1.[NH4+].[Cl-]>C1COCC1>[C:17]([O:16][C:13](=[O:15])[CH2:14][CH:29]([OH:30])[C:27]1[CH:26]=[CH:25][N:24]=[C:23]([S:22][CH3:21])[N:28]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CSc1nccc(C=O)n1
Reactant: CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1nccc(C(O)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
To a cold (0° C.) solution of diisopropylamine (5.7 mL, 40.5 mmol) in THF (130 mL) is added dropwise n-butyllithium (16.2 mL of a 2.5 M solution in hexanes, 40.5 mmol). The mixture is stirred for 45 min at 0° C., then the solution is cooled to −78° C. tert-Butyl acetate (5.5 mL, 40.5 mmol) is added dropwise to the reaction mixture. After stirring 40 min at −78° C., a solution of 2-methylsulfanyl-pyrimidine-4-carbaldehyde (5.0 g, 32.4 mmol) is added dropwise. After 30 min at −78° C., the solution is poured into aqueous saturated NH4Cl. The aqueous phase is extracted with EtOAc. The organic phase is dried (MgSO4), filtered and concentrated in vacuo. The crude residue is purified over silica (5% EtOAc/hexanes, followed by 20% EtOAc/hexanes) to afford 7.2 g (82% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.52 (d, J=5.1 Hz, 1H), 7.22 (d, J=5.1 Hz, 1H), 5.00 (dd, J=8.4, 3.6 Hz, 1H), 2.93 (dd, J=16.5, 3.6 Hz, 1H), 2.70 (dd, J=16.5, 7.8 Hz, 1H), 2.58 (s, 3H), 1.46 (s, 9H); ESI+ MS: m/z (rel intensity) 271.1 (85, M++H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]([O:21][Si](C)(C)C)C#N.[Br:26][C:27]1[S:31][C:30]([CH:32]=[O:33])=[CH:29][CH:28]=1>O1CCCC1>[Br:26][C:27]1[S:31][C:30]([CH:32]([OH:33])[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[O:21])=[CH:29][CH:28]=1
Reactant: C[Si](C)(C)OC(C#N)c1ccccc1Cl
Reactant: O=Cc1ccc(Br)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)C(O)c1ccc(Br)s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
Under an atmosphere of nitrogen, to a clod (−78° C.) solution of lithium bis(trimethylsilyl)amide (8.05 mL, 1.0M solution in THF, 8.05 mmol) was added a solution of (2-chloro-phenyl)-trimethylsilanyloxy-acetonitrile (1.69 g, 7 mmol) in tetrahydrofuran (10 mL) dropwise over 10 min. After stirring for another 30 min, a solution of 5-bromothiophen-2-carboxaldehyde in tetrahydrofuran (10 mL) was added dropwise. The reaction was stirred overnight from −78° C. to reach room temperature, then was quenched by adding 3N HCl (20 mL) and warming at 40° C. for 5 hrs. After cooling, the mixture was partitioned between ethyl ether and water. The organic layer was stirred with 1M NaOH (30 mL) for 2 hrs; and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Hexane/EtOAc, 8/2) to give a brown oil (320 mg, 14% yield). 1H-NMR (400 MHz, CDCl3): δ 4.35 (d, 1H), 6.12 (d, 1H), 7.02 (d, 1H), 7.26 (m, 2H), 7.41 (d, 1H), 7.44 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3(C#N)[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][S:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:34])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][S:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: N#CC1(CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2ccccc2CSc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(c2ccc(Cl)cc2)CCN(CCCC2c3ccccc3CSc3ccccc32)CC1
Yield: 68.6 %

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(11-cyano-6,11-dihydrodibenzo[b,e]thiepin-11-yl)propyl]piperidin-4-ol (430 mg) in THF (10 ml) was added 1M lithium aluminum hydride THF solution (1.5 ml) and the mixture was heated to reflux for 3 hours. The reaction mixture was cooled with ice, water (0.06 ml), then 15% aqueous sodium hydroxide (0.06 ml), then water (0.18 ml) were added carefully. The granular salt was filtered off and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:1) to give the titled compound (280 mg).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N:8]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1.CO>[CH3:1][O:20][C:19](=[O:21])[CH2:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[N:8]=[CH:9][CH:10]=[N:11]2
Reactant: O=C(O)Cc1ccc2nccnc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc2nccnc2c1

Procedure:
Trimethylsilyldiazomethane [2.0M in hexanes] (0.08 mL) was added dropwise to a solution of quinoxalin-6-yl-acetic acid (0.030 g, 0.159 mmol) in toluene/methanol [8/1] (0.5 mL) and stirred until the bubbling stopped. The reaction was then evaporated and the crude product was purified via silica gel column chromatography in hexane:ethyl acetate (1:1) to give 0.013 g of quinoxalin-6-yl-acetic acid methyl ester. This was added to a solution of hydrazine (0.10 mL) in methanol and stirred at room temperature overnight. The reaction mixture was evaporated in vacuo to give 0.019 g of quinoxalin-6-yl-acetic acid hydrazide. 1H NMR (400 MHz, DMSO-d6) δ 9.77 (bs, 1H), 9.35 (m, 2H), 8.46 (d, 1H, J=8.8 Hz), 8.39 (m, 1H), 8.19 (dd, 1H, J=2.0, 8.8 Hz), 4.68 (bs, 2H), 4.07 (s, 2H).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=2[CH:3]=1.[F:14][C:15]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[F:14][C:15]1[CH:20]=[C:19]([C:2]2[S:10][C:9]3[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[NH:5][C:4]=3[CH:3]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC1(C)OB(c2ccnc(F)c2)OC1(C)C
Reactant: CC1(C)NC(=O)c2sc(Br)cc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)NC(=O)c2sc(-c3ccnc(F)c3)cc2N1
Temperature: 70 °C
Yield: 68.5 %

Procedure:
A mixture of 6-bromo-2,2-dimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.052 g, 0.20 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.085 g, 0.60 mmol), 2 M sodium carbonate (0.30 mL, 0.60 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.033 g, 0.040 mmol) in 1,4-dioxane (2 mL) was degassed with nitrogen and heated at 70° C. for 15 h. Then, the reaction was cooled to room temperature, and concentrated with silica gel (2 mL), and the residue was purified by flash chromatography (silica gel, ethyl acetate to 80:20 ethyl acetate/methanol) to give the title compound (0.038 g, 69%) as a yellow solid:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[OH:24].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O1CCOCC1>[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[O:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(Cl)ccnc2c1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Temperature: 110 °C
Yield: 50 %

Procedure:
To 4-chloro-7-methoxyquinoline (0.900 g, 4.6 mmol), 2-fluoro-4-nitrophenol (2.3 g, 14 mmol), and N,N-dimethylpyridin-4-amine (0.068 g, 0.56 mmol) was added dioxane (10 mL) and pyridine (6.4 ml, 79 mmol). The resulting mixture was heated at 110° C. in an argon-purged sealed tube for 16 hours. An aliquot was analyzed by LCMS and indicated the presence of desired product. The reaction mixture was concentrated in vacuo and diluted with 2 N NaOH. The resulting solid was filtered, and the filtrate was extracted with CH2Cl2. The organic layers were dried over sodium sulfate and filtered through a pad of silica gel along with the solids using 10% MeOH/CH2Cl2 as eluent. The collected fractions were concentrated in vacuo to yield 4-(2-fluoro-4-nitrophenoxy)-7-methoxyquinoline (0.900 g, 2.3 mmol, 49% yield) as a brownish solid. Calcd for C16H11FN2O4: [M]+=314. Found: [M+H]+=315.