Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5](=O)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]=[CH2:15])[C:9]([Br:16])=[C:8]([O:17][CH2:18][CH:19]=[CH2:20])[CH:7]=1)C=C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[CH2:18]([O:17][C:8]1[CH:7]=[C:6]([CH2:5][OH:4])[CH:11]=[C:10]([O:12][CH2:13][CH:14]=[CH2:15])[C:9]=1[Br:16])[CH:19]=[CH2:20]
Reactant: C=CCOC(=O)c1cc(OCC=C)c(Br)c(OCC=C)c1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C=CCOc1cc(CO)cc(OCC=C)c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To a solution of 16 (30 g, 85 mmol) in THF (600 ml) at 0° C. was added lithium aluminum hydride (1.0M in THF, 175 mL, 2 equiv) dropwise over 45 minutes. The reaction was stirred at 0° C. for 2 hours, after which time saturated aqueous potassium sodium tartrate was added dropwise until bubbling ceased (25 mL, over 45 minutes). To the suspension was added ether (100 mL) and additional saturated aqueous potassium sodium tartrate (30 mL). The suspension was filtered through celite, the THF and ether were removed under reduced pressure, and water (250 mL) was added. The aqueous suspension was extracted into EtOAc (4×250 mL). The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (20→75% EtOAc/hexane) afforded 17 (11.93 g, 47%) as a white oil. Rf=0.39 (50% EtOAc/hexane); FTIR (neat, cm−1) 3363, 2924, 2869, 1587, 1435, 817; 1H NMR (400 MHz, CDCl3) δ, 6.56 (s, 2H), 6.10-6.00 (m, 2H), 5.48 (dd, J=17.4, 1.6 Hz, 2H), 5.29 (dd, J=10.6, 1.6 Hz, 2H), 4.62 (s, 2H), 4.60 (d, J=5.2 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ156.2, 141.4, 132.6, 117.6, 104.5, 100.9, 69.8, 65.0; MS EI+ calculated for C13H15BrO3 (M−H)+: 298, found: 298.
Reaction SMILES: C([NH:4][C:5]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[C:7]([Cl:13])[CH:6]=1)(=O)C.[OH-].[Na+]>C(O)(=O)C.Cl.O>[Br:11][C:10]1[CH:9]=[C:8]([CH3:12])[C:7]([Cl:13])=[CH:6][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1cc(Cl)c(C)cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Br)c(N)cc1Cl
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A solution of 4-acetamido-5-bromo-2-chlorotoluene (64 g, 0.245 mol) in glacial acetic acid (48 ml) and concentrated hydrochloric acid (96 ml) was heated at 118° C. for 24 h. The reaction mixture was allowed to cool to room temperature, diluted with water (200 ml), cooled in an ice-bath and the pH was. adjusted to 5 with a aqueous solution of NaOH (50% w/v). The precipitate was collected by filtration washed with water, and dried in vacuo over P2O5 to afford a white solid (50.7 g, 94%), mp 90° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:30][CH2:31][O:32][CH2:33][CH:34]=3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1.O[C:37]1[CH:41]=[CH:40][O:39][N:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:39]1[CH:40]=[CH:41][C:37]([O:15][CH2:16][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH2:30][CH2:31][O:32][CH2:33][CH:34]=4)=[C:25]([F:35])[CH:24]=3)[CH2:18]2)=[N:38]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(C2=CCOCC2)c(F)c1
Reactant: Oc1ccon1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(C2=CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
Diisopropylazodicarboxylate (248 mg, 1.22 mmol) was added dropwise, at ambient temperature, to a stirred solution of 5(R)-hydroxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one (International Patent Application Publication WO 97/09328) (300 mg, 1.02 mmol), 3-hydroxyisoxazole (104 mg, 1.22 mmol) and triphenylphosphine (340 mg, 1.30 mmol) in THF (8.0 ml). The resulting solution was stirred at ambient temperature for 30 minutes before evaporating the solvent to give an oil which was purified by flash chromatography (Merck 9385 silica, EtOAc/iso-hexane (7:3) eluant) to give the title product (219 mg, 59%) as a crystalline solid.
Reaction SMILES: C.[N+:2]([C:5]1[CH:10]=[C:9]([O:11]CC2C=CC=CC=2)[C:8]([O:19]CC2C=CC=CC=2)=[CH:7][C:6]=1[CH2:27][C:28]#[N:29])([O-:4])=[O:3].C1CCCCC=1>[Pd].C(O)C>[N+:2]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([OH:19])=[CH:7][C:6]=1[CH2:27][C:28]#[N:29])([O-:4])=[O:3]
Reactant: N#CCc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: N#CCc1cc(O)c(O)cc1[N+](=O)[O-]

Procedure:
0.75 g of palladium at a concentration of 10% on charcoal, to which 3 g of charcoal have been added, followed by 0.02 mole (7.5 g) of 2-nitro-4,5-dibenzyloxyphenylacetonitrile, are added with stirring to 30 ml of 96° C. ethanol containing 15 ml of cyclohexene; the reaction mixture is heated under reflux for 1 hour.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].[H-].[Na+].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][CH:13]=1>CN(C=O)C>[O:7]=[C:2]1[CH2:3][CH2:4][C:5](=[O:6])[N:1]1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([B:18]([OH:20])[OH:19])=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1
Reactant: OB(O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1Cc1ccc(B(O)O)cc1
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a solution (10 mL) of pyrrolidine-2,5-dione (500 mg) in DMF was added sodium hydride (60% dispersion in mineral oil, 252 mg) at 0° C., and the mixture was stirred for 1 hr. (4-(Bromomethyl)phenyl)boronic acid (903 mg) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and crystallized from ethyl acetate and diisopropyl ether to give the title compound (520 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:10][CH:9]=2)=[NH:8])=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(NC(=N)c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethylbenzonitrile (0.62 g, 3.6 mmol) and 4-methylthioaniline (0.5 g, 3.6 mmol) by following the procedure described in preparation 1, (0.495 g, 44.4%, purity 98.3% by HPLC), mp 144-146° C. 1H-NMR (CDCl3):δ 2.49 (s, 3H), 4.8 (bs, 2H), 6.93-6.95 (d, 2H), 7.26-7.32 (m, 2H), 7.70-7.72 (d, 2H), 7.99-8.01 (d, 2H). MS m/z:311.1(M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.[Cl:37][C:38]1[CH:39]=[C:40](I)[CH:41]=[CH:42][C:43]=1[Cl:44]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:41]2[CH:40]=[CH:39][C:38]([Cl:37])=[C:43]([Cl:44])[CH:42]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: Clc1ccc(I)cc1Cl
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)c(Cl)c2)cc1[N+](=O)[O-]

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1), bis(pinacolato)diboron and 3,4-dichloro-iodobenzene according to the general procedure C. Obtained as a yellow solid (540 mg).
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@H:17]([OH:19])[CH3:18])[C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[F:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1.CN(C=O)C>[C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@H:17]([OH:19])[CH3:18])[C:14]([NH:28][NH:27][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:30][CH:29]=2)=[O:16])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)O
Reactant: NNC(=O)c1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (intermediate 61a) (0.56 g, 2.02 mmol), 4-fluorobenzoic hydrazide (316 mg, 2.05 mmol), HOBt (277 mg, 2.05 mmol) in THF:DMF (1:1) (30 mL) was added EDC (583 mg, 3.04 mmol) and Et3N (0.43 mL, 3.08 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min., then at room temperature overnight. The reaction was quenched by adding water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent and purification of the residue gave two fractions. The first fraction (282 mg) contained mainly the title compound and some impurities. The second fraction was the pure desired compound N′-((2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)-4-fluorobenzohydrazide (0.42 g, 50%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.01 (dd, J=5.3, 8.8 Hz, 2H), 7.81 (d, J=5.7 Hz, 1H), 7.68 (d, J=5.7 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.25 (t, J=8.8 Hz, 2H), 6.68 (d, J=8.2 Hz, 1H), 6.39 (d, J=7.4 Hz, 1H), 4.19˜4.26 (m, 2H), 1.39 (d, J=6.2 Hz, 3H).
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][NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[O:15])=[N:2]1>FC(F)(F)C(O)=O.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:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[O:15])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)NCCNc2nsc3ccccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCNc1nsc2ccccc12)C1CCCNC1
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of tert-butyl 3-(2-(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)piperidine-1-carboxylate (360 mg, 0.89 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (2 mL) was cooled to 0° C. and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure and lyophilized to yield N-(2-(benzo[d]isothiazol-3-ylamino)ethyl)piperidine-3-carboxamide as a yellow oil (265 mg). MW=304 confirmed by LC-MS, tr=2.39 min (Method B) MH+=305.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=2)[CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)#[CH:18]>>[Cl:25][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[C:9]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[N:10]=3)[CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Brc1cnc2nc(N3CCOCC3)nn2c1
Reactant: C#Cc1cccc(Cl)c1
Product: Clc1cccc(C#Cc2cnc3nc(N4CCOCC4)nn3c2)c1

Procedure:
The title compound, a light brown solid, MS: m/e=340.0/342.1 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47, step 1) and ethynyl-3-chlorobenzene.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:14]([N:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH:15]([CH3:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>O1CCOCC1>[C:1]([NH:5][C:6](=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([N:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH:15]([CH3:17])[CH3:16])[CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(c1cccc(C(=O)NC(C)(C)C)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C(c1cccc(C(=O)NC(C)(C)C)c1)N1CCNCC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A mixture of tert-butyl 4-(1-(3-(tert-butylcarbamoyl)phenyl)-2-methylpropyl)piperazine-1-carboxylate (24 mg, 0,057 mmol) and 5M hydrochloric acid (0.20 mL) in 1,4-dioxane (2.0 mL) was stirred at 80° C. for 30 minutes. The reaction mixture was concentrated under vacuum and treated with strong cation exchange column chromatography to afford the title compound (13.6 mg).
Reaction SMILES: C(OP([CH:9]1[S:14][CH2:13][CH2:12][CH2:11][S:10]1)(OCC)=O)C.CCCCCC.C([Li])CCC.[CH:26]1[CH:31]=[CH:30][C:29]([C:32]([CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=O)=[CH:28][CH:27]=1.[Cl-].[Na+]>O1CCCC1>[O:36]([C:35]1[CH:27]=[CH:28][C:29]([C:30](=[C:9]2[S:10][CH2:11][CH2:12][CH2:13][S:14]2)[CH2:31][CH3:26])=[CH:32][CH:34]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCOP(=O)(OCC)C1SCCCS1
Reactant: O=C(CCOc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(=C1SCCCS1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
2-Diethoxyphosphoryl-1,3-dithiane, 4.18 g, was dissolved in 40 ml of tetrahydrofuran and 10.5 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow at -65° C. The mixture was stirred at the same temperature for an hour. Then, a solution of 36.2 g of 4-phenoxypropiophenone in 15 ml of tetrahydrofuran was dropwise added to the mixture at the same temperature. The reaction mixture was gradually warmed to room temperature overnight. This suspension was poured onto saturated sodium chloride aqueous solution followed by extraction with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform : hexane =1 : 1) to give 4.15 g of the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([OH:17])=O)[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2].CN(C=O)C.OCl.C(Cl)(=O)C([Cl:28])=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]([CH2:14][C:15]([Cl:28])=[O:17])[CH2:7][CH2:8][C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N(CCc1cccs1)CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: OCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)N(CCc1cccs1)CC(=O)Cl

Procedure:
2-(N-(Ethoxycarbonyl)-N-(2-(thiophen-2-yl)ethyl)amino)acetic acid (14 g, 54.41 mmol) was dissolved in dry dichloromethane (DCM) (300 mL). To this suspension was added 0.1 mL of DMF, followed by the careful addition of oxyl chloride (10.4 g, 81.93 mmol). The reaction mixture was stirred at room temperature for 1 hour, at which time 0.5 mL of additional oxalyl chloride was added. The solvent was evaporated under vacuum to give 2-(N-(ethoxycarbonyl)-N-(2-(thiophen-2-yl)ethyl)amino)acetyl chloride. This acid chloride was re-dissolved in dry DCM (300 mL) and AlCl3 (18.1 g, 135.74 mmol) was added at room temperature. The reaction was kept at room temperature for 1 hour then quenched by the slow addition of ethanol (about 10 mL). The mixture was then poured into ice and stirred for 1 hr. The aqueous mixture was extracted with DCM (3×150 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated to give a residue, which was purified by silica gel chromatography to produce ethyl 4,5,7,8-tetrahydro-4-oxothieno[3,2-d]azepine-6-carboxylate (7.4 g, 30.92 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[OH-].[NH4+:17]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH2:17])=[O:11])[CH2:7]1
Reactant: [NH4+]
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 48 h
Yield: 68.2 %

Procedure:
A solution of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was stirred at ambient temperature while 4 ml (0.06 mole) of 57% ammonium hydroxide was slowly added. After stirring for 48 hr, the reaction mixture was diluted with 100 ml of water and the resulting solid collected by filtration (5 g). Recrystallization from isopropanol yielded 3.7 g (59%) of fine beige crystals, m.p. 188°-189° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])=[O:2].S(Cl)([Cl:14])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 3-formylbenzoic acid (84 grams (g), 0.558 moles), thionyl chloride (80.5 g, 0.71 moles), and dimethylformamide (3 milliliters (ml)), in toluene (500 ml) was slowly warmed to 70° C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 97.7 g of 3-formylbenzoyl used in the next step as such.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[S:20][CH:19]=[N:18][CH:17]=1>>[S:20]1[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=2)=[CH:17][N:18]=[CH:19]1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Brc1cncs1
Product: O=C(O)CCc1ccc(C#Cc2cncs2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.50 mmol) and 5-bromothiazole (50 μL, 0.56 mmol) according to the general procedure IF. After concentration the residue was hydrolyzed according to the general procedure II to give 28 mg (21%) of a white solid after purification by flash chromatography (SiO2, EtOAc [with 1.25% AcOH]:PE, 1:2): Rf=0.12 ([EtOAc with 1.25% AcOH]:PE, 1:2); 1H NMR (DMSO-d6) δ 12.14 (s, 1H), 9.16 (d, J=0.6 Hz, 1H), 8.20 (d, J=0.6 Hz, 1H), 7.49 (d, J=8.2 Hz, 3H), 7.31 (d, J=8.3 Hz, 3H), 2.86 (t, J=7.5 Hz, 3H), 2.56 (t, J=7.6 Hz, 3H); 13C NMR (DMSO-d6) δ 173.5, 155.7, 147.2, 142.6, 131.2, 128.7, 118.8, 118.0, 96.0, 78.4, 34.6, 30.1; ESI-MS calcd for C14H11NO2S (M+Na+) 280.0403. found 280.0400.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29](=[O:42])(=[O:41])[NH:30]C(OCC3C=CC=CC=3)=O)=[CH:27][C:21]=2[S:20](=[O:44])(=[O:43])[N:19]=1>CO.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([NH2:30])(=[O:42])=[O:41])=[CH:27][C:21]=2[S:20](=[O:43])(=[O:44])[N:19]=1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)c(O)c2cccnc21
Agent: [Pd]
Solvent: CO
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(N)(=O)=O)ccc3N2)c(O)c2cccnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
A solution of the product of Example 436 (40 mg, 0.0625 mmol) in methanol (5 mL) was treated with 10% palladium on carbon (20 mg), and stirred at 25° C. for 5 hours under hydrogen atmosphere. The resulting solution was then filtered and the filtrate concentrated under reduced pressure to provide the title compound (25 mg, 78%). MS (ESI−) m/z 505 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98 (d, J=6.3 Hz, 6H), 1.57 (m, 2H), 1.66 (m, 1H), 4.42 (m, 2H), 7.38 (m, 1H), 7.43 (m, 2H), 7.59 (m, 1H), 8.52 (m, 1H), 8.82 (bs, 1H), 9.99 (bs, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].CC1(C)C(C)(C)OB([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)O1>>[NH2:35][C:34]1[CH:36]=[CH:37][C:31]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)c(F)cn2c1=O
Yield: 93.9 %

Procedure:
Ethyl 8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.54 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (439 mg, 2.00 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (550 mg, 93%).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].CO.Cl[CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:13][C:12]2[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:11]1=2>CN(C)C=O.O>[CH3:2][O:4][CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:13][C:12]2[CH:21]=[CH:22][C:23]([C:25]([O:27][CH3:28])=[O:26])=[CH:24][C:11]1=2
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc2c(c1)C(Cl)c1ccccc1CO2
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)C(OC)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Mix 0.415 gm of potassium tert-butoxide, 5 ml of methanol and 5 ml of dimethylformamide and add the mixture to a solution of 1.07 gm of methyl 6,11-dihydro-11-chlorodibenz[b,e]oxepin-2-carboxylate in 40 ml of dimethylformamide. Stir at room temperature for 3 days. Dilute with water and extract with ether. Evaporate to dryness and chromatograph over silica gel with benzene as the eluting solvent to obtain the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:15][CH2:14][C:13](=[O:16])[NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH2:22][CH3:23])CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:12]1[C:13](=[O:16])[CH2:14][CH2:15][CH:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:10])[CH2:2][CH2:3][CH:22]=[CH2:23]
Reactant: CCN(CC)CC
Reactant: O=C1CCC(C(=O)OCc2ccccc2)N1
Solvent: ClCCl
Product: C=CCCCOC(=O)N1C(=O)CCC1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
At 0° C., to a stirring solution of 5.5 g of 5-Oxo-pyrrolidine-2-carboxylic acid benzyl ester (25 mmol), 4 mL of triethylamine, 3.3 g of N,N-dimethylaminopyridine (27 mmol) in 40 mL of dichloromethane, was added 4.1 g of 4-pentenyl-1-yl chloroformate (27.6 mmol). The reaction mixture was then warmed to rt, and stirred over weekend. After concentration, the resulting residue was dissolved in ethyl ether 120 mL, washed with 30 mL of 1.0 N aq. HCl, brine subsequently, dried over anhydrous sodium sulfate. The organic solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography on silica gel using heptane/EtOAc (v/v 1/1), giving 7.3 g of colorless oil as intermediate 17-2 (88%). LC-MS: m/z=331.2 (ES+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N[CH2:11][C:12]1[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:14]([CH3:25])[CH:13]=1)CCC>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:11][C:12]1[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:14]([CH3:25])[CH:13]=1
Reactant: COCCN
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Product: CCOC(=O)COc1ccc(CNCCOC)cc1C

Procedure:
Prepared using 2-methoxyethylamine (1.4 mL, 16.2 mmol) and the synthetic procedure described for Intermediate 7. Purification of the crude product by SCX SPE (5×10 g) loading and washing with EtOH and then eluting product with 5% NH3 in EtOH, and removal of the solvent in vacuo yielded the title compound as a brown oil (1.8 g).