Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:37]=[CH:38][CH:39]=1)[CH2:7][N:8]([CH2:16][CH2:17][N:18]1[CH:27]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23](F)[CH:24]=2)[CH2:19]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([O-])=O.[BH4-].[Na+].O>CO.[Ni](Cl)Cl>[NH2:1][C:4]1[CH:5]=[C:6]([CH:37]=[CH:38][CH:39]=1)[CH2:7][N:8]([CH2:16][CH2:17][N:18]1[CH:27]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(CCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1)Cc1cccc([N+](=O)[O-])c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Cc1cccc(N)c1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Under an argon atmosphere, 190 mg of tert-butyl 3-nitrobenzyl[2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl]carbamate was dissolved in 8 mL of methanol, followed by stirring under ice-cooling. 343 mg of nickel chloride.hexahydrate was added thereto, and then 73 mg of sodium borohydride was slowly added thereto. After completion of addition of a reagent, the reaction liquid was warmed to room temperature, followed by stirring for 10 minutes. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 155 mg (yield 87%) of a title compound as a yellow oily substance.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:12]2[N:13]=[CH:14]C=CC=2N=N1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([I:35])=[C:30]([CH:34]=1)[C:31](O)=[O:32].CNC.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([I:35])=[C:30]([CH:34]=1)[C:31]([N:13]([CH3:14])[CH3:12])=[O:32]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Br)ccc1I
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.16 g, 3.06 mmol) was added to a solution of 5-bromo-2-iodo-benzoic acid (1.00 g, 3.06 mmol), dimethyl amine (2 M in THF, 3.06 ml, 3.06 mmol) and di-iso-propyl ethyl amine (1.59 ml, 9.18 mmol) in N,N-Dimethylformamide (12 ml). The reaction was stirred at room temperature overnight. Ethyl acetate was added and the mixture was washed with water, the organic layer was dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography to yield 5-bromo-2-iodo-N,N-dimethyl-benzamide as a white solid. (0.96 g, 90%). MS: m/z 328.1 (M+H+).
Reaction SMILES: CS[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[NH3:17]>ClCC(Cl)(Cl)Cl>[NH2:17][C:3]([N:14]1[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: N
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CN1CCNCC1
Agent: ClCC(Cl)(Cl)Cl
Product: CN1CCN(C(N)=C[N+](=O)[O-])CC1

Procedure:
An amount of 16.5 g of 1,1-bis-(methylthio)-2-nitroethene is dissolved at high temperature in 100 ml of tetrachloroethane, equimolar amounts of methyl-piperazine are added, the mixture is refluxed over 2 hours; the mass is cooled and anhydrous gaseous ammonia is added to it up to saturation.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](OC)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13](=O)=[O:14].C(O)(C)C.C1([Mg]Cl)C=CC=CC=1.[CH:28](=[O:32])[CH:29]([CH3:31])[CH3:30]>O1CCCC1>[CH3:13][O:14][C:2]1[CH:7]=[CH:6][C:5]([CH:28]([OH:32])[CH:29]([CH3:31])[CH3:30])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: COc1ccc(I)cc1[N+](=O)[O-]
Reactant: O=C=O
Reactant: CC(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1ccc(C(O)C(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
To a solution of 4-iodo-2-nitroanisole (2.79 g, 10.00 mmol) in anhydrous tetrahydrofuran (20 mL) cooled at minus 45° C. (dry ice-isopropanol bath) under nitrogen atmosphere, phenylmagnesium chloride (2 M in THF, 6 mL, 6.32 mmol) was added at a rate to keep the temperature at or below minus 40° C. Upon completion of the addition the mixture was stirred for five minutes, then isobutyraldehyde (1.816 mL, 20.00 mmol) was added. The mixture was allowed to gradually warm up to room temperature, then quenched with saturated NH4Cl (5 mL) and poured into water (30 mL)/dichloromethane (100 mL). The organic layer was separated; aqueous layer was extracted three times with dichloromethane (50 mL each). Combined organic extract was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to yield racemic (RS)-1-(4-methoxy-2-nitrophenyl)-2-methyl-1-propanol (1.502 g, 30%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.62 (AB d, 1 H, J=8.8 Hz, Ph-H), 7.34 (d, 1 H, J=2.6 Hz, Ph-H), 7.15 (dd, 1 H, J=2.6 and 8.8 Hz, Ph-H), 4.91 (m, 1 H, Ph-CH), 3.86 (s, 3H, MeO), 2.45 (br s, 1 H, OH), 2.00 (m, 1 H, CHCH, (CH3)2), 0.97 (d, 3 H, J=6.7 Hz, CH3), 0.86 (d, 3 H, J=6.9 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 158.76 (C), 149.07 (C), 130.79 (C), 129.88 (CH), 119.62 (CH), 108.66 (CH), 73.75 (CH), 55.81 (CH3), 34.27 (CH), 19.59 (CH3), 17.36 (CH3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[N:5]([CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26]CC2C=CC=CC=2)=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)CC(OC)OC)[CH3:2].[C:37](OCC)(=[O:39])C.CCCCCC>C(OCC)(=O)C.C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[NH:5][CH:12]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:39][CH3:37])[CH:15]=1)[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1ccccc1)c1ccc(OCc2ccccc2)c(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)NC(Cc1cccc(OC)c1)c1ccc(O)c(OC)c1
Reaction time: 15 h
Yield: 56 %

Procedure:
To a stirred solution of [1-(4-benzyloxy-3-methoxy-phenyl)-2-phenyl-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (10.5 g, 20 mmol) in ethyl acetate (100 mL) and ethanol (50 mL) was added 10% palladium on activated carbon (2 g). The mixture was hydrogenated at 1 atm for 15 hrs. The solution was filtered through a Celite plug and evaporated to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded (2,2-dimethoxy-ethyl)-[1-(4-hydroxy-3-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl-carbamic acid ethyl ester as a colorless oil. (4.87 g, 56% yield)
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2].[I:14]I.S(=O)(=O)(O)O>CC(O)=O>[CH2:1]([C:3]1[CH:12]=[C:11]([CH3:13])[C:10]([I:14])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCc1cc(C)ccc1C(=O)OC
Reactant: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCc1cc(C)c(I)cc1C(=O)OC
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a round-bottom flask was added a solution of methyl 2-ethyl-4-methylbenzoate (compound 48.1, 12.5 g, 70.1 mmol, 1.00 equiv) in AcOH (100 mL). NaIO4 (7.51 g, 35.1 mmol, 0.50 equiv) and I2 (21.4 g, 84.3 mmol, 1.20 equiv) were added in portions at 25° C. Sulfuric acid (1.60 g, 16.3 mmol, 0.20 equiv) was then added to the reaction mixture dropwise at 25° C. The resulting solution was stirred for 12 h at 110° C. in an oil bath, and then cooled to ambient temperature. The reaction was quenched with 150 mL of Na2S2O3 (aq., sat.). The aqueous phase was extracted with 2×200 mL of ethyl acetate. The combined organic layers were washed with 3×300 mL of sodium bicarbonate (aq.) and 1×150 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 20.0 g (94%) of methyl 2-ethyl-5-iodo-4-methylbenzoate as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:10]=[CH:11][C:3]=12.[I-:22].[Na+].[C:24](Cl)(=[O:26])[CH3:25]>C(#N)C>[C:24]([N:9]1[C:4]2=[N:5][CH:6]=[C:7]([F:8])[C:2]([I:22])=[C:3]2[CH:11]=[CH:10]1)(=[O:26])[CH3:25]
Reactant: [I-]
Reactant: CC(=O)Cl
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(F)cnc21
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)n1ccc2c(I)c(F)cnc21
Temperature: 150 °C

Procedure:
A microwave vial was charged with 4-chloro-5-fluoro-1-[tris(1-methylethyl)silyl]-1H-pyrrolo[2,3-b]pyridine (3.06 mmol, prepared as described in Tetrahedron Lett. 2004, 45, 2317-2319), sodium iodide (4.90 mmol), acetyl chloride (6.43 mmol) and dry acetonitrile (8 mL). The reaction tube was sealed, and heated in a microwave reactor at 150° C. for 15 minutes. Upon cooling to room temperature, the resultant precipitate was collected by filtration and washed with a minimal amount of cold acetonitrile. Drying under high vacuum provided the title compound as a yellow powder which was used without further purification. ESMS [M+H]+: 305.2
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.[CH:17](Cl)(Cl)Cl>O1CCOCC1.CO>[Br:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([O:14][CH3:17])=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(CCBr)cc1
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of thionyl chloride (4.8 g) in chloroform (10 ml) was added, dropwise, to a solution of 4-(2-bromoethyl)benzoic acid (5.7 g) in chloroform (40 ml) and anhydrous dioxan (20 ml). When the addition was complete, the mixture was heated under reflux for 2 hours then cooled to room temperature and further thionyl chloride (2.4 g) in chloroform (10 ml) was added. The mixture was heated under reflux for 2 hours then allowed to cool to room temperature and concentrated in vacuo to give an oil which was dissolved in methanol (50 ml) and heated under reflux for 10 minutes. On cooling to room temperature, the mixture was stirred for 48 hours then concentrated in vacuo. The residue was parititoned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate (200 ml), the layers were separated and the organic layer was washed with water (150 ml) then dried (MgSO4) and concentrated in vacuo to give the title compound as an oil, yield, 5.7 g.
Reaction SMILES: [Cl-].C([Al+][CH2:5][CH3:6])C.[CH2:7](Cl)Cl.[CH2:10]([C:14]([OH:26])([CH2:22][CH2:23][CH2:24][CH3:25])[C@@H](OS(C)(=O)=O)C)[CH2:11][CH2:12]C>P(=O)(O)(O)O.C(OCC)(=O)C>[CH3:7][C@@H:10]([CH2:11][CH2:12][CH2:5][CH3:6])[C:14](=[O:26])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCC(O)(CCCC)[C@H](C)OS(C)(=O)=O
Reactant: CC[Al+]CC
Reactant: ClCCl
Agent: O=P(O)(O)O
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: CCCCC(=O)[C@@H](C)CCCC
Temperature: 0 °C
Yield: 90 %

Procedure:
After 0.78 ml (0.78 mmol) of diethylaluminum chloride (hexane 1M solution) were added to a dried methylene chloride (3 ml) solution of 81.8 mg (0.31 mmol) of (S)-3-butyl-2-methanesulfonyloxy-3-heptanol (urefined) at -78° C. under stirring, and stirred for two and a half hours at -78° C., the temperature was raised to 0° C. over an hour and a half. The reaction was stopped with three drops of phosphoric acid buffer solution (pH 7). The resultant suspension was diluted with ethyl acetate, dried with anhydrous sodium sulfate, filtered and concentrated. The oily residue was separated and refined by the use of silica gel column chromatography (hexane/ethyl acetate=35/1) to obtain (S)-6-methyl-5-decanone as a pale yellow oily substance (46.9 mg, yield 90%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11](=[O:13])[CH3:12])[CH:9]=[CH:10][C:2]1=2.Cl.[CH3:15][NH:16][CH3:17].[CH2:18]=O>Cl.C(O)C>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11](=[O:13])[CH2:12][CH2:15][N:16]([CH3:18])[CH3:17])[CH:9]=[CH:10][C:2]1=2
Reactant: CNC
Reactant: CC(=O)c1ccc2c(c1)OCCO2
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone (XV) (11 mmol), dimethylamine hydrochloride (14 mmol), paraformaldehyde (16 mmol) and 12 N HCl (2 drops) in ethanol (5 mL) was refluxed overnight. The solution was cooled to room temperature and the ethanol was evaporated under vacuum. The residue was treated with ethyl acetate, heated slightly and sonicated to disperse into fine particles. The solids were filtered and dried at room temperature to produce 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(dimethylamino)propan-1-one (XVI) as a white solid, (82% yield), 1H NMR (CDCl3, 400 MHz): δ ppm 2.77 (s, 6H), 3.41 (m, 2H), 3.56 (m, 2H), 4.25 (m, 4H), 6.85 (m, 1H), 7.45 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[C:6](=[O:9])([O-])[O-:7].[K+].[K+].S(O[CH:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)(=O)(=O)C>C1COCC1.CCOCC>[CH2:4]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:3][N:2]1[CH:1]([CH:25]([CH3:30])[CH3:26])[C:6]([O:7][CH:17]([C:31]#[N:32])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)=[O:9]
Reactant: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the above acid (1 g, 4.6 mmol) in 12 ml THF is added 8 ml of DMF and potassium carbonate (0.63 g, 5 mmol) followed by α-cyano-m-phenoxybenzyl mesylate (1.31 g, 5 mmol). The reaction mixture is stirred, under nitrogen, at RT for 20 hours. The reaction mixture is then diluted with ether. The organic layer is washed with water and brine, dried and solvent removed under vacuum. The residue is purified by prep. TLC to give α-cyano-m-phenoxybenzyl 2-(2-isoindolinyl)-3-methylbutanoate.
Reaction SMILES: C(C(CCCC)COC(=O)C[CH2:8][S:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]1[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:21][N:22]=[C:15]1[CH:14]=[CH:13]2)C.FC1[N:40]=[C:39]([C:41]2([C:47]#[N:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH:38]=[CH:37][CH:36]=1.CC(C)([O-])C.[K+]>CN(C=O)C.CCOC(C)=O.O>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[N:16]2[C:17]3[C:12]([CH:13]=[CH:14][C:15]2=[N:22][N:21]=1)=[CH:11][C:10]([S:9][C:8]1[N:40]=[C:39]([C:41]2([C:47]#[N:48])[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)[CH:38]=[CH:37][CH:36]=1)=[CH:19][CH:18]=3
Reactant: N#CC1(c2cccc(F)n2)CCOCC1
Reactant: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC1(c2cccc(Sc3ccc4c(ccc5nnc(-c6ccccn6)n54)c3)n2)CCOCC1
Temperature: 80 °C

Procedure:
5m (93 mg, 0.2 mmol) and 4-(6-Fluoro-pyridin-2-yl)-tetrahydro-pyran-4-carbonitrile (5n, 41 mg, 0.2 mmol) were dissolved in DMF (2 mL) and degassed with N2. Potassium tert-butoxide (22 mg, 0.2 mmol) was added, and the reaction was sealed and heated to 80° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc and water, and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to obtain the desired product, 5p.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH2:9][CH:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCC[N:23]([CH3:25])C.C1C=CC2N(O)N=NC=2C=1.CN1CC[O:40][CH2:39]C1>C(Cl)Cl>[CH3:39][O:40][CH2:25][NH:23][C:12]([CH:10]1[CH2:9][S:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11]1)=[O:14]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C1CSC(c2ccccc2)=N1
Reactant: CN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCNC(=O)C1CSC(c2ccccc2)=N1
Reaction time: 0.17 h

Procedure:
A mixture of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (5 mmol), EDCI (6 mmol) and HOBt (5 mmol) in CH2Cl2 (50 mL) was stirred for 10 min. To this solution, NMM (5 mmol) and HNCH3OCH3 (5 mmol) were added and stirring continued at RT for 6-8 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to get 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide. A solution of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide (1 equiv) in CH2Cl2 was cooled to 0° C., and distilled DBU (2 equiv) was added. Bromotrichloromethane (1.7 equiv) was then introduced dropwise via syringe over 10 min. The reaction mixtures were allowed to warm to RT and stirred overnight. Upon washing with satd. aqueous NH4Cl (2×50 mL), the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography as needed providing 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (73.6%). 1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 7.99-7.96 (m, 2H), 7.47-7.44 (m, 3H), 3.88 (s, 3H), 3.49 (s, 3H). MS (ESI) m/z 271.0 (M+Na)+. To a solution of 3,4,5-trimethoxyphenylmagnesium bromide (0.5 N, 3 mL) in 2 mL THF was charged a solution of 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (1 mmol) in 3 mL THF at 0° C. The mixtures were stirred for 30 min until amides disappeared on TLC plates. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1h. Yield: 27.3%. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.03 (q, 2H), 7.80 (s, 2H), 7.49-7.47 (m, 3H), 3.96 (s, 6H), 3.97 (s, 3H). MS (ESI) m/z 378.1 (M+Na)+.
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[C:7]([Cl:13])[CH:6]=1>O.CS(C)=O>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:1]#[N:2])=[C:7]([Cl:13])[CH:6]=1
Reactant: [C-]#N
Reactant: Clc1cc(Br)ccc1CBr
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(Br)cc1Cl
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Potassium cyanide (587 g) was dissolved in a mixed solution of water (1408 mL) and dimethyl sulfoxide (767 g), and a solution of 4-bromo-2-chlorobenzyl bromide (512 g) of Reference Example 13 in dimethylsulfoxide (1663 g) was added dropwise at an inside temperature of 90° C. After stirring at the same temperature for 1 hr, the reaction mixture was poured into water. After partitioning and extraction with ethyl acetate, the organic layer was washed 4 times with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (383 g) as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH3:36])=[O:32])=[CH:19][C:20]=3[C:21]3[S:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:25]=3)=[CH:12][CH:13]=2)[C:8](=[O:37])[C:7]([C:38]([OH:40])=O)=[CH:6]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:75][N:76]([CH3:86])[S:77]([N:80]1[CH2:85][CH2:84][NH:83][CH2:82][CH2:81]1)(=[O:79])=[O:78]>CN(C)C=O>[CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]3[CH:16]=[N:17][C:18]([NH:30][C:31]([NH:33][CH2:34][CH2:35][CH3:36])=[O:32])=[CH:19][C:20]=3[C:21]3[S:22][CH:23]=[C:24]([C:26]([F:28])([F:27])[F:29])[N:25]=3)=[CH:12][CH:13]=2)[C:8](=[O:37])[C:7]([C:38]([N:83]2[CH2:82][CH2:81][N:80]([S:77]([N:76]([CH3:86])[CH3:75])(=[O:79])=[O:78])[CH2:85][CH2:84]2)=[O:40])=[CH:6]1
Reactant: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CCN(C)C)cn1
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCN(S(=O)(=O)N(C)C)CC2)cn3CCN(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-(dimethylamino)ethyl)-4-oxo-6-(6-(3-propylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylic acid (Example 153, 80 mg, 0.14 mmol) in dimethylformamide (0.5 mL) was added HATU (78.4 mg, 0.20 mmol) then diisopropylethylamine (95.2 uL, 0.55 mmol). This was followed by N,N-dimethylpiperazine-1-sulfonamide (52.7 mg, 0.27 mmol) and the reaction was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue purified by prep HPLC (Water-methanol-0.1% Formic acid).
Reaction SMILES: Cl.C(O[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:8])(C)(C)C.[NH:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1C(O)=O.[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C.C(N(CC)CC)C>[CH2:19]([O:18][C:16]([CH2:15][CH:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:9]1[C:7]([C@@H:29]1[CH2:28][CH2:27][CH2:23][N:22]1[C:38]([NH:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:39])=[O:8])[OH:21])=[O:17])[CH3:20]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C=NCc1ccccc1
Reactant: CCOC(=O)CC(O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
4N Hydrochloric acid (1,4-dioxane solution, 50 ml) was added to (S)-1-(tert-butoxycarbonyl)-2-[2-(ethoxycarbonyl)-1-hydroxyethyl]pyrrolidine (5.73 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness and the residue was reacted with N-(benzylamincarbonyl)-L-proline obtained by stirring L-proline (1.15 g), benzyl isocyanate (1.13 g) and triethylamine (1.01 g) in DMF (10 ml), at room temperature for 1 hour, in the same manner as in Example 3-a), to give the title compound (3.36 g).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([OH:21])=[O:20])[CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: O=C(O)c1cccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)c1
Yield: 96.1 %

Procedure:
3-nitrophthalic anhydride (0.79 g, 0.0041 mol) and m-aminobenzoic acid (0.56 g, 0.0041 mol) were refluxed as above overnight. Concentration of the solution under vacuum by rotary evaporator and crystallisation of the product from EtOH/H2O yielded 1.23 g (76%) of 126 as a vibrant yellow powder: mp=354–355° C.; Rf 0.77 (A): Rf 0.84 (C): Rf 0.54 (D): IR (cm−1): 2740–3100 (OH), 3088 (C═CH), 2665 (C—H), 1776 (C═O), 1725 (bs, C═O), 1614 (C═C), 1542 (N═O), 1460 (C═C), 1420 (C═C), 1382 (C—O), 1356 (N═O), 1120 (C—O), 717 (C═CH); MS m/z (rel intensity) 311 (100), 267 (65), 191 (60).