Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2I)[C:12](=[O:21])[C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:5]=1.[Br-].[CH3:31][CH:32]([CH3:36])[CH2:33][CH2:34][Zn+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)/[C:13](=[C:14](/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)\[CH2:34][CH2:33][CH:32]([CH3:36])[CH3:31])/[C:12]2=[O:21])[CH:5]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2I)c1
Reactant: CC(C)CC[Zn+]
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/CCC(C)C)c3ccccc3)c3ccccc32)c1
Temperature: 40 °C
Reaction time: 6 h
Yield: 27.3 %

Procedure:
To a degassed refluxing solution of 3-{[(2-iodo-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester (100 mg, 0.2 mmol) and Ni(PPh3)2I2 (16 mg, 0.02 mmol) in CH2Cl2 (8 ml) was added 3-methylbutylzinc bromide (151 mg, 0.7 mmol) in CH2Cl2 (1 ml). The reaction was stirred at 40° C. for 6 h and then the solution was cooled to room temperature. The resultant solution was diluted with ethyl acetate (50 ml). The organic layer was washed with aqueous HCl solution (4%, 10 ml), brine (3×10 ml). The aqueous layer was back-extracted with ethyl acetate (3×10 ml). The combined organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with petrol ether-ethyl acetate, to give 3-{3-[4-methyl-1-phenyl-pent-(Z)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester (24 mg, 28%) as light yellow solid. 1H NMR (300 Hz, CDCl3): δppm 0.88 (d, 6H), 1.43-1.55 (m, 2H), 1.68-1.72 (m, 1H), 2.93-2.99 (m, 2H), 3.91 (s, 3H), 4.89 (s, 2H), 6.64 (d, 1H), 7.05 (t, 1H), 7.15 (t, 1H), 7.28-7.38 (m, 4H), 7.40-7.47 (m, 3H), 7.62 (d, 1H), 7.91 (d, 1H), 7.95 (s, 1H); and 3-{3-[4-methyl-1-phenyl-pent-(E)-ylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid methyl ester (29 mg, 33%) as light yellow solid. 1H NMR (300 Hz, CDCl3): δ ppm 0.88 (d, 6H), 1.36-1.44 (m, 2H), 1.64-1.68 (m, 1H), 3.33-3.38 (m, 2H), 3.91 (s, 3H), 5.04 (s, 2H), 6.01 (d, 1H), 6.58-6.61 (m, 2H), 6.96-7.02 (t, 1H), 7.26-7.29 (m, 2H), 7.37 (t, 2H), 7.43-7.52 (m, 3H), 7.93 (d, 1H), 8.03 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@@:13]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]3=[O:27])[CH3:9])=[CH:6][CH:7]=2)=[CH:31][CH:30]=1
Reactant: Nc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc(N)nc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (520 mg, 1.2 mmol) and 6-aminopyridin-3-ylboronic acid (280 mg, 1.44 mmol), Pd(Ph3P)2Cl2 (100 mg), and aq Cs2CO3 solution (3 mL, 2M) in 1,4-dioxane (20 mL) was stirred and heated to reflux for 2 h. The organic phase was separated, and concentrated to give crude product, which was purified by preparative TLC to give (R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxy propyl)-1,3-oxazinan-2-one. (400 mg, 74%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22](O)[CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH:28]=[CH:29][CH2:30][CH3:31].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[Br:20][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31]
Reactant: CCC=CCC=CCCCO
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CC/C=C\C/C=C\CCCBr
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 32 %

Procedure:
A solution of triphenylphosphine (20.9 g, 80 mmol) in CH2Cl2 (100 ml) was treated with Br2 (7.8 g, 49 mmol) in CH2Cl2 (15 mL, 0° C.) and the mixture was stirred at room temperature for 20 min. Into the slightly yellow suspension that formed, the crude mixture of 4 and 4Z,7Z)-4,7-decadien-1-ol (12.4 g) in CH2Cl2 (15 ml) was added dropwise. After stirring for 1 hour, a solution of saturated NaHCO3 (50 mL) and water (50 ml) were added. The mixture was extracted with pentane and combined extracts were stored overnight in a freezer. In this way, triphenylphosphine oxide could be crystallized and removed by filtration. Column chromatography followed by distillation at reduced pressure afforded 5 (3.48 g, 32% yield based on 1 of b.p. =80°-85° C./2.5 torr. 1H NMR (200 MHz) δ: 5.37 (m, 4H, CH=CH), 3.41 (t, J=6.6, 6.6 Hz, 2H, CH2 --Br), 2.80 (dd, J=6.4, 6.5 Hz, 2H, =CH--CH2 --CH=), 2.21 (dt, J=7.0, 6.9, 6.8, 6.9 Hz, 2H, CH2 -3), 2.07 (dq, J=7.4 Hz, CH2 -9), 1.91 (tt, J=6.7, 6.6, 7.0, 7.0, 2H, CH2 -2), 0.97 (t, J=7.5, 7.5 Hz, 3H, CH3). 13C NMR (100.6 MHz) δ: 132.1 (8), 129.8 (5), 127.6 (7), 127.0 (4), 33.4 (1), 32.5 (2), 25.6 (3), 25.5 (6), 20.6 (9), 14.3 (10). MS [EI, m/z (%)] 218 (M+, 15), 216 (17), 137 (6), 109 (13), 107 (18), 96 (14), 95 (78), 82 (18), 81 (74), 79 (22), 68 (27), 67 (100), 55 (17), 53 (15), 42 (11), 41 (38), 40 (40).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)[N:3]=1.C(OC([N:30]1[C:34]([CH3:35])=[CH:33][C:32]([NH2:36])=[N:31]1)=O)(C)(C)C.CC(O)=O>CC(N(C)C)=O>[Br:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[N:3]=[C:2]2[NH:36][C:32]1[CH:33]=[C:34]([CH3:35])[NH:30][N:31]=1
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(Br)c3n2)nc1
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(Br)cccc23)n[nH]1
Temperature: 100 °C
Yield: 21.8 %

Procedure:
To 4-chloro-2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-bromo-quinazoline (0.19 g, 0.49 mmol) in DMA (1.0 mL) were added 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.30 g, 1.53 mmol) and HOAc (0.065 mL, 1.1 mmol) and the mixture was heated to 100° C. for 5 h. The mixture was allowed to cool to rt and purified by reverse phase HPLC (ammonium acetate modifier). Fraction 1 containing pure product was treated with saturated aq NaHCO3 (2-4 mL) and concentrated under reduced pressure. The aqueous residue was extracted with DCM (3×30 mL) and the combined extracts were washed with sat aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to afford 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (48 mg, 20%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.22 (br s, 1H), 10.87 (br s, 1H), 8.57-8.81 (m, 2H), 8.24 (d, J=7.5 Hz, 1H), 8.02 (d, J=5.3 Hz, 2H), 7.54 (t, J=7.9 Hz, 1H), 5.95 (s, 1H), 2.17 (s, 3H); LC-MS (ESI) m/z 449/451 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([CH2:12][N:13]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH:23](OCC)[O:24]CC)[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([C:8]2[CH:31]=[CH:30][C:11]([CH2:12][N:13]3[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16]([CH:23]=[O:24])[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C(OCC)OCC)ncn1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c(C=O)ncn1Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
In 20% aqeuous acetic acid (10 ml) was dissolved ethyl 1-[4-(4-chlorobenzoyl)benzyl]-4-(diethoxymethyl)-imidazole-5-carboxylate (1.20 g) and the mixture was stirred at room temperature for 8 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed serially with water, saturated aqueous NaHCO3 solution, and water, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (671 mg; yield 67%). 1H-NMR (CDCl3) δ: 1.38(3H,t,J=7.OHz), 4.41(2H,q,J=7.OHz), 5.66(2H,s), 7.26(2H,d,J=8.8Hz), 7.46(2H,d,J=8.8Hz), 7.70-7.79(5H,m), 10.42(1H,s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12].[Cl:13][CH2:14][C:15](O)=[O:16].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[Cl:13][CH2:14][C:15]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12])=[O:16]
Reactant: CC1=C(C)C(=O)N(CCO)C1=O
Reactant: O=C(O)CCl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(C)C(=O)N(CCOC(=O)CCl)C1=O
Yield: 83.9 %

Procedure:
With stirring, 169.2 g (1 mole) of N-(2-hydroxyethyl)dimethylmaleimide, 113.4 g (1.2 moles) of chloroacetic acid and 11.8 g of concentrated sulfuric acid are heated to reflux in 1000 ml of toluene using a water separator. The formation of water ceases after about 2 hours and 18 ml have separated. The reaction solution is washed with saturated sodium bicarbonate solution and water. The organic phase is dried over magnesium sulfate and concentrated in a rotary evaporator at 40° C. The residue is dried for 2 hours at 60° C./0.1 mm, affording 206 g of a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:3]=1[C:4]([NH:6][C:7](=[O:25])[NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[O:5].O.[OH-].[Li+].Cl>C1COCC1>[Cl:1][C:2]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:3]=1[C:4]([NH:6][C:7](=[O:25])[NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])=[O:5]
Reactant: COC(=O)C=Cc1cc(C(=O)OC)ccc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=Cc1cc(C(=O)O)ccc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reaction time: 2 h
Yield: 9.1 %

Procedure:
0.22 g (0.5 mmol) of methyl 4-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-3-(2-methoxycarbonylvinyl)benzoate (example 11 c) were dissolved in 10 ml of THF, after which 10 ml of H2O and 0.06 g (2.4 mmol) of lithium hydroxide were added. After 2 hours, the mixture was made acid with 2 N hydrochloric acid; this was then followed by extraction with ethyl acetate and concentration. Following preparative HPLC (column: Waters Xterra ™MS C18, 5 μm, 30×100 mm, mobile phase: A: H2O+0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17.5 minutes 10% A/90% B), 0.02 g (10%) of the desired product was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=O)=[CH:4][CH:3]=1.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][NH2:19])[CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(Cl)cc1)c1ccccc1
Reactant: NN
Solvent: CCO
Product: NN=C(c1ccc(Cl)cc1)C(O)c1ccccc1
Yield: 62.8 %

Procedure:
To a solution of 3.5 g 4-chlorobenzil in 15 ml ethanol is added 0.45 g anhydrous hydrazine. The solution is refluxed for 1 hour, filtered and water added to the cloud point, and allowed to crystallize yielding 2.3 g of 4-chlorobenzoin hydrazone.
Reaction SMILES: C(O)(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=O.[C:13]([O:16][C:17](=[O:19])[CH3:18])(=[O:15])[CH3:14]>>[CH2:4]([O:6][C:9]1[CH:10]=[CH:2][C:3]([CH3:4])=[C:14]2[C:13]([O:16][C:17](=[O:19])[C:18]=12)=[O:15])[C:3]1[CH:2]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccccc1C(=O)O
Product: Cc1ccc(OCc2ccccc2)c2c1C(=O)OC2=O

Procedure:
The crude phthalic acid prepared above is heated in 150 ml acetic anhydride for two hours. The solvent is removed under reduced pressure and the crystalline residue collected and washed with ether. The anhydride may be recrystallized from nitromethane to give an analytical sample m.p. 200°-203° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[F:31])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[F:31][C:22]1[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][NH:18][C:12]1[N:13]=[C:14]([O:16][CH3:17])[N:15]=[C:10]([C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:39](=[O:41])[CH3:40])[CH:9]=[CH:8][CH:7]=2)[CH:11]=1
Reactant: CC(=O)Cl
Reactant: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CCN)c2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CCNC(C)=O)c2)n1
Reaction time: 0.17 h

Procedure:
A solution of {6-[3-(2-amino-ethyl)-phenyl]-2-methoxy-pyrimidin-4-yl}-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine [150 mg, 0.35 mmol, see Example 64, step 2] and triethylamine (0.24 mL, 1.73 mmol) in DCM (5 mL) is treated with acetyl chloride (54 mg, 0.69 mmol) at 10° C. After 10 min at 10° C., the mixture is quenched with aqueous NaHCO3 solution (8 mL), and filtered through Chem-Elut with CH2Cl2 washing (10 mL). The filtrate is concentrated, and subjected to chromatography on silica gel eluting with 80% EtOAc in Heptane to 5% MeOH in CH2Cl2 to give N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-acetamide, which is treated with saturated solution of hydrogen chloride in EtOAc followed by lyophilization to afford N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-acetamide hydrochloride [70 mg, Example 65]. LCMS: RT=2.2 minutes, MS: 477 (M+H); 1H NMR (300 MHz, CDCl3) □9.1 (1H, s), 7.95 (1H, brs), 7.7-7.4 (7H, m), 6.65 (1H, s), 4 (3H, s), 3.8-3.75 (2H, m), 3.3 (2H, q, J=6.9 Hz), 3.04 (2H, t, J=6.6 Hz), 2.78 (2H, t, J=7.5 Hz), 2.49 (3H, s). IC50=37 nM
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[CH:14]=[C:15]([N:26]=[C:27]=[O:28])[CH:16]=[CH:17][C:18]=1[O:19][C:20]([F:25])([F:24])[CH:21]([Cl:23])[F:22]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.CO>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:6][C:27]([NH:26][C:15]1[CH:16]=[CH:17][C:18]([O:19][C:20]([F:24])([F:25])[CH:21]([Cl:23])[F:22])=[C:13]([Cl:12])[CH:14]=1)=[O:28])=[O:5]
Reactant: O=C=Nc1ccc(OC(F)(F)C(F)Cl)c(Cl)c1
Reactant: NC(=O)c1ccc(F)cc1Cl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: CO
Product: O=C(NC(=O)c1ccc(F)cc1Cl)Nc1ccc(OC(F)(F)C(F)Cl)c(Cl)c1
Yield: 78.3 %

Procedure:
3.47 g (0.02 mol) of 2-chloro-4-fluorobenzamide and 7.2 g (0.022 mol) of 3-chloro-4-(2-chloro-1,1,2-trifluoroethoxy)-phenyl isocyanate are melted for two hours at 180° C., in the presence of one drop of dibutyl-tin dilaurate. After the mixture has been cooled, the solid product is comminuted in hot methanol, and the product is filtered off under suction and dried. 7.2 g (76.5% of theory) of 1-(2-chloro-4-fluoro-benzoyl)-3-(3-chloro-4-(2-chloro-1,1,2-trifluoro-ethoxy)-phenyl)-urea of melting point 186° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:14][CH2:15][CH2:16][C:17](O)=[O:18].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15](=[O:14])[CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CCO
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCO)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperazine, 3-hydroxypropionic acid, 1-hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), and DMF was stirred at ambient temperature for 24 hours to yield 3-(4-tert-butoxycarbonylpiperazin-1-yl)-3-oxopropan-1-ol, which was stirred together with 4M HCl-dioxane solution and MeOH at ambient temperature for 16 hours to yield 3-oxo-3-piperazin-1-ylpropan-1-ol hydrochloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][CH:9]3[CH2:14][CH:10]3[C:11]=2[NH:12][N:13]=1)=O)C.[OH-].[NH4+:16]>O1CCOCC1>[CH2:14]1[CH:9]2[CH2:8][C:7]3[C:6]([C:4]([NH2:16])=[O:3])=[N:13][NH:12][C:11]=3[CH:10]12
Reactant: [NH4+]
Reactant: CCOC(=O)c1n[nH]c2c1CC1CC21
Agent: [OH-]
Solvent: C1COCCO1
Product: NC(=O)c1n[nH]c2c1CC1CC21
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of the ester from Step C (14.2 g, 73.9 mmol) in dioxane (140 mL) was added ammonium hydroxide (28% NH3 in H2O, 750 mL). The mixture was placed in a 1000 mL pyrex bottle and agitated on a shaker plate for 22 h at rt. The mixture was concentrated in vacuo to a total volume of 100 mL at which time a light yellow precipitate was evident. The mixture was filtered and the solid was washed with H2O (2×100 mL). Further drying of the solid in vacuo gave 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide [HPLC/MS: Discovery® C18 column (5 μ, 50×2.1 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 0.75 mL/min, tr=1.09 min, ESI+=164.0 (M+H)] as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:20])=[C:16](Cl)[CH:17]=2)[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1)[CH3:8]>>[CH3:8][CH2:7][N:9]1[C:18]2[CH:17]=[C:16]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)[C:15]([F:20])=[CH:14][C:13]=2[C:12](=[O:21])[C:11]([C:22]([OH:24])=[O:23])=[CH:10]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: C1CNCCN1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21

Procedure:
In Canadian patent 1,178,961 piperazine is condensed with 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid to give norfloxacin. Canadian patent 1,214,466 claims the process of making the ester analogues of norfloxacin by the condensation of piperazine with the ester of the above compound. Hydrolysis of the ester leads to norfloxacin. Canadian patent 1,273,936 relates only to the synthesis of the quinolone carboxylic acid by cyclocondensation of a 2-benzoyl-3-amino-acrylonitrile followed by hydrolysis.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12](=[O:18])[C:13]1[S:17][CH:16]=[CH:15][CH:14]=1.[C:19](=[O:25])=[N:20]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19]([NH2:20])=[O:25])[C:6](=[O:11])[CH:5]2[C:12](=[O:18])[C:13]1[S:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1Nc2ccc(Cl)nc2C1C(=O)c1cccs1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2nc(Cl)ccc21

Procedure:
The title compound was prepared from 5-chloro-3-(2-thenoyl)-4-azaoxindole (Example 1B), according to the procedure of Example 2C, using 5-chloro-3-(2-thenoyl)-4-azaoxindole (500 mg, 1.79 mmol), N-chlorosulfonyl isocyanate (0.18 mL, 2.15 mmol), and acetonitrile (15 mL). The crude N-chlorosulfonyl carboxamide was hydrolyzed by stirring in DMSO (1.5 mL) for 1 hour in a flask open to the air. The product was precipitated by addition of water and the precipitate was collected by filtration, and recrystallized from acetic acid. Yield: 36 mg (6%). MS m/e (relative percent) 323 (7), 321 (17), 280 (9), 278 (24), 196 (22), 194 (62), 170 (25), 168 (100). Exact mass calc'd for C13H8ClN3O3 S: 320.9975; found: 320.9977. IR (KBr disc) 1724, 1623, 1570, 1512, 1415 cm-1. M.p. 222°-224° C.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:16]([OH:18])=[O:17].[N+:19]([O-])([OH:21])=[O:20]>>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([N+:19]([O-:21])=[O:20])[C:8]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccc(Br)c(C(=O)O)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccc(Br)c(C(=O)O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a 3-L 4-neck round-bottomed flask equipped with a mechanical stirrer, thermometer, 250-mL addition funnel and charged with concentrated H2SO4 (577 mL), was added 4-bromoisophthalic acid (75.0 g, 306 mmol). The white suspension was cooled to ice-bath temperature and a nitrating reagent (pre-prepared by the careful addition of H2SO4 (169 mL) to HNO3 (107 mL)) was slowly added while maintaining an internal reaction temperature of less than 15° C. When addition was complete, the ice-bath was removed and the suspension stirred overnight at room temperature. After approximately 14 hours, the flask was placed in an ice-bath and crushed ice was added to quench the excess nitrating reagent while maintaining an internal temperature less than 40° C. The cream-colored suspension was filtered, and the solids were collected by filtration and washed with a small volume of ice-cold water. The solids were dissolved in methanol and the volatile components were evaporated. The resulting solids were dried at 60° C. in a vacuum oven overnight to afford Intermediate 39(a) (79.6 g) in 87% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][Si]([N-][Si](C)(C)C)(C)C.[K+].S(OC)(OC)(=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:22])[CH:9]1[CH:13]([O:14][CH3:23])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)OC(C)(C)C)CC1O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)CC1N(C)C(=O)OC(C)(C)C

Procedure:
Compound 6 (9.9 kg) was treated with a solution of KHMDS (35 kg, 20% w/w) in THF, followed by dimethyl sulfate (4.7 kg). After completion of the reaction, the reaction mixture was quenched with 5% acetic acid in water. The product was extracted with MTBE, and the organic layer concentrated to give crude product (7). This was treated with p-toluene sulfonic acid monohydrate (TsOH) in a tetrahydrofuran-methanol mixture. After completion of the reaction, the slurry was cooled and the product is isolated by filtration to give 12.2 kg of Compound 8.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16]CC(C)(C)C(O)=O)=[CH:14][N:15]=1.C(Br)C1C=CC=CC=1.C([O:46][C:47](=[O:58])[C:48](SC1SC(N)=NC=1)([CH3:50])[CH3:49])C>>[CH2:4]([O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][C:48]([CH3:50])([CH3:49])[C:47]([OH:58])=[O:46])=[CH:14][N:15]=1)[C:3]1[CH:2]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: BrCc1ccccc1
Product: CC(C)(Sc1cnc(NC(=O)N(CCOCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using benzyl bromide and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.