Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([C:8](=[N:21][NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1O
Reactant: NNC(=O)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=NNC(=O)c1ccccc1)c1cccc(Cl)c1O
Temperature: 60 °C
Yield: 59.1 %

Procedure:
A suspension of 1-(3-chloro-2-hydroxyphenyl)-ethanone (0.100 g, 0.586 mmol), benzoic acid hydrazide (0.080 g, 0.586 mmol), and glacial acetic acid (0.180 mL) in ethanol (1.8 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish benzoic acid [1-(3-chloro-2-hydroxy-phenyl)-ethylidene]-hydrazide as a yellow solid (0.100 g, 59%): mp 202-203° C.; 1H NMR (400 MHz, DMSO) δ 14.36 (s, 1H), 11.50 (s, 1H), 7.96 (d, J=7.3 Hz, 2H), 7.68-7.61 (m, 2H), 7.56 (t, J=6.7 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H), 6.92 (t, J=8.0 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 289 ([M+H]+), 287 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1F
Temperature: 95 °C
Yield: 69 %

Procedure:
A solution of N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (120 mg, 0.281 mmol), 2-fluorophenylboronic acid (472 mg, 0.337 mmol, CAS RN 1993-03-9) and K2CO3 (155 mg, 1.124 mmol) in a mixture of water:ethanol:toluene (10 mL; 0.5:1:3) was thoroughly degassed for 30 min at 25° C. under an atmosphere of argon in a sealed tube. Pd(PPh3)4 (32.5 mg, 0.0281 mmol, CAS RN 14221-01-3) was then added to the mixture, and continued degassing for another 15 min. The reaction mixture was heated to 90-100° C. for 14 hours. After the completion of reaction, the mixture was filtered though a bed of celite and the residue washed with EtOAc. The combined filtrates were evaporated in vacuo and the resultant residue was diluted with EtOAc. The organic layer washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue thus obtained was purified by preparative HPLC to afford the desired compound as an off-white solid (69%). MS (ESI): m/z=443.2 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14]([O:17]C(=O)C)(=[O:16])[CH3:15].[C:21]([O-:24])(=[O:23])[CH3:22].[Na+]>>[C:21]([O:24]/[C:15](=[CH:1]\[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1)/[C:14]([OH:17])=[O:16])(=[O:23])[CH3:22]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: COc1cc(/C=C(\OC(C)=O)C(=O)O)cc(OC)c1O

Procedure:
Batch: 1) 2 kg (11 moles) syringaldehyde; 2) 8.64 kg acetic anhydride; 3) 0.01 kg 4-N,N-dimethylaminopyridine, 4) 0.902 kg sodium acetate, 5) 3.349 kg acetic anhydride
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH2:46]O)=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([Cl:61])(C1C=CC(C)=CC=1)(=O)=O.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:48][O:49][CH3:50])[C:27]([NH:29][CH:30]2[C:37](=[O:38])[N:36]3[CH:31]2[CH2:32][S:33][C:34]([CH2:46][Cl:61])=[C:35]3[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(CO)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(CCl)SCC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 38.3 %

Procedure:
623 mg of the alcohol of Step F were dissolved in 8 ml of dichloromethane with 834 mg of tosyl chloride and a solution of 534 mg of 4-dimethylamino-pyridine and 5 ml of dichloromethane was introduced over 20 minutes. After 1 hour of stirring, 2.2 ml of N hydrochloric acid were added with stirring and the decanted organic phase was dried and distilled under reduced pressure. The residue was chromatographed on silica and eluted with dichloromethane ethyl acetate (9-1) and crystallized from ether to obtain 245 mg of 1,1-dimethylethyl 7-[2-(2-tritylaminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-3-chloromethyl-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1.CCOCC>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:29][C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: Cn1ccc(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: Cn1ccc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.100 g, 0.297 mmol), 1-methyl-1H-pyrazole-3-amine (0.058 g, 0.595 mmol) and p-toluenesulfonic acid monohydrate (0.006 g, 0.030 mmol) in 1,4-dioxane (2.0 mL) was stirred in a microwave reactor at 120° C. for 3 hours. The reaction mixture was adsorbed onto SiO2 and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-5% MeOH in DCM) to give a gummy solid. The solid was suspended in a mixture of Et2O and petroleum benzine 40-60° C. (1:1) and sonicated for 10 minutes. The precipitate was isolated by vacuum filtration and dried to give the title compound 28 as a yellow solid (0.014 g, 12%). LCMS-D: rt 3.26 min; m/z 397 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6](CC(N2CCOCC2)=S)[CH:7]=1.[C:24]([OH:27])(=[O:26])[CH3:25].O.S(=O)(=O)(O)O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([CH2:25][C:24]([OH:27])=[O:26])[CH:7]=1
Reactant: CC(=O)O
Reactant: S=C(Cc1cc(Cl)ccc1Oc1ccccc1)N1CCOCC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: O=C(O)Cc1cc(Cl)ccc1Oc1ccccc1

Procedure:
To this morpholine residue is added 290 ml of glacial acetic acid, 61 ml of water and 87 ml of sulfuric acid (96%), and the mixture refluxed for a period of 21 hours. On cooling, the reaction mixture is dissolved in ethyl ether, washed with water until the water wash appears neutral and extracted with a 10% sodium carbonate solution. The aqueous alkaline layer is acidified with a 2 N solution of hydrochloric acid and re-extracted into diethyl ether. The ether solution is washed with water until the water washings are neutral, dried over anhydrous sodium sulfate and filtered. The solvent is removed by distillation from the filtrate and the remaining residue is crystallized from cyclohexane to yield 30.5 grams of (5-chloro-2-phenoxyphenyl)acetic acid having a m.p. of 119°-123° C.
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])([C:21]#[N:22])[CH2:17][CH2:16]1)=O)(C)(C)C>>[ClH:29].[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:18]1([C:21]#[N:22])[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(c2ccccc2Cl)CCNCC1
Yield: 200 %

Procedure:
A solution of HCl in dioxane (4M, 200 mL, 800 mmol) was added to the Boc-protected amine 18.15 (18.4 g, 57.4 mmol). After 1.5 h the solvent was evaporated and the residue dried in vacuo, giving 14.8 g (57.4 mmol, 100%) of 7.15, colorless solid, mp 241-243° C. (decomp.). 1H NMR (200 MHz, CDCl3): δ=2.5-2.8 (brm, 4H), 3.4-3.6 (brm, 2H), 3.6-3.8 (brm, 2H), 7.33-7.39 (m, 3H), 7.48-7.53 (m, 1H), 10.01 (brs, 2H). C12H14Cl2N2 (257.16): calcd. C, 56.05, H, 5.49, Cl, 27.57, N, 10.89; found C, 55.67, H, 5.48, Cl, 27.86, N, 10.61.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[NH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:16]1[C:15]([C:14]([F:13])([F:25])[F:24])=[CH:19][C:18]([C:20]([F:21])([F:22])[F:23])=[N:17]1
Reactant: FC(F)(F)c1cc(C(F)(F)F)[nH]n1
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2nc(C(F)(F)F)cc2C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 95.8 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (1.81 g), 3,5-bis(trifluoromethyl)-1H-pyrazole (2.0 g) and potassium carbonate (1.63 g) were stirred in DMF (20 ml) at 60° C. for 1 hour. After finishing the reaction, water (100 ml) was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride (100 ml) and dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-3,5-bis-(trifluoromethyl)-1H-pyrazole (3.3 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[CH2:8][CH2:9][C:10]1C=[CH:14][CH:13]=[CH:12][CH:11]=1.[H-].[Na+].C[N:19](C)C=O>>[N:19]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:9][CH2:8][N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C1CCCN1
Reactant: CN(C)C=O
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C1CCCN1CCc1ccccn1

Procedure:
1-(2-(Pyridin-2-yl)ethyl)pyrrolidin-2-one is prepared from 2-pyrrolidone and 2-bromo-ethylbenzene in N,N-dimethylformamide in the presence of sodium hydride (according to M. Matsukawa et al., NeuroToxicology 2004, 25, 293-302).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]([O:14]C)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[K+]>CO>[Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]([OH:14])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(OC)c(Cl)c(C)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(Cl)c(O)cc(C(=O)O)c1Cl
Temperature: 50 °C
Reaction time: 19 h
Yield: 95.2 %

Procedure:
Methyl 2,4-dichloro-5-methoxy-3-methylbenzoate (238 mg, 0.96 mmol) was dissolved in MeOH (30 mL) and flushed with argon. Potassium hydroxide (308 mg, 4.78 mmol) was added and the reaction mixture was stirred at 50° C. for 19 h. The solvent was evaporated and the residue was dried in vacuum. Hydrobromic acid 30 mL, 48%, aq) was added and the mixture was heated to 110° C. After 3 days most of the HBr was removed by vacuum-distillation. The crude product was mixed with H2O (10 mL), concentrated NH3 (1 mL) and EtOAc (40 mL) were added, the aqueous phase (pH 1) was extracted with EtOAc (2×20 mL) and the combined organic phase was washed with brine (10 mL) and dried (MgSO4). Evaporation of the solvent gave 202 mg of the title compound. 1H NMR (DMSO-D6): δ 10.68 (br, 1H), 7.15 (s, 1H), 2.42 (s, 3H); 13C NMR (DMSO-d6): δ 166.68, 151.82, 135.87, 131.24, 123.70, 121.17, 114.36, 17.93; MS (EI, 70 eV): m/z (rel.int.) 222/220 (M+, 56/100), 205/203 (36/59), 185 (26).
Reaction SMILES: [CH2:1]([C:3]([CH2:21][CH3:22])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C(N)=O)[CH3:2].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(#[N:46])C>O>[CH2:1]([C:3]([CH2:21][CH3:22])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:46])[CH3:2]
Reactant: CCC(CC)(C(N)=O)c1ccccc1OCc1ccccc1
Reactant: CC#N
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: CCC(N)(CC)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of α,α-diethyl-2-(phenylmethoxy)-benzeneacetamide (Example 266c, 0.77 g) in acetonitrile (6 mL) and water (6 mL) was treated with (bis(trifluoroacetoxy)iodo)benzene (1.113 g) under nitrogen and the reaction stirred at room temperature for 16 h. Further (bis(trifluoroacetoxy)iodo)benzene (1.0 g) was added and the reaction stirred for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified on SCX resin eluting with methanol (discarded) followed by 7N NH3 in methanol. The basic fractions were collected and the volatiles were removed in vacuo to afford subtitle compound (0.83 g).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH3:13][C:14]([O:17][C:18](=[O:35])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28])([CH3:16])[CH3:15]>C(O)C>[CH3:13][C:14]([O:17][C:18](=[O:35])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][P:27]([O:29][CH2:30][CH3:31])([O:32][CH2:33][CH3:34])=[O:28])[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])([CH3:15])[CH3:16]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCOP(=O)(CCNCCCCNC(=O)OC(C)(C)C)OCC
Solvent: CCO
Product: CCOc1c(N(CCCCNC(=O)OC(C)(C)C)CCP(=O)(OCC)OCC)c(=O)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.8 mL, 39 mmol) in absolute ethanol (200 mL) prepared under nitrogen, was added a solution of [4-[[2-(diethoxyphosphinyl)ethyl]amino]butyl]carbamic acid 1,1-dimethylethyl ester (13.7 g, 39 mmol) in ethanol (75 mL) over 1.75 hour. The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in chloroform (150 mL), preadsorbed onto silica gel, and purified by flash chromatography (9 cm diameter, elution with 2.5% methanol in dichloromethane) to yield [4-[[2-(diethoxyphosphinyl)ethyl](2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]-butyl]carbamic acid 1,1-dimethylethyl ester as a yellow viscous oil (16.8 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[SH:9].[C:10](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][CH3:10]
Reactant: Fc1ccc(Br)c(S)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CSc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
76.61 g of 2-bromo-5-fluorothiophenol were dissolved in 740 ml of DMF and 62.23 g of potassium carbonate were added. A solution of 26.07 ml of iodomethane in 130 ml of DMF was then added dropwise at a temperature between 3° C. and 11° C. The reaction mixture was stirred for 3 h at room temperature, then diluted with 3 l of water and extracted four times with 500 ml each of MTB. The combined extracts were dried over sodium sulfate and the solvent was removed in vacuo. 72.71 g of the title compound were obtained as a pale brown oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:30][C:31](=[O:39])[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[CH:13]=[CH:12]2>ClCCl>[NH3:15].[NH2:22][CH2:21][CH2:20][CH2:19][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([Cl:8])[C:10]=2[NH:30][C:31](=[O:39])[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[N:15]=1
Reactant: CC(C)(C)OC(=O)NCCCc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N
Product: NCCCc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Reaction time: 2 h
Yield: 85.2 %
Yield: 10 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of [3-[6-chloro-5-[(cyclohexylacetyl)amino]-2-quinolinyl]propyl]carbamic acid, 1,1-dimethylethyl ester (Example 23(a)) (0.9 g) in dichloromethane (15 mL). After stirring for 2 hours the solvent was removed under reduced pressure and the resulting residue was purified (Varian Chem elute cartridge with dichloromethane as eluant). Further purification (Varian SCX cartridge using methanol (100 mL) and then 10% ammonia in methanol (100 mL) as eluant) afforded the title compound (300 mg).
Reaction SMILES: Cl[C:2]1C2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1C=O.O[CH:21]1[CH2:26]S[CH:24]([OH:27])[CH2:23][S:22]1.C(N(CC)CC)C.O>N1C=CC=CC=1>[C:12]1([CH:4]2[C:3]3[CH:2]=[C:23]([CH:24]=[O:27])[S:22][C:21]=3[C:26]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:5]2)[CH:13]=[CH:14][CH2:15][CH2:16][CH:17]=1
Reactant: OC1CSC(O)CS1
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1cc2c(s1)-c1ccccc1OC2C1=CCCC=C1
Reaction time: 8 h

Procedure:
To a suspension of 4.2 g 4-chloro-3-formyl-flav-3-ene in 10 ml pyridine is added a solution of 2.6 g 2,5-dihydroxy-1,4-dithian and 2.2 g triethylamine in 11 ml pyridine. After overnight stirring one adds slowly 100 ml water and the precipitate is collected, washed with water, dried, and crystallized in absolute ethanol. Pure 4H-4-phenyl-thieno[3,2-c][1]benzopyran-2-carboxaldehyde is obtained; m.p. 117°-118° C.
Reaction SMILES: [CH:1](/[OH:6])=[CH:2]\[CH2:3][C:4]#[CH:5].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC>[CH3:8][CH:7]([O:6][CH2:1]/[CH:2]=[CH:3]/[C:4]#[CH:5])[O:9][CH2:10][CH3:11]
Reactant: C=COCC
Reactant: C#CC/C=C/O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C#C/C=C/COC(C)OCC
Reaction time: 0.33 h

Procedure:
The 2-trans-penten-4-yn-1-ol (47.7 g) was dissolved in ether (50 ml), cooled to 0° and treated with ethyl vinyl ether (50 mL). To this solution, solid p-toluene sulfonic acid (0.1 g) was added and after a slight exothermic reaction, the mixture was stirred for a further 20 min and quenched with triethylamine (2 mL). The solvents were removed in vacuo and the residue was dissolved in ether, washed with aqueous NaHCO3 solution, dried (MgSO4) and concentrated. The residue was purified by liquid chromatography (two columns, 6:1 parts by volume hexane-ethyl acetate) and distilled, bp 88°-98° (26 mmHg) to give (E)-4-methyl-3,5-dioxa-7-decen-9-yne.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11]([CH:13](P(OC)(OC)=O)[NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:12].[N+:31]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[N+:42]([O-:44])=[O:43])[CH:37]=O)([O-:33])=[O:32]>O1CCCC1>[CH3:9][O:10][C:11](=[O:12])[C:13]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])=[CH:37][C:36]1[CH:39]=[CH:40][C:41]([N+:42]([O-:44])=[O:43])=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1,1,3,3-Tetramethylguanidine (41.2 mL, 329 mmol) was added at room temperature to a solution of N-(benzyloxycarbonyl)-alpha-phophonoglycine trimethyl ester (114.1 g, 344 mmol) in tetrahydrofuran (800 mL). The mixture was stirred at room temperature for 15 min and cooled to −78° C. A solution 3,4-dinitro-benzaldehyde (61.4 g, 313 mmol) in tetrahydrofuran (200 mL) was slowly added via cannula. The resulting mixture was stirred at −78° C. for 2 h and then allowed to warm to room temperature overnight. Solvents were removed in vacuo, and the yellow residue was dissolved in 4.5 L of ethyl acetate. The solution was washed with 1.5 L of 1N sulfuric acid, water twice, brine and dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was crystallized from ethyl acetate (20 g crude product/100 mL of ethyl acetate). The yellow crystals were collected and further purified by chromatography on silica gel using methylene chloride as eluent. The title compound was obtained a s yellow crystals (77%). 1H-NMR (CDCl3, 500 MHz) δ 7.85 (d, J=1.5 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.62 (dd, J=8.5, 1.5 Hz, 1H), 7.35-7.34 (m, 3H), 7.34 (br s, 2H), 7.23 (s, 1H), 6.95 (br s, 1H), 5.07 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25](OCC)=[O:26])[C:5]2[C:6](=O)[CH:7]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:6]3=[N:31][NH:32][C:25](=[O:26])[C:4]([CH:3]=1)=[C:5]23
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccccc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cc(F)cc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 24 %

Procedure:
To a solution of ethyl 7-fluoro-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (186 mg, 0.47 mmol) in methanol (1 mL) was added hydrazine monohydrate (0.5 mL), and the mixture was stirred at 25° C. for 15 hr. Then the mixture was filtered to obtain a white solid (40 mg, yield 24%). LC-MS (ESI) m/z: 363 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.63 (s, 3H), 4.94-5.03 (m, 2H), 6.91-6.94 (dd, J1=11.6 Hz, J2=2.4 Hz, 1H), 7.05-7.08 (dd, J1=9.6 Hz, J2=2.4 Hz, 1H), 7.29-7.35 (m, 3H), 7.42-7.48 (m, 2H), 7.74 (s, 1H), 7.79 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:18])=[C:11]([NH:14][CH2:15][CH2:16][OH:17])[CH:12]=3)[C:7](=[O:19])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCOCC)C.C(#N)C>C(Cl)(Cl)Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:18])=[C:11]([N:14]4[CH2:15][CH2:16][O:17][CH2:25]4)[CH:12]=3)[C:7](=[O:19])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(NCCO)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCOCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(C2CC2)c2cc(N3CCOC3)c(F)cc2c1=O
Reaction time: 3 h

Procedure:
A mixture of 0.67 g of ethyl 1-cyclopropyl-6-fluoro-7-(2-hydroxyethylamino)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 0.08 g of p-toluenesulfonic acid, 2.08 g of diethoxymethane and 20 ml of acetonitrile was stirred for 3 hours under reflux. After the reaction mixture was allowed to cool down, 100 ml of chloroform was added to the reaction mixture. The resultant mixture was successively washed with 5% aq. sodium carbonate solution and saturated saline, dried over anhydrous magnesium sulfate and then concentrated.