Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](Cl)(=[O:16])[CH3:15].[OH-].[K+].O>C(O)C>[C:14]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Oc1ccc(C(C)=O)cc1[N+](=O)[O-]

Procedure:
A mixture containing 36.2 g (0.2 mole) of 4'-hydroxy-3'-nitroacetophenone, 15.7 g of acetyl chloride, 22 mL of 50% KOH solution, 200 mL of H2O and 300 mL of 95% ethanol is stirred and heated to reflux for 18 hours. The mixture is evaporated to remove ethanol, and the aqueous mixture is extracted with CHCl3 to solubilize the product. The CHCl3 extract is evaporated to dryness to afford 4'-acetoxy-3'-nitroacetophenone, which is brominated with an equimolar quantity of Br2 in CHCl3 (100 mL) to afford 2-bromo-4'-acetoxy-3-nitroacetophenone. This phenacyl bromide is then reacted in 100 mL of ethanol with 2 equivalents of isopropylamine to afford 4'-acetoxy-3'-nitro-2-isopropylaminoacetophenone, which isolated as the hydrochloride by the procedure reported by Larson et al. in Journal of Medicinal Chemistry, 10, 467 (1967) for a related compound. This ketoamine is then hydrogenated in 90% aqueous ethanol with 0.5 g of 10% Pd-C/3.5 kg/cm2H2 pressure in a Parr hydrogenator until the uptake of H2 is completed. The mixture is filtered, and the filtrate is evaporated to dryness to afford the crude title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].ClC1C=CC(O[CH2:23][C:24]#[N:25])=CC=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH3:1][N:2]([CH3:16])[C:3]1[C:4]([C:12]([F:13])([F:14])[F:15])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH2:23][C:24]#[N:25])[CH:8]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: CN(C)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1cc(CC#N)c([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 1 h
Yield: 9.9 %

Procedure:
To a solution of dimethyl-(4-nitro-2-trifluoromethylphenyl)amine (0.95 g) in N,N-dimethylformamide (20 mL) were added (4-chlorophenoxy)acetonitrile (0.75 g) and 1 mol/L potassium tert-butoxide (4.5 mL, in tetrahydrofuran solution) under ice cooling, and this mixture was stirred at the same temperature for 1 hour. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.11 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[CH2:38]([N:40]1[N:44]=[N:43][C:42]([CH2:45][N:46]2[C:51]3[CH:52]=[C:53]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)[S:54][C:50]=3[C:49](=[O:61])[N:48]([CH:62]3[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]3)[C:47]2=[O:68])=[N:41]1)[CH3:39]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:65]4[CH2:66][CH2:67][CH:62]([N:48]5[C:49](=[O:61])[C:50]6[S:54][C:53]([C:55]7[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=7)=[CH:52][C:51]=6[N:46]([CH2:45][C:42]6[N:43]=[N:44][N:40]([CH2:38][CH3:39])[N:41]=6)[C:47]5=[O:68])[CH2:63][CH2:64]4)=[O:22])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (160 mg; compound C10) dissolved in DCM (20 ml) HBTU (167 mg) and DIPEA (0.21 ml) are added and the reaction mixture is stirred for 30 min at RT. Subsequently, 1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (175 mg; compound B39) is added and the reaction mixture is stirred for 24 h at RT. After extraction with a saturated solution of sodium hydrogen carbonate and a saturated solution of sodium chloride the organic phase is separated and dried over Na2SO4. After filtration the solvent is removed under reduced pressure to give the crude title product. After purification by flash column chromatography (silica gel, eluent: EtOAc) the title compound is obtained as a solid.
Reaction SMILES: [O:1]=[C:2]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27]CC2C=CC=CC=2)[CH:22]=1)[CH:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[CH3:4].[ClH:35].[H][H]>CO.[C].[Pd]>[ClH:35].[OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[CH:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[CH3:4]
Reactant: [H][H]
Reactant: CC(C(=O)c1cccc(OCc2ccccc2)c1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C(O)c1cccc(O)c1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reaction time: 24 h
Yield: 88.6 %

Procedure:
0.7 g of 1-[3-oxo-3-(3-benzyloxyphenyl)-2-propyl]-4-(2-keto-1-benzimidazolinyl)-piperidine is dissolved in 50 ml of methanol, and 1 ml of methanol solution containing 0.1 g of hydrogen chloride is added thereto. Further, 0.2 g of palladium-carbon is added to the solution, and the mixture is shaked in an autoclave at room temperature with a hydrogen pressure of 10 atmospheric pressures to reduce the compound. After 24 hours, the reaction solution is subjected to filtration, and the mother liquor is concentrated under reduced pressure. Ethyl acetate is added to the residue, and filtered. The mixture is dried to obtain 0.55 g of 1-[3-hydroxy-(3-hydroxyphenyl)-2-propyl]-4-(2-keto-1-benzimidazolinyl)piperidine hydrochloride as powder.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[C:23]([O-:25])=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].CN1CCOCC1.C(Cl)(=O)C(C)(C)C.[CH2:47]([O:49][C:50]([C@@:52]1([NH:57][C:58]([C@H:60]2[NH:64][CH2:63][C@H:62]([O:65][C:66]([N:68]3[CH2:76][C:75]4[C:70](=[CH:71][CH:72]=[CH:73][C:74]=4[F:77])[CH2:69]3)=[O:67])[CH2:61]2)=[O:59])[CH2:54][C@H:53]1[CH:55]=[CH2:56])=[O:51])[CH3:48].Cl>C1COCC1.O>[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]=[CH2:32])[C:23]([N:64]1[C@H:60]([C:58](=[O:59])[NH:57][C@:52]2([C:50]([O:49][CH2:47][CH3:48])=[O:51])[CH2:54][C@H:53]2[CH:55]=[CH2:56])[CH2:61][C@@H:62]([O:65][C:66]([N:68]2[CH2:76][C:75]3[C:70](=[CH:71][CH:72]=[CH:73][C:74]=3[F:77])[CH2:69]2)=[O:67])[CH2:63]1)=[O:25])=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(F)c3C2)CN1)C(=O)OCC
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)[O-]
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N2Cc3cccc(F)c3C2)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Temperature: 22.5 °C
Reaction time: 0.75 h
Yield: 110.2 %

Procedure:
A solution of 1.15 g (2.55 mmol) (S)-2-tert-butoxycarbonylamino-non-8-enoic acid dicyclohexylammonium salt (commercially available from Synthetech Oregon, USA) and 469 mg (4.64 mmol) NMM in 9.0 mL of THF was added dropwise to a solution of 302 mg (2.53 mmol) pivaloyl chloride in 1.5 mL of THF while maintaining the temperature at 20-25° C. The suspension was stirred for 45 min, then cooled to 0° C. A solution of 1.00 g (2.32 mmol) of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester in 13 mL of THF was added to the mixed anhydride at 0° C. within 25 min. The mixture was first stirred for 2.5 h at 2° C., then for 19 h at 26° C. after which 9.5 mL water and 14.8 mL aqueous HCl (0.5 N) were added. The phases were separated and the aqueous layer was extracted with toluene (3×3 mL). The combined organic layers were washed with 2 mL of water, 5 mL of aqueous Na2CO3 (5 wt %) and dried (Na2SO4). The solvent was removed at 50° C. under reduced pressure using a rotary evaporator. The resulting oil was finally dried under oil pump vacuum yielding 1.75 g (88.3%) of 4-fluoro-1,3-dihydro-isoindole-2-carboxylic acid (3R,5S)-1-((S)-2-tert-butoxycarbonylamino-non-8-enoyl)-5-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-pyrrolidin-3-yl ester as a brown resin with an assay of 80.5 wt %.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:15][CH2:14][CH2:13]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[F:32])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14][CH2:15]3)[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:28])=[CH:25][C:24]=4[F:32])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(N)CC1
Reactant: CN1C(=O)C2(CCC2)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3F)ncc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC3(CCC3)C(=O)N4C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluorobenzoic acid (Intermediate 10) (100 mg, 0.23 mmol, 1 eq), DIPEA (80 μl, 0.46 mmol, 2 eq) and TBTU (80 mg, 0.25 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution stirred at rt for 10 min before the addition of 1-amino-4-methylpiperazine (33 μL, 0.27 mmol, 1.2 eq). The RM was then stirred at rt for 1 hour before splitting into two equal batches and purifying by preparative RP-HPLC-MS (Preparative—3) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclobutane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-fluoro-N-(4-methylpiperazin-1-yl)benzamide (0.05 g, 41%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-].CC[O:11][C:12]([CH3:14])=[O:13]>C(OC(=O)C)(=O)C>[C:12]([O:13][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)(=[O:11])[CH3:14]
Reactant: CCOC(C)=O
Reactant: Cc1cccc[n+]1[O-]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccccn1

Procedure:
A solution of the 2-methyl pyridine N-oxide (1.0 mmol) in acetic anhydride (5 mL) was heated to reflux for 0.5 h. Work-up (EtOAc), drying (MgSO4), evaporation and purification by preparative TLC or flash chromatography afforded the 2-(acetoxymethyl) pyridine.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]#[C:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[C:6]=1[CH3:13].[NH2:16][C:17]1[C:18](=[O:30])[N:19]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[N:20]([CH3:23])[C:21]=1[CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:24]1([N:19]2[C:18](=[O:30])[C:17]([NH:16][C:10]([C:7]3[C:6]([CH3:13])=[C:5]([C:4]#[C:3][C:2]([CH3:1])([CH3:15])[CH3:14])[O:9][N:8]=3)=[O:12])=[C:21]([CH3:22])[N:20]2[CH3:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Cc1c(C(=O)O)noc1C#CC(C)(C)C
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C#CC(C)(C)C
Reaction time: 16 h

Procedure:
5-(3,3-Dimethylbut-1-yn-1-yl)-4-methylisoxazole-3-carboxylic acid (85 mg, 0.410 mmol) and 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (86 mg, 0.410 mmol) in DMF (2 mL) were treated with DIPEA (0.287 mL, 1.641 mmol) and HATU (172 mg, 0.451 mmol) at room temperature and stirred for 16 hours. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with a 0.5 M Lithium Chloride (aq) solution, dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH2:34][CH2:35][CH:36]([OH:42])[CH2:37][NH:38][CH:39]1[CH2:41][CH2:40]1>>[CH:39]1([NH:38][CH2:37][CH:36]([OH:42])[CH2:35][NH:34][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:41][CH2:40]1
Reactant: NCC(O)CNC1CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCC(O)CNC1CC1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 1-amino-3-cyclopropylamino-propan-2-ol to give the titled compound as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].Cl>C1(C)C=CC=CC=1.CN(C)C=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 83518.1 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 500 ml were charged 55.3 g (0.40 mol) of potassium carbonate, 200 ml of N,N-dimethylformamide, 54.0 g (0.40 mol) of dimethyl malonate with a purity of 98% and 32.5 g (0.20 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at 70° C. for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, 160 ml of toluene was added to the mixture, and 50 ml (0.60 mol) of 12 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 50 ml of water and 50 ml of a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, this organic layer was analyzed (absolute quantitative method) by high performance liquid chromatography, it was found that 45.3 g (reaction yield: 84%) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate was formed.
Reaction SMILES: [F:1][C:2](=[C:16]([F:18])[F:17])[CH2:3][P:4](=[O:15])([O:10]C(C)(C)C)[O:5]C(C)(C)C.Cl>CO>[F:1][C:2](=[C:16]([F:18])[F:17])[CH2:3][P:4](=[O:5])([OH:15])[OH:10]
Reactant: CC(C)(C)OP(=O)(CC(F)=C(F)F)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: O=P(O)(O)CC(F)=C(F)F
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
The above di-t-butylphosphonate (0.5 g) was dissolved in 3 mL of methanol and treated with 0.5 mL, of 3N HCl and allowed to stand at r.t. for 30 min. The solution was concentrated and the residue was redissolved in 10 mL of water and washed with 10 mL of ether. Evaporation of the aqueous layer gave 0.14 g of 2,3,3-trifluoro-2-propenylphosphonic acid as a yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].CN1CCOCC1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>CC(C)=O>[Cl:23][CH2:24][C:25]([NH:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:6]([NH:8][CH:9]1[CH2:10][CH2:11]1)=[O:7])=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: Cl
Solvent: CC(C)=O
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)CCl
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a suspension of 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (1A) (22.7 g, 0.1 mol) in acetone (200 mL) was added 4-methyl morpholine (42.4 mL, 0.3 mol). The solution was cooled to −20° C. and chloroacetyl chloride (12 mL, 0.15 mol) was added dropwise. The reaction mixture was stirred at −10° C. for 10 min before being quenched with H2O (200 mL). The precipitate formed was collected by vacuum filtration and dried to provide 25.3 g (95% yield) of 3-(2-chloro-acetylamino)-N-cyclopropyl-4-methylbenzamide, mp: 150° C. (dec.); 1H NMR (500 MHz, DMSO-D6) δ 9.83 (s, 1H), 8.39 (d, J=3.8 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J=6.6 Hz, 1H), 7.28 (d, J=8.3, 1H), 4.32 (s, 2H), 2.82 (m, 1H), 2.22 (s, 3H), 0.66 (m, 2H), 0.56 (m, 2H); 13C NMR (100 MHz, DMSO-D6) δ: 167.2, 165.4, 136.0, 135.8, 132.8, 130.5, 124.8, 124.7, 43.4, 23.4, 18.1, 6.0; Anal. Calcd for C13H15ClN2O2: C, 58.54; H, 5.66; N, 10.50; Cl, 13.29. Found: C, 53.72; H, 5.95; N, 9.65; Cl, 13.52.
Reaction SMILES: C1(S(C2CCCNC2)(=O)=O)C=CC=CC=1.C(Cl)(Cl)=O.[C:20]1([S:26]([CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35](Cl)=[O:36])[CH2:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:38]([NH:40][CH2:41][CH2:42][NH2:43])[CH3:39]>>[CH2:38]([NH:40][CH2:41][CH2:42][NH:43][C:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:29]([S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH2:30]1)=[O:36])[CH3:39]
Reactant: CCNCCN
Reactant: O=C(Cl)N1CCCC(S(=O)(=O)c2ccccc2)C1
Agent: O=C(Cl)Cl
Agent: O=S(=O)(c1ccccc1)C1CCCNC1
Product: CCNCCNC(=O)N1CCCC(S(=O)(=O)c2ccccc2)C1

Procedure:
The title compound is prepared by reacting 3-(phenylsulfonyl)piperidine with phosgene and reacting the resulting 3-(phenylsulfonyl)piperidine-1-carbonylchloride with N-ethylethylenediamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7](C(OC)=O)[CH:6]2[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Cl-].[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH:6]2[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC1c2cc(OC)ccc2NC(=O)C1C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CC1CC(=O)Nc2ccc(OC)cc21
Temperature: 155 °C

Procedure:
A mixture of 67.0 g of 1,2,3,4-tetrahydro-6-methoxy-3-(methoxycarbonyl)-2-oxo-4-quinoline acetic acid, methyl ester and 13 g of sodium chloride in 23 ml of water and 300 ml of dimethyl sulfoxide was heated at 155° C. for 6 hours, cooled, and diluted with 1.2 l of a 1:1 mixture of ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate, and the combined organic layers were washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 1,2,3,4-tetrahydro-6-methoxy-2-oxo-4-quinoline acetic acid, methyl ester.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:17]=[C:16](Br)[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=[O:23])[C:12]=2[CH:24]=1.BrC1C=CC2C(Br)=CC3C=CC=CC=3C(=O)C=2C=1.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C(O)(C)(C)C>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:17]([N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[CH:16][C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[C:13](=[O:23])[C:12]=2[CH:24]=1
Reactant: O=c1c2cc(Br)ccc2cc(Br)c2ccccc12
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: O=c1c2ccccc2cc(Br)c2ccc(Br)cc12
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN1CCN(c2cc3ccccc3c(=O)c3cc(Br)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (6.8 g., 0.06 mole) was added to a stirred slurry of 3,10-dibromo-5H-dibenzo[a,d]cyclohepten-5-one and 3,11-dibromo-5H-dibenzo[a,d]cyclohepten-5-one (18.2 g., 0.05 mole), 4-methylpiperazine (10 ml.), and dry tert-butyl alcohol (200 ml.) at room temperature and under nitrogen. The dark orange mixture was heated to refluxing for 2 hours and then stirred at room temperature overnight. The mixture was poured into approximately 800 ml. of ice and water and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated. The mixture of 3-bromo-10-(4-methylpiperazinyl)-5H-dibenzo[a,d]cyclohepten-5-one and 3-bromo-11-(4-methylpiperazinyl)-5H-dibenzo[a,d]cyclohepten-5-one was obtained as a residual red-yellow gum; yield, 19.4 g. 100%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.C(OC([NH:33][CH2:34][CH2:35][C:36](O)=[O:37])=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.[ClH:50].C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl.CO>CO>[ClH:50].[ClH:50].[NH2:33][CH2:34][CH2:35][C:36]([N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1)=[O:37]
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CO
Solvent: CN1CCOCC1
Product: NCCC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Temperature: 60 °C
Yield: 0 %

Procedure:
In a similar manner to Example 5, the product obtained using Compound 18 (300 mg, 0.90 mmol), 3-(tert-butoxycarbonylamino)propionic acid (143 mg, 0.75 mmol), 1-hydroxybenzotriazole monohydrate (132 mg, 0.98 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg, 1.05 mmol) and N-methylmorpholine (0.16 mL, 1.50 mmol) was dissolved in methanol (2.00 mL), and the solution was added with 4 moL/L hydrogen chloride-methanol solution (1.50 mL), followed by heating under reflux at 60° C. for 40 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from acetone to obtain Compound 129 (0.11 mg, 24%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[N:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([N:22]3[CH:30]([OH:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[N:19]2)=[CH:14][CH:13]=1>N1C=CC=CC=1>[Cl:11][C:12]1[N:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([N:22]3[CH:30]([O:31][C:2]([O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[O:3])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])=[N:19]2)=[CH:14][CH:13]=1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
Phenyl chloroformate (126 g.) is added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (86.5 g.) in pyridine (980 cc.), whilst keeping the temperature at about 25° C. The reaction mixture is stirred for 3 hours at a temperature of about 20° C. and then poured into ice-water (9,000 cc.). The product which crystallises is filtered off, washed with water (6×500 cc.) and then with acetonitrile (3×200 cc.). After drying, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (96.7 g.), which melts at 235° C. with decomposition, is obtained.