Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=O)([CH3:5])[CH3:4])#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[I:46][C:47]1[CH:48]=[C:49]([CH:51]=[CH:52][C:53]=1[CH3:54])[NH2:50]>CN(C=O)C>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([NH:50][C:49]1[CH:51]=[CH:52][C:53]([CH3:54])=[C:47]([I:46])[CH:48]=1)=[O:11])([CH3:4])[CH3:5])#[N:2]
Reactant: Cc1ccc(N)cc1I
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1I
Temperature: 50 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
A solution of 3-(2-cyanopropan-2-yl)benzoic acid 3 (2.64 mmol, 500 mg), TBTU (2.77 mmol, 891 mg) and DIPEA (5.29 mmol, 0.873 mL) in DMF (4 mL) was stirred at 50° C. for 15 min. 3-iodo-4-methylaniline (2.77 mmol, 647 mg) was added and stirred overnight at 50° C. Quenched in citric acid solution and extracted with ethyl acetate. Organic layer was washed with brine, dried and evaporated. Purification with chromatography (30% ethyl acetate in heptane) gave 3-(2-cyanopropan-2-yl)-N-(3-iodo-4-methylphenyl)benzamide 111 (861 mg, 81%). NMR (400 MHz, CDCl3) 1.78 (s, 6H), 2.42 (s, 3H), 7.23 (d, J=8.2 Hz, 1H), 7.52 (dd, J=8.2 Hz and 7.4 Hz, 1H), 7.58 (dd, J=8.2 Hz and 2.3 Hz, 1H), 7.71 (dq, J=7.8 Hz and 1.2 Hz), 7.76 (m, 1H), 7.78 (m, 1H), 7.96 (t, J=1.6 Hz, 1H), 8.11 (d, J=2.3 Hz, 1H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([O:15][C:16]1[C:21]([C:22]#N)=[CH:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:17]=1)[CH2:12][CH2:13][CH3:14].[OH2:41]>C1(C)C=CC=CC=1.CO>[CH2:11]([O:15][C:16]1[C:21]([CH:22]=[O:41])=[CH:20][C:19]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[N:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C=O
Temperature: 25 °C

Procedure:
Diisobutyl aluminum hydride (1.0M in toluene, 3 mL, 3 mMol) was added in three portions over 26 hours (0 hours, 24 hours, 26 hours) to a solution of 2-butoxy-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine-3-carbonitrile, Example 14, (0.42 gm, 1 mMol) in toluene (75 mL) and stirred at room temperature. Methyl alcohol (5 mL) was added dropwise followed by a solution of water (5 mL) in methyl alcohol (25 mL). The layers were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a semi-solid. The products were separated and purified by silica gel chromatography. Example 29 Anal. Calc'd. C23H24NO4SF: C, 64.32; H, 5.63; N, 3.26. Found: C, 64.27; H, 5.59; N, 3.23. Example 30 Anal. Calc'd. C23H22NO4SF: C, 64.62; H, 5.19; N, 3.28. Found: C, 64.84; H, 5.39; N, 3.58.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:19])[O:13][CH2:14][C:15]([Cl:18])([Cl:17])[Cl:16].N1C=CC=CC=1>ClCCl>[Cl:16][C:15]([Cl:18])([Cl:17])[CH2:14][O:13][C:12](=[O:19])[NH:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][O:7][C:8]2=[O:11]
Reactant: Nc1ccc2c(c1)C(=O)OC2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)C(=O)OC2)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a suspension of 6-aminoisobenzofuran-1(3H)-one 1 (Maybridge, 13.43 g, 90 mmol) in dichloromethane (DCM, 200 mL) at 0° C. was added 2,2,2-trichloroethyl carbonochloridate 1a (18.23 mL, 135 mmol) and pyridine (17.79 mL, 180 mmol). The reaction mixture was stirred at room temperature (RT, ca. 25° C.) for 1 h. Thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) showed the reaction was complete. The reaction mixture was filtered and washed with DCM (2×30 mL) to afford carbamate 2 as a white solid (17.03 g, 58%). LCMS: [M+1]=324.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:12].[F:13][C:14]([F:35])([F:34])[C:15]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([C:6]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([C:15]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:14]([F:35])([F:13])[F:34])=[CH:22][CH:23]=3)[CH2:29][CH2:30]2)=[O:8])=[CH:9][C:10]=1[F:11]
Reactant: Nc1c(F)cc(C(=O)O)cc1F
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1c(F)cc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 2 h
Yield: 36 %

Procedure:
4-Amino-3,5-difluorobenzoic acid (1.899 mmol, 329 mg), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (1.899 mmol, 650 mg) and triethylamine (5.70 mmol, 0.792 mL, 576 mg) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (2.85 mmol, 1.696 mL, 1813 mg; 50% solution in ethyl acetate) was added and the reaction stirred for 2 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (340 mg) as a pale pink solid. MS (ESI) m/z 498.7 [M+H]+
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH2:13][OH:14].O.[OH-].[Na+].S(OC)(O[CH3:22])(=O)=O>C1(C)C=CC=CC=1>[CH3:22][O:14][CH2:13][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([CH2:9][OH:10])=[C:5]([F:11])[C:4]=1[F:12]
Reactant: OCc1c(F)c(F)c(CO)c(F)c1F
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COCc1c(F)c(F)c(CO)c(F)c1F
Temperature: 65 °C
Yield: 100.8 %

Procedure:
Into a reaction vessel that was charged nitrogen, 5.00 g (23.1 mmol) of 2,3,5,6-tetrafluoro-1,4-benzenedimethanol, 15.00 g of water and 6.85 g (46.3 mmol) of 27% aqueous sodium hydroxide solution were charged subsequently, and heated to 65° C. with stirring. The starting compound was completely dissolved to be clear solution. Then, the reaction mixture was allowed to cool to room temperature with stirring. At this time, some precipitate was observed. To the reaction mixture, 20.0 g of toluene was added and then 4.33 g (32.6 mmol) of dimethyl sulfate was added dropwise over 7.5 hours at room temperature. After the addition, the pH of the aqueous layer became 13.5. The layers of the reaction mixture were separated, and the pH of the aqueous layer was adjusted to about 3 by adding 10% sulfric acid. The aqueous layer was extracted with 30 ml of ethyl acetate, and the combined organic layers were washed- with 30 ml of water, concentrated, and dried under a reduced pressure to give 5.22 g of crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol. The crude 4-methoxymethyl-2,3,5,6-tetrafluorobenzenemethanol was subjected to content analysis by GC internal standard method (Analytical method 1 given later). GC area percentage of the crude product: 85% of the objective compound, 1% of the starting compound and 13% of the by-product compound Content analysis by GC internal standard method: 85% of the objective compound and 86% of the yield of pure compound
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]2[C:15]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)[S:7][CH:8]=1.[N:24]([CH2:27][CH3:28])=[C:25]=[O:26]>CN(C=O)C>[CH2:17]([O:16][C:15]1[C:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:25]([NH:24][CH2:27][CH3:28])=[O:26])[N:5]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCc1csc(Nc2ncccc2OCc2ccccc2)n1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)NCCc1csc(Nc2ncccc2OCc2ccccc2)n1
Reaction time: 2 h
Yield: 30.2 %

Procedure:
Crude 4-(2-aminoethyl)-N-(3-(benzyloxy)pyridin-2-yl)thiazol-2-amine (Example 134, Step A; 0.25 g, 0.766 mmol) was dissolved in DMF (20 mL), and isocyanatoethane (0.109 g, 1.53 mmol) was added. The reaction mixture was stirred for 2 hours, then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with ethyl acetate to afford the title compound (0.092 g, 30.2% yield) as a light yellow powder. 1H NMR (DMSO-d6) δ 0.97 (t, 3H), 2.67 (t, 2H), 2.98 (m, 2H), 3.29 (m, 2H), 5.26 (s, 2H), 5.82 (bt, 2H), 6.64 (s, 1H), 6.88 (m, 1H), 7.32-7.43 (m, 4H), 7.58 (d, 2H), 7.85 (d, 1H), 7.95 (s, 1H), 9.91 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 62 was prepared from 1-(4-chloro phenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 496.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]4[CH:29]5[CH2:30][C:25]6([C:32](O)=[O:33])[CH2:26][CH:27]([CH2:31][CH:23]4[CH2:24]6)[CH2:28]5)=[O:20])[CH2:15]3)=[N:12][CH:13]=2)=[CH:4][C:3]1=[O:35].C1C=CC2N(O)N=[N:42]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]4[CH:23]5[CH2:24][C:25]6([C:32](=[O:33])[NH2:42])[CH2:26][CH:27]([CH2:28][CH:29]4[CH2:30]6)[CH2:31]5)=[O:20])[CH2:15]3)=[N:12][CH:13]=2)=[CH:4][C:3]1=[O:35]
Reactant: On1nnc2ccccc21
Reactant: Cn1ccc(-c2cnc(C3CCN(C(=O)OC4C5CC6CC4CC(C(=O)O)(C6)C5)C3)nc2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(-c2cnc(C3CCN(C(=O)OC4C5CC6CC4CC(C(N)=O)(C6)C5)C3)nc2)cc1=O

Procedure:
A solution of 4-((3-(5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2-yl)pyrrolidine-1-carbonyl)oxy)adamantane-1-carboxylic acid (20 mg, 0.04 mmol), HOBt (11.3 mg, 0.08 mmol), EDCl (16.5 mg, 0.08 mmol) and i-Pr2NEt (27 mg, 0.21 mmol) in dichloromethane (5 mL) was stirred overnight under ammonia gas. The reaction mixture was concentrated to afford an oil which was purified by basic preparative HPLC to afford two isomers:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][C:6]#[CH:7].I[C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=1>C1COCC1.C(NC(C)C)(C)C.[Cu](I)I.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>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][C:6]#[C:7][C:21]1[CH:33]=[CH:32][C:24]([O:25][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:23][CH:22]=1
Reactant: C#CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: Ic1ccc(Oc2ncccn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(CC#Cc1ccc(Oc2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
Under an argon atmosphere, copper iodide (2.8 mg) and dichlorobis(triphenylphosphine)palladium (5.2 mg) were added to a solution of 2-(2,6-dichlorobenzamido)pent-4-ynoic acid methyl ester (74 mg) and 2-(4-iodophenoxy)pyrimidine (81 mg) in THF/diisopropylamine (3/1) mixture (5 ml), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and ethyl acetate was added to the residue. The insoluble matter was removed by filtration, and the filtrate was washed once with water and once with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→cyclohexane/chloroform=1/3) to obtain 2-(2,6-dichlorobenzamido)-5-[4-(pyrimidin-2-yloxy)phenyl]pent-4-ynoic acid methyl ester (100 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[C@H:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28](O)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34]1([CH2:40][S:41]([NH2:44])(=[O:43])=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH2:40]([S:41]([NH:44][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([CH2:24][C@@H:19]2[CH2:20][CH2:21][CH2:22][CH:23]=[C:18]2[C:9]2[O:10][C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH:26]=1)(=[O:42])=[O:43])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: NS(=O)(=O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)Cc1ccccc1)c1cccc(C[C@@H]2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.9 %

Procedure:
To a mixture of 3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (250 mg, 0.575 mmol) and α-toluenesulfonamide (98 mg, 0.575 mmol) in DMF (6 ml) was added 4-dimethylaminopyridine (105 mg, 0.863 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (220 mg, 1.15 mmol). After stirring the resulting mixture at room temperature for 16 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N-hydrochloric acid, water and brine successively, dried over dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 1:1 elution) to give N-benzylsulfonyl-3-{[(1S)-2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzamide (216.4 mg, 64%).
Reaction SMILES: [N+]([O-])([O-])=[O:2].[NH4+].[Ce].[F:7][C:8]1[C:21]2[C:20]([OH:22])=[C:19]3[C:14]([CH:15]=[CH:16][N:17]=[CH:18]3)=[CH:13][C:12]=2[C:11]([O:23][CH3:24])=[CH:10][CH:9]=1>O.C(#N)C>[F:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[CH:18]=[N:17][CH:16]=[CH:15][C:14]=3[C:13](=[O:2])[C:12]=2[C:11]([O:23][CH3:24])=[CH:10][CH:9]=1
Reactant: COc1ccc(F)c2c(O)c3cnccc3cc12
Reactant: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(F)c2c1C(=O)c1ccncc1C2=O
Temperature: 60 °C

Procedure:
A solution of cerium ammonium nitrate (CAN; 13.70 g) in water (50 mL) is added during twenty minutes to a stirred suspension of 9-fluoro-10-hydroxy-6-methoxybenzo[g]isoquinoline in acetonitrile (150 mL). At the end of the addition the obtained suspension is heated at 60° C. for two hours to give a clear, dark solution which is cooled to room temperature and diluted with water (100 mL). Following removal of acetonitrile by distillation at reduced pressure the aqueous phase is saturated with sodium chloride and extracted with methylene chloride (3×150 mL). The combined organic solutions are dried over anhydrous sodium sulphate and the solvent is removed at reduced pressure. The obtained residue is purified by silica-gel column chromatography (eluant: methylene chloride/ethyl acetate from 85/15 to 75/25 v/v) to give 9-fluoro-6-methoxybenzo[g]isoquinoline5,10-dione as a brown-yellow solid (0.48 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([C:8]2[S:12][C:11]([NH2:13])=[N:10][N:9]=2)[CH2:7][CH2:6]1>C(OCC)(=O)C>[CH:5]1([C:8]2[S:12][C:11]([N:13]=[C:1]=[O:2])=[N:10][N:9]=2)[CH2:7][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: Nc1nnc(C2CC2)s1
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CC2)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-cyclopropyl-2-amino-1,3,4-thiadiazole (6 grams) in ethyl acetate (100 ml) was added to the reaction vessel, and the resulting mixture was stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture was then purged with nitrogen gas to remove unreacted phosgene. The purged mixture was filtered to recover the desired product 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]#[N:20])[NH:14]1.N1C=CC=CC=1.[F:27][C:28]([F:32])([F:31])[S:29]Cl>ClCCl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:29][C:28]([F:32])([F:31])[F:27])[C:15]([C:19]#[N:20])=[N:14]1
Reactant: N#Cc1cc(=O)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Reactant: FC(F)(F)SCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.1 %

Procedure:
To a solution of 0.25 g (0.78 mmole) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyanopyrazol-5-one in 15 ml of dichloromethane and 0.069 ml (0.86 mmole) of pyridine, cooled to -70° C. and kept under nitrogen, was added 0.1 ml (1.0 mmole) of trifluoromethanesulfenyl chloride. After stirring for 3 hrs., the reaction was allowed to warm to ambient temperature. The excess of trifluoromethanesulfenyl chloride was removed and the reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated to an orange colored oil. Chromatographic purification afforded 0.04 g of white solid, m.p. 325° C. (decomp.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8](=[N:16][OH:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8](=[N:16][O:17][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)CBr
Reactant: ON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.45 g., 80% w/w suspension in mineral oil) was added gradually to a stirred solution of 4,4'-dichlorobenzophenone oxime (4.0 g.) in dry dimethylformamide (20 ml.) keeping the temperature below 30° C. After 30 minutes, ethyl bromoacetate (1.7 ml.) was added to the stirred solution and the temperature was allowed to rise to 30° C. After 16 hours stirring at ambient temperature the mixture was poured into water (100 ml.) and the subsequent mixture was extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give ethyl di-(4-chlorophenyl)methyleneamino-oxyacetate, as an oil (3.8 g.), essentially pure and having a characteristic ester absorption at 1740-1760 cm-1 in the infra-red spectrum.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]=[CH2:12].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.O.Cl.C1(N)CC1>C1COCC1>[CH:13]1([NH:16][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]=[CH2:12])[CH2:15][CH2:14]1
Reactant: C=Cn1cnc2c(Cl)ncnc21
Reactant: NC1CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=Cn1cnc2c(NC3CC3)ncnc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6-Chloro-9-vinylpurine (0.54 g, 3 mmol) was mixed with cyclopropylamine (1.71 g, 30 mmol) in THF (10 mL) and the mixture was stirred for 5 h at rt. Water was added to dissolve the white precipitate (cyclopropylamine hydrochloride). The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, concentrated on a rotavap, and then recrystallized from EtOAc/hexanes yielding the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH:7]([C:9]([OH:11])=[O:10])[NH2:8])[CH2:5][C:4](=[O:12])[NH:3]1.[OH-].[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])O.[Na+]>O.O1CCOCC1>[CH2:15]([O:22][C:23]([NH:8][CH:7]([CH:6]1[CH2:5][C:4](=[O:12])[NH:3][C:2]1=[O:1])[C:9]([OH:11])=[O:10])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(C(=O)O)C1CC(=O)NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1

Procedure:
In 250 ml of water-dioxane (1:1) was suspended 10 g of 2-(2,5-dioxopyrrolidin-3-yl)glycine and under cooling at 0°-5° C. the above amino acid was dissolved by addition of 70 ml of 1 N sodium hydroxide. To this solution was added 15 ml of benzyloxycarbonyl chloride and, with adjusting pH to 7.1-7.4 with sodium hydrogen carbonate, the mixture was stirred at the same temperature as above for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent and the concentrate was washed with ethyl acetate. The aqueous layer was adjusted to pH 1 with conc. hydrochloric acid and allowed to stand in a refrigerator overnight to give crystals. Yield 15.8 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([Cl:13])[C:10]=1[O:11][CH3:12])[CH:6]=O.[C:14]([O:19]CC)(=[O:18])/[CH:15]=[CH:16]/[CH3:17].CC(C)([O-])C.[K+].Cl>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:17][CH:16]=[CH:15][C:14]([OH:19])=[O:18])[CH:8]=[C:9]([Cl:13])[C:10]=1[O:11][CH3:12]
Reactant: C/C=C/C(=O)OCC
Reactant: COc1cc(C=O)cc(Cl)c1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(C=CC=CC(=O)O)cc(Cl)c1OC

Procedure:
To a solution containing 10.0 g of 3,4-dimethoxy-5-chlorobenzaldehyde and 8.3 ml of ethyl crotonate in 65 ml of N-methylpyrrolidone 6.7 g of potassium tert.-butoxide was added with stirring. The solution was stirred for 0.5 h more at 20° C. and the solution was poured then to a mixture of ice and hydrochloric acid and extracted with ether. The ether extract was washed with water and extracted then with NaHCO3 -solution. The aqueous phase was acidified with hydrochloric acid and the semisolid product was separated and washed with water. Yield 7.3 g (55%).