Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.O.C(OCC)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][OH:21])[C:13](=[O:29])[N:12]([CH3:30])[C:11]=2[N:10]=[C:9]1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)c2c1nc(-c1ccc(Cl)c(Cl)c1)n2Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(-c1ccc(Cl)c(Cl)c1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Step 2 7-Benzyl-1-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(3,4-dichlorophenyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.49 g, 0.854 mmol) was dissolved in ethanol (15 mL) and 6 N HCl (2.0 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with DCM (3×75 ml). The combined extracts were dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to give a white solid. The solid was slurried in diethyl ether (5 mL) and filtered to give 7-benzyl-8-(3,4-dichlorophenyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.28 g, 71% yield) as a white solid. LCMS retention time=3.567 min and 96% purity, LCMS MH+=459. 1H NMR (CDCl3) δ 7.71 (s, 1H), 7.53 (d, 1H, J=8 Hz), 7.38-7.41 (d, 1H, J=4 Hz), 7.26-7.29 (m, 3H), 7.04 (d, 2H), 5.64 (s, 2H), 4.20 (t, 2H, J=8 Hz), 3.65 (s, 3H), 3.47-3.54 (m, 2H), 3.30 (t, 2H, J=8 Hz).
Reaction SMILES: [CH:1]1[CH:6]=[N+:5]([C@@H:7]2[O:11][C@H:10]([CH2:12][O:13][P:14]([O:17][P:18]([O:21][CH2:22][C@H:23]3[O:27][C@@H:26]([N:28]4[C:32]5[N:33]=[CH:34][N:35]=[C:36]([NH2:37])[C:31]=5[N:30]=[CH:29]4)[C@H:25]([OH:38])[C@@H:24]3[OH:39])([OH:20])=[O:19])([OH:16])=[O:15])[C@@H:9]([OH:40])[C@H:8]2[OH:41])[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH:2]=1.C([O-])=O.[NH4+]>C(O)C(N)(CO)CO>[CH:34]1[N:35]=[C:36]([NH2:37])[C:31]2[N:30]=[CH:29][N:28]([C@@H:26]3[O:27][C@H:23]([CH2:22][O:21][P:18]([O:17][P:14]([O:13][CH2:12][C@H:10]4[O:11][C@@H:7]([N:5]5[CH:4]=[C:3]([C:42]([NH2:44])=[O:43])[CH2:2][CH:1]=[CH:6]5)[C@H:8]([OH:41])[C@@H:9]4[OH:40])([OH:16])=[O:15])([OH:20])=[O:19])[C@@H:24]([OH:39])[C@H:25]3[OH:38])[C:32]=2[N:33]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: NC(CO)(CO)CO
Agent: O=C[O-]
Agent: [NH4+]
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1

Procedure:
A mixture of substrate (5 mM), oxidized cofactor NAD+ (100 μM), ammonium formate (20 mM) in 50 mM Tris buffer pH 7.5 (0.8 ml) was admixed with FDH (10 u), after the enzyme (100-200 μg) had been added, and the reaction was carried out at 30° C. (140 rpm) for 48 hours.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11](=[O:12])[CH:10]=[CH:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:7]=1)=[O:5].[CH3:24][CH2:25][Mg+].[Br-]>C1COCC1>[C:4]([C:6]1[C:11](=[O:12])[CH:10]=[CH:9][N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)[N:7]=1)(=[O:5])[CH2:24][CH3:25]
Reactant: CON(C)C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of N-methoxy-N-methyl-4-oxo-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (1.20 g, 3.52 mmol) in THF (20 mL) was added EtMgBr (1.0 M in THF, 7.04 mL, 7.04 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 1 h. The reaction was quenched with saturated NH4Cl aqueous solution at −78° C. The mixture was warmed to room temperature, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (767 mg, 74% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 1.06 (3H, t, J=7.2 Hz), 2.99 (2H, q, J=7.2 Hz), 6.73 (1H, d, J=8.3 Hz), 7.79-7.88 (2H, m), 8.06-8.17 (2H, m), 8.97 (1H, d, J=8.3 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[NH2:13]C(N)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:7])[NH:13][C:9]2=[O:8]
Reactant: NC(N)=O
Reactant: O=C1OC(=O)c2cc(F)ccc21
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2cc(F)ccc21
Temperature: 25 °C
Yield: 100.6 %

Procedure:
To 4-fluorophthalic anhydride (5.0 g, 30.10 mmol) in toluene (15 mL) is added urea (2.1 g). The reaction mixture is stirred at refluxed for 16 h. The reaction mixture is allowed to cool to room temperature, concentrated under reduced pressure and triturated with H2O (250 mL) to afford 5-fluoro-isoindole-1,3-dione (5.0 g, 100%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([NH:22][CH3:23])=[CH:20][CH:19]=1>C(O)(=O)C>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([N:22]([CH3:23])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1cc(Cl)c2ccccc2n1
Reactant: CNc1ccc(OC)cc1
Solvent: CC(=O)O
Product: COc1ccc(N(C)c2cc(C(F)(F)F)nc3ccccc23)cc1
Temperature: 105 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A mixture of 4-chloro-2-(trifluoromethyl)quinoline 0.232 g (1.0 mmol) and 4-methoxy-N-methylaniline 0.137 g (1.0 mmol) in glacial acetic acid 3 mL was stirred at 100-110° C. for 24 h. The reaction mixture was directly subjected to gradient column chromatography (EtOAc/hexanes, 0% to 50%) to give the titled compound in 70% yield. 1H NMR (CDCl3, 400 MHz): δ 8.11-8.08 (m, 1H), 7.62-7.58 (m, 1H), 7.58-7.55 (m, 1H), 7.27-7.22 (m, 2H), 6.97 (d, 2H, J=9.0 Hz), 6.84 (d, 2H, J=9.0 Hz), 3.79 (s, 3H), 3.49 (s, 3H). m/z: 333.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Br:17]N1C(=O)CCC1=O.C(O)(C)C>O>[NH2:1][C:2]1[C:7]([Br:17])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(C)O
Solvent: O
Product: Nc1ccc(Oc2ccnc(N)c2Br)cc1Cl

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (1.0 g), N-bromosuccinimide (0.78 g) and isopropanol (10 ml) were stirred for 15 minutes under reflux. The mixture was returned to room temperature, water was added, and extraction was performed with ethyl acetate. Silica gel was added to the extract solution and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (hexane:ethyl acetate=2:1, followed by 1:1, ethyl acetate) to obtain 400 mg of the target substance as a brown oil.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)[CH:12]=[C:11]([S:36][CH3:37])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1C=C(Cl)C=C(C(OO)=[O:46])C=1>C(Cl)Cl>[NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)=[CH:19][CH:18]=[CH:17][C:16]=2[O:31][CH2:32][CH:33]2[CH2:34][CH2:35]2)[CH:12]=[C:11]([S:36]([CH3:37])=[O:46])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(SC)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(S(C)=O)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
To a cold (0° C.) solution of tert-butyl 2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-4-(methylsulfanyl)nicotinate (1.72 g, 3.30 mmol) in CH2Cl2 (20 mL) was added m-CPBA (69%, 0.82 g, 3.30 mmol). The reaction mixture was stirred at 0° C. for 15 min, quenched with saturated aqueous NaHCO3 solution (20 mL) containing Na2S2O3 (1 g). The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography on silica gel (hexane/ethyl acetate=3:2 to 1:1) gave solid, which was triturated with ethyl acetate and diisoproyl ether to give tert-butyl 2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}-4-(methylsulfinyl)nicotinate as a white powder (1.112 g, yield; 63%).
Reaction SMILES: [H-].[Na+].C(=NO)C.[OH:7][C:8]1[CH:27]=[CH:26][C:11]([C:12]([C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[C:16](Cl)[CH:15]=2)=[O:13])=[CH:10][CH:9]=1.OC1C=CC(C(C2C=CC(OCC(O)=O)=CC=2Cl)=O)=CC=1>O.CN(C)C=O>[OH:7][C:8]1[CH:27]=[CH:26][C:11]([C:12]([C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(O)COc1ccc(C(=O)c2ccc(O)cc2)cc1Cl
Agent: O=C(O)COc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC=NO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc(C(=O)c2ccc(O)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (4.32 g., 0.09 mole, 50% suspension in mineral oil) in 50 ml. of dimethylformamide was added by dropwise addition acetaldoxime (5.31 g., 0.09 mole) at 5°. The mixture was stirred for 10 minutes at 20°-25° and then treated by dropwise addition with a solution of 10 g. (0.03 mole) of ethyl 4-(4-nitrobenzoyl) phenoxy acetate in 50 ml. of dimethylformamide. The resulting mixture was stirred at room temperature for 5 hrs. and poured into cold water. Acidification with concentrated hydrochloric gave a solid which was collected by filtration and dried. There was obtained 7 g. of product. This material was used without purification for the next step. In a similar manner were prepared the following two compounds: 4-(4-hydroxybenzoyl)-2-chlorophenoxy acetic acid and 4-(4-hydroxybenzoyl)-3-chlorophenoxy acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH3:14])[CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:7]([Br:15])=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([CH3:14])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCc1ccc(N)cc1C
Solvent: CC#N
Product: COC(=O)CCc1cc(Br)c(N)cc1C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
A solution of Intermediate 8 (1.4 g) in acetonitrile (20 ml) was added with N-bromosuccinimide (1.4 g, WAKO) under ice cooling, stirred for 10 minutes under ice cooling, and then stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, then added with ethyl acetate (10 ml), and successively washed with saturated aqueous ammonium chloride, 5% aqueous sodium sulfite, saturated aqueous sodium hydrogencarbonate and saturated brine, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1) to obtain the title compound (1.0 g).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][CH:9]([CH3:14])[CH:10]([OH:13])[CH:11]=[CH2:12].C(=O)(O)[O-].[Na+].N1CCCC1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:8][CH:9]([CH3:14])[C:10](=[O:13])[CH2:11][CH2:12][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(O)C(C)C
Reactant: Ic1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)C(=O)CCc1cccnc1

Procedure:
The title compound was prepared according to General Method 4a using 3-iodo-pyridine (36.6 mmol), 4-methyl-1-penten-3-ol (54.9 mmol), tetrabutyl ammonium chloride (36.6 mmol), sodium bicarbonate (91.5 mmol), pyrrolidine (˜1.5 mL), DMF (15 mL), and palladium acetate (0.51 g). The title compound was flash chromatographed eluting with EtOAc:CH2Cl2:hexane 50:25:25.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[S:21]([N:18]1[CH2:19][CH2:20][CH:15]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:32])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[CH:14]=2)[CH2:16][CH2:17]1)(=[O:23])=[O:22]
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3Cl)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(Cl)cc3Cl)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To a stirred solution of {4-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (115 mg, 0.23 mmol) in THF (6 mL) was added a solution of lithium hydroxide monohydrate (50 mg, 1.2 mmol) in water (1.5 mL) and the reaction mixture was stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {4-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid (100 mg, 89%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (br s, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.96-8.00 (m, 2H), 7.87-7.95 (m, 1H), 7.68-7.73 (m, 2H), 7.34-7.44 (m, 2H), 3.87 (d, J=12.2 Hz, 2H), 3.72 (s, 2H), 3.04 (t, J=11.5 Hz, 2H), 1.89-1.96 (m, 2H), 1.67-1.78 (m, 2H); MS cald. for C23H19Cl2FNO4S [(M−H)−]: 494, obsd. 494.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:19]=[C:18]([CH3:20])[C:12]2[N:13]=[C:14]([NH2:17])[N:15]=[N:16][C:11]=2[CH:10]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([S:34]([C:37]2[CH:42]=[CH:41][C:40](Br)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([NH:17][C:14]3[N:15]=[N:16][C:11]4[CH:10]=[C:9]([C:3]5[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[CH:19]=[C:18]([CH3:20])[C:12]=4[N:13]=3)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: Cc1cc(-c2c(Cl)cccc2Cl)cc2nnc(N)nc12
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: Cc1cc(-c2c(Cl)cccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12
Yield: 43.7 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.205 g, 0.672 mmol, 1 equiv), 4-(4-bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (0.408 g, 1.01 mmol, 1.5 equiv), cesium carbonate (0.657 g, 2.02 mmol, 3 equiv); 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.078 g, 0.134 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.0615 g, 0.067 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (20 mL) and outfitted with a reflux condenser. The reaction was heated to reflux for 2 hours, then filtered hot, and the solvents were evaporated. Purification on silica gel flash column provided desired product as a yellow solid (0.185 g, 44% yield). MS (ESI+): m/z=529.0 (M−100), LC retention time: 3.51 min. 1H NMR (DMSO-d6): δ 1.33 (s, 9H), 2.72 (s, 3H), 2.87 (m, 4H), 3.4 (m, 7.5 (m, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.78 (m, 3H), 8.18 (d, J=1.7 Hz, 1H), 8.30 (d, J=8.8 Hz, 2H), 11.53 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]([O:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][CH:21]1[CH2:22][CH2:23][N:24]([C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=2[OH:1])[CH2:25][CH2:26]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: O=C(O)c1ccc(O)cc1O
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(O)cc2O)CC1
Yield: 38.2 %

Procedure:
2,4-Dihydroxy benzoic acid (1.25 g, 8.11 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (1.85 g, 8.11 mmol) and other reagents as described in Example 9(e) were used to afford 1.13 g of the required product. 1H NMR (DMSO-d6): δ 1.05 (2H, m), 1.25 (2H, m), 1.4 (9H, s), 1.65 (2H, m), 2.75 (2H, m), 2.95 (2H, m), 3.15 (1H, m), 4.0 (2H, m), 6.24 (2H, m), 6.78 (1H, m), 6.9 (1H, d), 9.6 (2H, brs).
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)[CH:2]=[CH2:3].[Cl:12][CH2:13][NH:14][CH2:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[Cl:12][CH2:13][N:14]([CH2:15][CH2:16][CH:17]=[O:18])[C:10]([NH:9][C:7]1[S:8][C:4]([CH2:1][CH:2]=[CH2:3])=[N:5][N:6]=1)=[O:11]
Reactant: O=CCCNCCl
Reactant: C=CCc1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C=CCc1nnc(NC(=O)N(CCl)CCC=O)s1

Procedure:
A mixture of 5-allyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-chloromethylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-chloromethyl-3-(5-allyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: [CH3:1][C:2]1(C(OC)=O)[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]1=[O:13].Cl>C(O)(=O)C>[CH3:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]1=[O:13]
Reactant: COC(=O)C1(C)CCCc2ccccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Product: CC1CCCc2ccccc2C1=O

Procedure:
A solution of methyl 6-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate (35.13 g, 151.2 mmol) and conc. hydrochloric acid (50 ml) in acetic acid (100 ml) was stirred overnight at 110° C. The reaction solution was concentrated, diluted with water and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to give the objective substance.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH:15]=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5])[CH3:2].CC(=CC)C.[O-:23]Cl=O.[Na+]>CC(O)(C)C>[CH3:2][CH2:1][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]([OH:23])=[O:16])=[CH:12][CH:11]=[C:10]([Cl:17])[CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1[nH]c2cc(Cl)ccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
To a solution of commercially available 6-chloro-3-formyl-1H-indole-2-carboxylic acid ethyl ester in t-BuOH and 2-methyl-2-butene (50 eq) was added 9.2 eq NaClO2 (9 eq) and aq. NaH2PO4 (7 eq) and stirred 12 h at room temperature. After concentration the mixture was dissolved in H2O and adjusted to pH7 and then extracted with EtOAc; partial concentration of the organic phase precipitated the product in 52% yield.
Reaction SMILES: C=CCCCCCCCC.C(=O)=O.O=[O+][O-].[C:17](O)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC(C)=O>[CH:17](=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCC(=O)O
Agent: C=CCCCCCCCC
Agent: O=C=O
Agent: O=[O+][O-]
Solvent: CC(C)=O
Product: CCCCCCCCC=O
Yield: 108.6 %

Procedure:
1-Decene was supplied from a raw-material tank 4 using a high-pressure pump, and the raw material was preheated in an ozonization reaction vessel 3 at 20° C. The preheated raw material was then combined with the high-pressure carbon dioxide solution of ozone, and continuous ozonization proceeded in a stainless steel coil-shaped ozonization reaction section 1 having an inside diameter of 1 mm and a length of 26 cm and set to 20° C. The reaction mixture that exited from the ozonization vessel 3 was subsequently subjected to a continuous thermal decomposition reaction in a stainless steel coil-shaped decomposition reaction section 11 having an inside diameter of 1 mm and a length of 100 cm and set to 200° C. The residence time corresponding to the reaction time was 6 seconds in the ozonization reaction section and 24 seconds in the decomposition reaction section, making a total of 30 seconds. The product was passed via the pressure-regulating valve 30 and was dissolved in acetone placed in a gas-liquid separation device 40. Quantification of the acetone solution by FT-NMR using coumarin as an internal standard confirmed that 0.58 mmol of nonanoic acid and 0.63 mmol of nonanal were produced in 30 minutes.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][C:12]([NH2:14])=[O:13])[N:6]=1.[N:17]([C:20]1[CH:33]=[CH:32][C:23]([O:24][CH2:25][CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[CH:22][CH:21]=1)=[C:18]=[S:19].O>C1COCC1>[N:27]1([CH2:26][CH2:25][O:24][C:23]2[CH:32]=[CH:33][C:20]([NH:17][C:18](=[S:19])[CH:11]([C:7]3[N:6]=[C:5]([C:4]([F:3])([F:15])[F:16])[CH:10]=[CH:9][N:8]=3)[C:12]([NH2:14])=[O:13])=[CH:21][CH:22]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: S=C=Nc1ccc(OCCn2ccnc2)cc1
Reactant: NC(=O)Cc1nccc(C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C(C(=S)Nc1ccc(OCCn2ccnc2)cc1)c1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Sodium hydride (0.531 g of a 60 wt % dispersion in oil, 13.3 mmol) was added in portions to a stirred solution of 2-(4-trifluoromethylpyrimidin-2-yl)acetamide (0.911 g; 4.43 mmol) in THF (20 mL) over 10 min. A solution of 1-[2-(4-isothiocyanatophenoxy)ethyl]-1H-imidazole (1.21 g; 4.92 mmol) in THF (10 mL) was then added over 15 min. The mixture was stirred at room temperature for a further 1 hr, and then water (1 mL) was added and the mixture was concentrated under reduced pressure. Water (75 mL) was added to the residue, the pH adjusted to 7 with 2N hydrochloric acid, and the mixture was extracted three times with EA. The combined EA extracts were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 3-{-4-[2-(1H-imidazol-1-yl)ethoxy]phenylamino}-3-thioxo-2-(4-trifluoromethylpyrimidin-2-yl)propanamide (1.47 g) as an orange semi-solid.