Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](Cl)=[C:4](Cl)[C:5](Cl)=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:16]1([S:22][C:2]2[C:3]([S:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:4]([S:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]([S:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=23)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1OC(=O)c2c(Sc3ccccc3)c(Sc3ccccc3)c(Sc3ccccc3)c(Sc3ccccc3)c21

Procedure:
30.88 g (108 millimols) of tetrachlorophthalic anhydride, 48.79 g (443 millimols) of thiophenol, 91.06 g (659 millimols) of potassium carbonate and 300 ml of tetrahydrofuran are stirred under reflux for 3 hours. The mixture is evaporated and the residue is taken up in methylene chloride/2N HCl solution. The organic phase is separated off, dried over sodium sulfate and evaporated. After recrystallisation from toluene/cyclohexane, 44.71 g (71% of theory) of tetrakis-(phenylthio)-phthalic anhydride are obtained; melting point 141°-2° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[Br-].[N+:16]([C:19]1[CH:20]=[C:21]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:22][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:18])=[O:17].C[O-].[Na+].C(O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:46][O:45][C:44]1[CH:43]=[CH:42][C:21]([CH:22]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:20][C:19]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: C[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(C=Cc2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
3,4,5-Trimethoxybenzaldehyde (5, 54.7 g), (4-methoxy-3-nitrobenzyl)triphenylphosphonium bromide (4, 148.6 g) and 1300 ml of toluene are charged, at 20° C. and under nitrogen, into a 2 litre three-necked flask equipped with a mechanical stirrer, a thermometer, a T piece, a dropping funnel and a reflux condenser surmounted by a bubble counter. The stirred suspension is cooled to 5° C. using an ice bath and then 63.2 g of a 25% w/w solution of sodium methoxide in methanol are added at 5° C. over 40 minutes. As the addition progresses, the suspension color changes from off-white to yellow and then to brown. The mixture is stirred for 1 hour at 5° C. and the end of the reaction is monitored by HPLC (complete consumption of the aldehyde). Acetic acid (3 g, 0.05 mol) is then added. The suspension is heated to 40° C. and is maintained at 40° C. for 30 minutes. At this temperature, only the salts remain insoluble. The mixture is filtered at 40° C. through a sintered glass filter (No. 3) and the salts are washed on the filter 3 times with 100 ml portions of toluene. The filtrate is returned to a round-bottomed flask with 250 ml of distilled water, and the two-phase mixture is stirred for 20 minutes at 40° C. and then the phases are separated. The toluene phase is washed twice with 250 ml portions of distilled water and then concentrated to dryness on a rotary evaporator. The residue is taken up in 600 ml of isopropanol and 12 ml of toluene at 40° C. The expected product begins to crystallize and the temperature is allowed to return to ambient temperature overnight with slow stirring. The stirred suspension is cooled to and maintained for 1 hour at 5° C., then filtered through a sintered glass filter, and the filter cake is washed twice with 125 ml portions of isopropanol, sucked dry and dried in an oven under vacuum (35° C./30 mmHg/18 hours). A mixture of Z and E isomers (6) and (7) (91.7 g) is obtained with a Z/E ratio of 75/25 (IS IPLC) and a yield of 95%.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:8])[CH2:3][C:4]([CH3:7])(O)[CH3:5].OS(O)(=O)=O>O>[CH3:7][C:4]1([CH3:5])[CH2:3][C:2]([CH3:1])([CH3:8])[C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:15]1
Reactant: CC(C)(O)CC(C)(C)c1ccccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)CC(C)(C)c2ccccc2O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2.98 g (14.3 mmol) of 2-(1,1,3-trimethyl-3-hydroxybutyl) phenol (Compound 39) and 40 ml of 20% aqueous H2SO4 was heated at reflux, under nitrogen, for 4 h. The mixture was stirred at room temperature for a further 72 h and then diluted with 50 ml of water. The mixture was extracted with 3×20 ml of hexanes. The organic extracts were then combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was then removed in vacuo to give the title compound as a colorless oil. PMR (CDCl3): & 1.36 (6H, s), 1.37 (6H, s), 1.83 (2H, s), 6.71 (1H, dd, J-8.2 Hz, 1.5 Hz) 6.92 (1H, td, J-8.2 Hz, 1.5 Hz), 7.09 (1H, td, J-8.2 Hz, 1.5 Hz), 7.29 (1 H, dd, J-8.2 Hz, 1.5 Hz).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].CO[C:13]([C:15]1[C:16]2[CH:17]=[CH:18][NH:19][C:20]=2[CH:21]=[CH:22][CH:23]=1)=[O:14].[C:24]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38]C#N)[CH2:34][CH2:33]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1C=C(Cl)C=C(C(OO)=[O:49])C=1>C1COCC1>[C:24]([N:32]1[CH2:37][CH2:36][N:35]([C:38](=[O:49])[C:13]([C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[CH:18][NH:19]3)=[O:14])[CH2:34][CH2:33]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#CCN1CCN(C(=O)c2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C(=O)N1CCN(C(=O)c2ccccc2)CC1)c1cccc2[nH]ccc12
Reaction time: 8 h
Yield: 28518.5 %

Procedure:
NaHMDS (1.3 mL of a 1.0 M in THF solution, 1.3 mmol) was added to a stirring solution of 1H-indole-4-carboxylic acid methyl ester (0.048 g, 0.27 mmol) and (4-benzoyl-piperazin-1-yl)-acetonitrile (63 mmol, 0.27 mmol) in THF (3 mL) and the reaction mixture was stirred overnight. mCPBA (0.01 g of 77% max., 0.43 mmol) was added to the reaction mixture, stirred 1 d, and the solution was partitioned between brine (15 mL) and EtOAc (3×10 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and purified using Shimadzu automated preparative HPLC System to give 1-(4-benzoyl-piperazin-1-yl)-2-(1H-indol-4-yl)-ethane-1,2-dione (0.028 mg, 77 mmol, 29%) as a yellow solid: MS m/z: (M+H)+ calcd for C21H19N3O3:362.14; found 362.09. HPLC retention time: 1.13 minutes (column A).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[OH2:16].[OH:17]OS([O-])=O.[K+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)(=[O:17])=[O:16]
Reactant: COC(=O)c1ccc(SCCCCl)cc1
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(S(=O)(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 91 %

Procedure:
Methyl 4-(3-chloropropylsulfanyl)benzoate (1.84 g, 7.52 mmol) was dissolved in methanol (46 mL), followed by the addition of water (4.6 mL) and Oxone (4.62 g, 7.52 mmol). The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was filtered and the solvent removed in vacuo. The resulting solid was dissolved in dichloromethane and washed with water (2×10 mL). The organic layer was dried over Na2SO4, filtered and the solvent removed in vacuo to yield methyl 4-(3-chloropropylsulfonyl)benzoate (1.89 g, 91%) as a viscous liquid. ESI-MS m/z calc. 276.0. Found 277.1 (M+1)+; Retention time: 1.36 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J=8.3 Hz, 2H), 8.07 (d, J=8.3 Hz, 2H), 3.92 (s, 3H), 3.73-3.46 (m, 4H), 2.21-1.79 (m, 2H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:27]=[N:26][C:8]2[O:9][CH2:10][CH2:11][N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:7]=2[CH:6]=1)=[NH:4].C(O)(=O)C.[CH3:32][C:33]([CH3:35])=O>>[CH3:32][C:33]1([CH3:35])[O:1][NH:2][C:3]([C:5]2[CH:27]=[N:26][C:8]3[O:9][CH2:10][CH2:11][N:12]([S:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=4)(=[O:15])=[O:14])[C:7]=3[CH:6]=2)=[N:4]1
Reactant: CC(C)=O
Reactant: N=C(NO)c1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Solvent: CC(=O)O
Product: CC1(C)N=C(c2cnc3c(c2)N(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCO3)NO1
Temperature: 80 °C
Reaction time: 48 h
Yield: 44.7 %

Procedure:
To a solution of N-hydroxy-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboximidamide (25 mg, 0.062 mmol) in acetone (2 mL) was added acetic acid (500 μL, 8.73 mmol). The reaction was heated to 80° C. and stirred at that temperature for 48 h. The reaction mixture was concentrated under reduced pressure. The resulting paste was purified by flash column chromatography using a gradient elution of hexanes with 20-100% EtOAc to provide 7-(5,5-dimethyl-2,5-dihydro-1,2,4-oxadiazol-3-yl)-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (12.3 mg, 0.028 mmol, 44.7% yield) as a white solid. LCMS (+ESI) m/z=443.1 [M+H]+; 1H-NMR (CDCl3) δ 8.45 (d, 1H), 8.38 (br s, 1H), 7.84 (d, 2H), 7.78 (d, 2H), 4.55 (br s, 1H), 4.02 (dd, 2H), 3.91 (dd, 2H), 1.63 (s, 6H).
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([F:18])=[C:4](F)[C:3]=1[F:20].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:23]=1[NH2:24]>>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:23]=1[NH:24][C:4]1[C:3]([F:20])=[C:2]([F:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[F:18].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:23]=1[NH:24][C:4]1[C:3]([NH:24][C:23]2[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:22]=2[Cl:21])=[C:2]([F:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[F:18]
Reactant: Cc1cccc(Cl)c1N
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Product: Cc1cccc(Cl)c1Nc1c(F)c(F)c2c(c1F)C(=O)c1ccccc1C2=O
Product: Cc1cccc(Cl)c1Nc1c(F)c2c(c(F)c1Nc1c(C)cccc1Cl)C(=O)c1ccccc1C2=O
Reaction time: 6 h

Procedure:
2 g of 1,2,3,4-Tetrafluoroanthraquinone and 25 g of 2-chloro-6-methylaniline were charged in a 50 cc, four necked flask and then the reaction was carried out at 140° C. for about 6 hours. After completion of reaction, 2-chloro-6-methylaniline was distilled out from the reaction solution and a column purification thereof was effected to give rise to 1.07 g of 2-(2-chloro-6-methylanilino)-1,3,4-trifluoroanthraquinone (Dye 8') yield 37.3 mol %) and 0.78 g of 2,3-bis(2-chloro-6-methylanilino)-1,4-difluoroanthraquinone (Dye 21') (yield 24.2 mol %). The physical properties of Dye 8' and analytical values defining the compound are tabulated in Table 22 and the physical properties of Dye 21' and analytical values defining the compound are tabulated in Table 24.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([CH2:9][CH2:10][CH2:11]Cl)=[O:8].NC(N)=[S:15].[CH3:17][N:18]1[C:22](Cl)=[N:21][N:20]=[N:19]1.[OH-].[Na+]>C(O)C>[CH3:17][N:18]1[C:22]([S:15][CH2:11][CH2:10][CH2:9][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:8])=[N:21][N:20]=[N:19]1
Reactant: O=C(CCCCl)c1ccccn1
Reactant: Cn1nnnc1Cl
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nnnc1SCCCC(=O)c1ccccn1
Reaction time: 2 h
Yield: 7.7 %

Procedure:
3-Chloropropyl 2-pyridyl ketone (1.8 g) and thiourea (0.8 g) are dissolved in ethanol (50 ml), and the solution is refluxed with stirring for 2 hours. To the mixture are added 1-methyl-5-chloro-1,2,3,4-tetrazole (1.2 g) and 10% aqueous sodium hydroxide (5 ml), and the mixture is refluxed for 3 hours. After evaporating ethanol under reduced pressure, water is added to the residue. The mixture is extracted with chloroform, and the extract is washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography (Wakogel C-200, eluting agent, chloroform), followed by recrystallized from hexane-ether to give 1-methyl-5-[3-(2-pyridylcarbonyl)propyl]thio-1,2,3,4-tetrazole (0.2 g) as colorless crystals, m.p. 73°-75° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C:9]([OH:11])=[O:10].C(N(CC)CC)C.[C:19]([O:23][C:24](N=[N+]=[N-])=[O:25])([CH3:22])([CH3:21])[CH3:20]>CC(C)=O>[C:19]([O:23][C:24]([NH:1][CH2:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[CH2:8][C:9]([OH:11])=[O:10])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: NCc1ccsc1CC(=O)O
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCc1ccsc1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture of 3-aminomethyl-2-thienylacetic acid 8 (3.1 g, 18 m. moles) and triethylamine (8 g. 80 m moles) in 50% aqueous acetone (80 ml) was added dropwise t-butoxycarbonyl azide (5.7 g, 40 m moles) over a period of 20 mins. at 0° C with vigorous stirring. The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The concentrate was washed with ether (2 × 20 ml), adjusted to pH 2 with conc. HCl and extracted with ethyl acetate (2 × 50 ml). The ethyl acetate extracts were washed with saturated aqueous sodium chloride, dried over MgSO4, treated with charcoal and evaporated under reduced pressure. The residue was triturated with n-hexane and crystallized from n-hexane and benzene to give 4.5 g (92%) of colorless needles 9, melting at 62° - 63° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:11])[CH:3]=1.CN(C=O)C.[Br:17][CH2:18][C:19](Br)=[O:20]>O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:19](=[O:20])[CH2:18][Br:17])[CH:3]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1cc(F)ccc1C(=O)O
Temperature: -5 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A solution of 4-fluoro-2-aminobenzoic acid (5.0 g, 32.2 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask which was equipped with a constant addition funnel (60 mL) was cooled with an ice-bath to -5° C. Bromoacetyl bromide (6.44 g, 2.8 mL, 32.2 mmol) was added dropwise while keeping the internal temperature between -5° and 0° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to room temperature and stirred overnight. To this solution was slowly added 150 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 8.13 g (91.4%) of the title compound as a white solid, mp 166°-168° C.: 1H NMR (DMSO-d6) δ13.92 (bs, 1H), 11.83 (s, 1H), 8.32 (dd, J=12, J=2.4, 1H), 8.09 (dd, J=9.2, J=6.8, 1H), 7.06 (ddd, J=8.8, J=9.2, J=2.4, 1H), 4.29 (s, 2H); 13C NMR (DMSO-d6) δ168.55, 165.60, 164.80 (d, J=248), 142.29 (d, J=12.9), 133.93 (d, J=10.6), 113.19, 110.42 (d, J=22), 106.43 (d, J=28), 30.54; MS (EI, m/z) 275 (M+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][CH2:62][O:63][CH:64]3[CH2:69][CH2:68][CH2:67][CH2:66][O:65]3)[CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][CH2:62][O:63][CH:64]3[CH2:69][CH2:68][CH2:67][CH2:66][O:65]3)[CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 70 °C

Procedure:
To a solution of Intermediate 96c (100 mg, 0.25 mmol) in 1,4-dioxane (3.00 mL) was added DIPEA (89.0 μL, 0.51 mmol) and Intermediate 39b (133 mg, 0.25 mmol). The reaction was heated to 70° C. overnight then cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-8% MeOH in DCM to give the title compound. LCMS (Method 4): Rt 4.09 min, m/z 777 [MH+].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:40][OH:41])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:38]#[N:39])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:44])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:40][OH:41])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:38]([NH2:39])=[O:44])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(N6CCOCC6)nc54)c3CO)ncc2c1
Reactant: CCO
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccc(N6CCOCC6)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-morpholino-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (75 mg, 136 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (2 mg, 4.66 μmol, Eq: 0.0343) were combined with ethanol (1 ml) and water (1.00 ml) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h, then concentrated in vacuo. Mixture was diluted with acetonitrile and water and filtered. The resultant filtrate was lyophilized to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (70 mg, 90%, [M+H]+ 571).
Reaction SMILES: [C:1](OC)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].[H][H]>[Cr].[Cu]>[OH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: [H][H]
Reactant: COC(=O)CCCCCCCCCCCCCC(=O)OC
Agent: [Cr]
Agent: [Cu]
Product: COC(=O)CCCCCCCCCCCCCCO
Reaction time: 2 h
Yield: 35 %

Procedure:
150 g (499 mmol) of dimethyl 1,15-pentadecandioate and 750 mg (0.5% by weight per the diester) of a commercial copper-chromium catalyst (content of copper as copper oxides: 42% by weight) were added to an autoclave and subjected to hydrogenation reaction at the hydrogen pressure of 20.0 Mpa at 280° C. After 2 hours, methyl 15-hydroxypentadecanoate was obtained in 35% yield. The degree of the conversion was 67% the selectivity was 53%, and the yield was 35%.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:14][CH:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12]2)=[N:4][CH:3]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[CH3:23][N:15]([CH:13]1[CH2:14][N:11]([C:5]2[C:6]3[N:7]([N:8]=[N:9][N:10]=3)[C:2]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[CH:3][N:4]=2)[CH2:12]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: OB(O)c1cccs1
Reactant: CN(C(=O)OC(C)(C)C)C1CN(c2ncc(Br)n3nnnc23)C1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)C1CN(c2ncc(-c3cccs3)n3nnnc23)C1
Temperature: 80 °C
Reaction time: 14 h
Yield: 69.5 %

Procedure:
A 3 L round bottom flask was charged with tert-butyl (1-(5-bromotetrazolo[1,5-a]pyrazin-8-yl)azetidin-3-yl)(methyl)carbamate (50 g, 0.13 mol), thiophene-2-boronic acid (22 g, 0.17 mol), tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol), Cs2CO3 (50 g, 0.15 mol), 1,4-dioxane (1.5 L) and water (500 mL). After the air was purged by bubbling N2 into the solution, the resulting solution was stirred at 80° C. under N2 for 14 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 0-25% ethyl acetate in CH2Cl2, and then crystallized from methanol, to afford 35 g (70%) of the product as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1)C(=O)C.[OH-].[K+]>C(O)C>[CH3:1][NH:2][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH3:21])=[N:19][N:20]=3)[N:17]=2)[CH:7]=1
Reactant: CC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNc1cccc(-c2ccc3nnc(C)n3n2)c1
Yield: 101.5 %

Procedure:
A mixture of 13.5 g of N-methyl-N-[3-(3-methyl-1,2,4-triazolo[4,3-b]-pyridazin-6-yl)phenyl]acetamide and 10 g of potassium hydroxide in 500 ml of ethanol was heated to reflux for 12 hours. The solution was concentrated in vacuo and the residue partitioned between 200 ml of brine and 300 ml of dichloromethane. The aqueous layer was extracted with 150 ml portions of dichloromethane. The combined organic layer and extracts were dried, concentrated in vacuo and the residue recrystalized from dichloromethane-hexane, to give 11.66 g of yellow crystal, mp 223°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[C:25]([O:27]CC)=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([CH2:30][CH:31]2[CH2:32][CH2:33]2)[C:25]([OH:27])=[O:26])[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(CC1CC1)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.68 g, 0.4 mmol) and lithium hydroxide monohydrate (100 mg, 4.6 mmol) in a MeOH/THF/Water solvent mixture (15 ml/15 ml/15/ml) was stirred for 3 h at room temperature. After completion of reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by Flash Column Chromatography to give 2-(5-Chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoic acid in 88% yield (0.4 g). 1H-NMR (CDCl3, 500 MHz): 7.72 (d, 2H); 7.65 (d, 2H), 7.43 (s, 1H); 7.24 (s, 1H); 3.98 (q, 2H); 3.72 (t, 1H); 1.94 (m, 1H), 1.78 (m, 1H); 0.71 (m, 1H), 0.46 (m, 2H), 0.02-0.19 (m, 2H).