Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17]C(OCC)=O)[CH2:15][N:16]=1)=[CH:8]2.[CH3:31][Mg]Br.[Cl-].[NH4+].[O:36]1[CH2:40][CH2:39]CC1>>[OH:36][C:40]([CH3:39])([CH3:31])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:23]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:25])=[N:16][CH2:15]1
Reactant: C[Mg]Br
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: CN(c1cccc2cc(C3=NCC(CC(C)(C)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of ethyl (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.204 g) in absolute tetrahydrofuran (10 mL) was added a 1.0M tetrahydrofuran solution (4.4 mL) of methylmagnesium bromide, and the mixture was stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-80:20), and recrystallized from hexane-ethyl acetate to give the title compound (0.142 g, yield 72%) as colorless crystals. melting point 156-158° C.
Reaction SMILES: [F:1][C@H:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][OH:4].N1C=CC=CC=1.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>O>[S:17]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)([O:4][CH2:3][C@H:2]([F:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:19])=[O:18]
Reactant: CCCCCC[C@@H](F)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCC[C@@H](F)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 6 h
Yield: 93.1 %

Procedure:
A reaction vessel was charged with 10.0 g of (2R)-2fluorooctanol and 25 ml of pyridine, and 13.0 g of tosyl chloride was added with stirring at 0°-5° C. After the reaction was effected for 6 hours, the mixture was poured into water and extracted with 100 ml of benzene. The resultant solution in benzene was washed sequentially with water, an aqueous solution of NaHCO3 and water in that order, and dried over Glauber's salt. The solvent was distilled off to obtain 19.0 g (yield 92.6%) of crude (2R)-2-fluorooctyl tosylate as the residue.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(N1C2C=CC=CC=2N=N1)(=O)=O.CCN(C(C)C)C(C)C>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: Nc1ccccc1
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: CS(=O)(=O)n1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)cc1C(=O)Nc1ccccc1
Temperature: 160 °C
Yield: 63.7 %

Procedure:
A mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (203 mg, 0.9354 mmol), aniline (87.11 mg, 85.23 μL, 0.9354 mmol), 1-methylsulfonylbenzotriazole (276.7 mg, 1.403 mmol) and DIPEA (241.8 mg, 325.9 μL, 1.871 mmol) in THF (2.0 mL) was heated in the microwave at 160° C. for 10 mins. The reaction mixture was concentrated and the residue partitioned between EtOAc and 2M NaOH. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo to give the product as a yellow solid (174 mg, 64% Yield). 1H NMR (400.0 MHz, DMSO) δ 7.77 (br s, 2H), 8.18 (d, 1H) and 8.32 (d, 1H); ppm; MS (ES+) 293.94.
Reaction SMILES: [NH2:1][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[CH:5]=[CH:4][C:3]=1[CH3:18].[Br:19]Br>CC(O)=O>[NH2:1][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]([Br:19])=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(Br)c2c(c1N)C(=O)c1ccccc1C2=O
Temperature: 40 °C
Yield: 90 %

Procedure:
1-Amino-2-methylanthraquinone (300 g) is slurried with 1500 ml of HOAc in a 5-liter flask. The temperature is raised to 40° C. Neat bromine (405 g) is added over 21/2 hours with stirring at 40°-50° C. The mixture is stirred for 20 additional minutes and filtered. The solids to recovered are washed with HOAc and water and sucked dry with an aspirator and transferred to a reaction flask along with 150 g of NaHSO3 and 1.5 liters of water. The mixture is gradually heated to 90° C. (over two hours) with stirring to give 1-amino-2-methyl-4-bromoanthraquinone (A) (also marketed as AMBAX) as a solid which is recovered from the reaction mixture by filtration in 90% yield, rinsed with water and dried overnight at 155° C. and 1 mm Hg absolute vacuum.
Reaction SMILES: [OH:1][CH:2]([CH2:41][OH:42])[CH2:3][N:4]([CH3:40])[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:37])[F:36])=[C:25]([CH3:39])[CH:24]=3)=[O:22])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6].C(N(CC)C(C)C)(C)C.[C:52](N1C=CN=C1)(N1C=CN=C1)=[O:53]>ClCCl>[CH3:40][N:4]([CH2:3][CH:2]1[CH2:41][O:42][C:52](=[O:53])[O:1]1)[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:37])([F:38])[F:36])=[C:25]([CH3:39])[CH:24]=3)=[O:22])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)CC(O)CO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)CC4COC(=O)O4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid (2,3-dihydroxypropyl)-methyl-amide of Example 2 (0.50 g, 0.87 mmol) in dichloromethane (17 mL) at 0° C. was added N,N-diisopropylethyl amine (0.30 mL, 1.72 mmol) followed by 1,1′-carbonyldiimidazole (0.14 g, 0.87 mmol). The reaction was allowed to warm to room temperature while stirring overnight then concentrated in vacuo to give a white solid. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a white foam. Purification by flash chromatography using a solvent system of 80% ethyl acetate in hexane provided the title product, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (0.48 g).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.C(N(CC)CC)C.[O:54]1[CH:58]=[CH:57][CH:56]=[C:55]1[C:59](Cl)=[O:60].C(=O)(O)[O-].[Na+]>O1CCCC1>[NH:17]1[C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:59]([C:55]3[O:54][CH:58]=[CH:57][CH:56]=3)=[O:60])=[CH:42][CH:41]=2)=[N:20][CH:19]=[N:18]1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)cc1)c1ccco1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.7 %

Procedure:
To a solution of 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]1H-indazol-3-yl}phenylamine (0.300 g, 0.498 mmol) was added tetrahydrofuran (4.50 mL), triethylamine (0.345 mL, 2.48 mmol), and 2-furoyl chloride (0.058 mL, 0.735 mmol). The mixture was stirred for 16 h at ambient temperature and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by preparative HPLC (30-80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0086 g, 5% yield). 1H NMR (DMSO-d6) δ 8.75 (d, 1H), 8.10 (m, 6H), 7.74 (m, 1H), 7.39 (d, 1H), 6.75 (m, 1H). ES-MS (m/z) 371 [M+1]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=2[Cl:26])=[N:8][N:7]=1.O>CN(C=O)C>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[CH2:18][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6]2=[N:7][N:8]=[N:3][N:2]2[N:1]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nn3nnnc3c2c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 78.5 %

Procedure:
NaN3 was added to a solution under N2 of 4-chloro-1-(3,5-dichloro-pyridin4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), obtained as described in example 13, in anhydrous DMF (20 ml) and the mixture was heated at 80° C. overnight, then at 120° C. for 7 hours, then poured into water (10 volumes) and extracted 3 times with CH2Cl2, dried and concentrated under vacuum to give a solid which was purified by flash chromatography (eluent:60:80 petrolatum/ethyl acetate 6:4). The eluate was crystallised from acetonitrile (75 ml) to give 0.36 g of the title compound (yield: 78.5%). m. p.: 275-276° C.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[C:14]([CH2:15]O)=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2]2.O=S(Cl)[Cl:19]>ClCCl>[Cl:19][CH2:15][C:14]1[C:9]([N:3]2[CH2:4][CH:5]3[O:8][CH:1]([CH2:7][CH2:6]3)[CH2:2]2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccnc1N1CC2CCC(C1)O2
Solvent: ClCCl
Product: ClCc1cccnc1N1CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a cooled (0° C.) solution of (2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methanol (0.070 g, 0.32 mmol) in dichloromethane was added SOCl2 (0.23 mL, 3.2 mmol) and the reaction mixture was allowed to warm to ambient temperature. After 1 h, the reaction mixture was concentrated and azeotroped with toluene three times to provide 3-(3-(chloromethyl)pyridin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.075 g, 98%) as a clear oil. MS (ES) for C12H15ClN2O: 239 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:17](=[O:18])[C:16]2[C:15](=[O:19])[C:14]3[CH:13]=[CH:12][C:11]([Cl:20])=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([OH:21])=[N:5]1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO.Cl>CN(C)C=O>[Cl:20][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:19])[C:16]3[C:17](=[O:18])[N:4]([CH2:3][CH2:2][N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)[N:5]=[C:6]([OH:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Agent: Cl
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCN3CCN(c4ccccc4)CC3)c(=O)c12
Temperature: 110 °C
Reaction time: 120 h

Procedure:
2(2-Bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (0.500 g, 1.35 mM) was stirred in dimethylformamide (10 mL), and N-phenylpiperazine (10 mL, 10.6 g, 65.5 mM) was added. The resulting yellow suspension was heated to ˜110° C. to form a clear yellow solution. The solution was heated for 6 hours during which time a precipitate formed. The suspension was cooled to room temperature and stirred for five days. The resulting yellow suspension was dissolved into aqueous methanol (500 mL, 50%). The pH of this solution was carefully adjusted to pH=6 with 1N hydrochloric acid (˜20 mL) which gave a yellow precipitate. This suspension was stirred for 1 hour and filtered to give the title compound contaminated with N-phenylpiperazine (0.753 g). This material was recrystallized from hot ethanol (200 mL) to give the title compound (0.428 g, 70%) as a yellow powder, mp 361-364° C.; MS(CI): 452 (M+H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[C:13]([F:32])=[CH:14][C:15]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[F:35][C:36]1[C:41](B(O)O)=[CH:40][C:39]([CH3:45])=[CH:38][N:37]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:32][C:13]1[C:12]2[O:11][C:10]3[C:19](=[CH:20][C:7]([C:41]4[C:36]([F:35])=[N:37][CH:38]=[C:39]([CH3:45])[CH:40]=4)=[CH:8][CH:9]=3)[C@@:18]3([CH2:24][O:23][C:22]([NH2:25])=[N:21]3)[C:17]=2[CH:16]=[C:15]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:14]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(OS(=O)(=O)C(F)(F)F)ccc1Oc1c(F)cc(N3CCOCC3)cc12
Reactant: Cc1cnc(F)c(B(O)O)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: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(F)c(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(N4CCOCC4)cc(F)c2O3)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A resealable vial was charged with (S)-2-amino-4′-fluoro-2′-morpholino-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (130 mg, 0.258 mmol; prepared as described in Method BB40), tetrakis(triphenylphosphine)palladium(0) (29.8 mg, 0.026 mmol), 2-fluoro-5-methylpyridin-3-ylboronic acid (64.0 mg, 0.413 mmol), DMF (1.3 mL) and 2 M aqueous sodium carbonate (387 μL, 0.775 mmol). The vial was sealed and the mixture stirred for 2 hr at 85° C. The mixture was cooled and diluted with EtOac (6 mL) and water (2 ml). The organic layer was filtered through celite, concentrated, and purified by reverse phase HPLC (Gilson, 15-90% MeCN in 0.1% aq. TFA). The fractions containing product were concentrated in vacuo, neutralized with saturated sodium bicarbonage and extracted with ethyl acetate. Organic layer was washed with brine, and concentrated. The residue was redissoved in ˜1 mL 1:1 MeCN/water and liophilized to afford (S)-4′-fluoro-7′-(2-fluoro-5-methylpyridin-3-yl)-2′-morpholino-5H-spiro[oxazole-4,9′-xanthen]-2-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([CH:18]=[O:19])[CH:12]=2)[CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[C:15]([O:17][CH3:22])[CH:14]=[C:13]([CH:18]=[O:19])[CH:12]=2)[CH:3]=1
Reactant: CI
Reactant: N#Cc1ccc(Cl)cc1Oc1cc(O)cc(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(Oc2cc(Cl)ccc2C#N)c1
Reaction time: 16 h

Procedure:
4-Chloro-2-(3-formyl-5-hydroxyphenoxy)benzonitrile (0.20 g, 0.75 mmol) in DMF (5 ml) was treated with sodium hydride (60% in mineral oil, 30 mg, 0.78 mmol) followed after 10 min by methyl iodide (0.1 ml). After 16 h, a further amount of sodium hydride (8 mg) and methyl iodide (0.1 ml) were added. After 3 h, the mixture was diluted with water, extracted with ethyl acetate, the extracts washed with water, dried over sodium sulphate and evaporated to give the sub-title compound as a pale yellow solid (213 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>O>[C:29]([O:10][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:32])[CH:30]=[CH2:31]
Reactant: C=CC(=O)Cl
Reactant: OCc1ccccc1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(=O)OCc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Into a 200 mL three-neck flask equipped with a stirrer, a thermometer, a cooling tube, and a calcium chloride tube, 20.0 g of ortho-phenylbenzyl alcohol, 100.0 g of anhydrous toluene, 13.2 g of triethylamine, and 7.8 mg of methoquinone were charged, and they were cooled to 10° C. or less using an ice bath. Into the flask, 11.8 g of acryloyl chloride was dropped over 30 minutes. The temperature was increased to room temperature and a reaction was caused to proceed for two hours. After the reaction, the reaction solution was poured into water and washed with a 5% NaOH aqueous solution and a saline solution, and the solvent was distilled off to obtain an orange liquid. The orange liquid was purified with a silica gel column to obtain 20.44 g of ortho-phenylbenzyl acrylate. The obtained ortho-phenylbenzyl acrylate was a colorless, transparent liquid at ordinary temperature and had a refractive index of 1.5776 and a viscosity of 27 mPa·s at 25° C. The measurement result of 1H-NMR is shown below.
Reaction SMILES: O[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][N:4]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:12][C:13](=[O:14])[N:8]2[CH2:7][C:6]([CH3:22])([CH3:21])[CH2:5]1.[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:22][C:6]1([CH3:21])[CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:10]=[C:9]2[N:4]([CH2:3][CH:2]([N:33]2[C:29](=[O:39])[C:30]3[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:34])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:5]1
Reactant: CC1(C)CN(CC(O)c2ccccc2)c2nc(-c3ccncc3)cc(=O)n2C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CC1(C)CN(CC(c2ccccc2)N2C(=O)c3ccccc3C2=O)c2nc(-c3ccncc3)cc(=O)n2C1
Reaction time: 18 h

Procedure:
To a solution of 0.2 g (0.531 mmol) of 9-(2-Hydroxy-2-phenyl-ethyl)-7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one, 0.080 g (0.584 mmol) of phthalimide and 0.195 g (0.742 mmol) in 30 ml of anhydrous tetrahydrofuran at 0° C. was added 0.142 ml (0.903 mmol) of diethyl azodicarboxylate and the reaction mixture stirred for 18 h.
Reaction SMILES: OS(O)(=O)=O.O.[C:7]1([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[I:18]I>CC(O)=O.CCOC(C)=O>[I:18][C:10]1[CH:11]=[CH:12][C:7]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:9]=1
Reactant: II
Reactant: O=C(O)CCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of H2SO4 (1.25 mL), water (12.5 mL) and AcOH (25 mL) in a 250 mL flask and 3-phenylpropanoic acid (3.00 g, 20.0 mmol), iodine (1.40 g, 5.5 mmol) and KIO3 (0.98 g, 4.6 mmol) was added. The reaction was heated to reflux and a solution of iodine (1.40 g, 5.5 mmol) in AcOH (25 mL) was added in portions of 5 mL as the colour of the reaction faded from purple to orange. After 3 hours when no further colour changes appeared the reaction was cooled to room temperature. before quenching with 1M NaHSO3. The reaction was added water and extracted with EtOAc. The organic phases were combined, washed with brine, dried over MgSO4 and concentrated under vacuum. The product (4.15 g, 75%), containing minor impurites of starting material and the ortho-iodinated product, was recrystallised from PE to provide 1.83 g (33%) of the pure and white crystalline product. Rf: 0.10 (EtOAc:hexanes, 1:4); 1HNMR (CDCl3) δ 7.62-7.59 (m, 2H), 6.97-6.95 (m, 2H), 2.92-2.87 (t, 2H, J=7.5 Hz), 2.68-2.63 (t, 2H, J=7.5 Hz); 13CNMR (CDCl3) δ 178.5, 139.7, 137.6, 130.4, 91.6, 35.2, 30.0.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].C(N(CC)C(C)C)(C)C.[F:27][C:28]1[CH:29]=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[CH:32][C:33]=1F>C(#N)C>[F:27][C:28]1[CH:29]=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[CH:32][C:33]=1[N:14]1[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][F:8])[C:12](=[O:17])[CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C1CNCCN1CCF
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2F)CCN1CCF
Yield: 72.4 %

Procedure:
1-(2-Fluoroethyl)-2-oxopiperazine trifluoroacetate (6.1 g) was dissolved in acetonitrile (100 ml). N,N-Diisopropylethylamine (13 ml) was added to the mixture, followed by 3,4-difluoronitrobenzene (3.39 g), and the mixture heated to reflux for 18 hours. Solvent was evaporated, and the residue chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 4% methanol in dichloromethane. Relevant fractions were combined and evaporated to give 3-fluoro-4-(4-{2-fluoroethyl}-3-oxopiperazin-1-yl)nitrobenzene product as a solid (4.4 g).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O>[F:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccccc1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccccc1F
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a solution of ethanesulfonyl chloride (0.368 ml, 3.89 mmol) in DCM (1 ml) and pyridine (1 ml) was added 2-fluoroaniline (0.360 ml, 3.89 mmol) at rt and the reaction was stirred at 50° C. for 5 hours. The reaction was then stirred at rt overnight. The reaction was diluted with EtOAc and washed with H2O and sat. NaCl solution. The organic layer was dried over Na2SO4 and concentrated. Purification of the residue by flash chromatography on silica gel (eluent: 0% to 35% EtOAc/hexane) provided the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29](Cl)=[O:30]>ClCCl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N+:33]([O-:35])=[O:34])=[C:28]([CH:32]=1)[C:29]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[N:10]=1)=[O:30]
Reactant: Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine (520 mg, 2.29 mmol, 1.00 equiv) in dichloromethane (5 mL), pyridine (540 mg, 6.84 mmol, 3.00 equiv), and 5-chloro-2-nitrobenzoyl chloride (500 mg, 2.27 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with 2×50 mL of water, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (10:1). This resulted in 800 mg (85%) of product as a yellow solid.