Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]([C:24]#[C:25][CH3:26])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[CH2:27]([O:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)[CH3:28].[F-].[Cs+]>COCCOC.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>[CH2:27]([O:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH:7]([O:11][C:12]2[CH:13]=[CH:14][C:15]([C@H:18]([C:24]#[C:25][CH3:26])[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=2)[CH2:6][CH2:5]3)[CH:33]=[CH:32][CH:31]=1)[CH3:28]
Reactant: CC#C[C@H](CC(=O)OC)c1ccc(OC2CCc3cc(Br)ccc32)cc1
Reactant: CCOc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CC#C[C@H](CC(=O)OC)c1ccc(OC2CCc3cc(-c4cccc(OCC)c4)ccc32)cc1
Temperature: 95 °C

Procedure:
A mixture of 59.2 (30 mg, 0.073 mmol), 3-ethoxyphenylboronic acid (14.5 mg, 0.087 mmol) and CsF (55 mg, 0.36 mmol) in 1,2-dimethoxyethane (2 mL) was degassed with N2 for 3 minutes. Pd(PPh3)4 (20 mg, 0.017 mmol) was added, and the resulting mixture was heated to 95° C. for 8 hours. After cooling, the reaction mixture was quenched with water and extracted with EtOAc to obtain the ester 59.3, which was directly hydrolyzed in next step.
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([C:8]([N:10]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=5)[CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:11]2=[O:12])=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(O)C>[Pd].CN(C=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=5)[CH2:25][CH2:26]4)=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:11]2=[O:12])=[O:9])=[CH:39][CH:40]=1
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3ccc(N)cc3)CC2)cc1OC
Yield: 31.7 %

Procedure:
To a mixture of 1-(4-nitrobenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (1.5 g) and ethanol (30 ml) were added DMF (5 ml) and 10% palladium on carbon (300 mg). The mixture was hydrogenated at 50° to 60° C. After competion of reaction, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent:dichloromethane:methanol= 100:2) and recrystallized from ethanol to give 1-(4-aminobenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (0.45 g).
Reaction SMILES: Br[C:2](=[CH:6]OCC)[C:3](=[O:5])[CH3:4].Cl.[OH:11][CH2:12][C:13]([NH2:15])=[NH:14].CN(C)C(N(C)C)=N>CC(C)=O>[OH:11][CH2:12][C:13]1[NH:14][CH:6]=[C:2]([C:3](=[O:5])[CH3:4])[N:15]=1
Reactant: CCOC=C(Br)C(C)=O
Reactant: N=C(N)CO
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)c1c[nH]c(CO)n1
Reaction time: 48 h
Yield: 21 %

Procedure:
9.7 g (0.05 mol) of 3-bromo-4-ethoxy-3-buten-2-one was combined with 5.53 (0.05 mol) of hydroxyacetamidine hydrochloride in 100 ml acetone to form a slurry. To the slurry at 25° was added 11.5 g (0.1 mol) of 1,1,3,3-tetramethylguanidine over a period of 5 minutes. After stirring for 48 hours the slurry was filtered and the mother liquors were concentrated in vacuo to an oil which was chromatographed on silica gel 60 (E. Merck) using chloroform as eluent to give 1.48 g (21%) of 2-hydroxymethyl-4-acetylimidazole, mp 147°-148° . nmr (DMSO-d6) (δ): 7.73 (s, 1H); 5.46 (very broad s, 1H); 4.5 (broad s, 2H); 2.4 (s, 3H).
Reaction SMILES: [Si]([O:8][C@H:9]([C:69]1[CH:78]=[CH:77][C:76]([OH:79])=[C:75]2[C:70]=1[CH:71]=[CH:72][C:73](=[O:80])[NH:74]2)[CH2:10][N:11]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]1([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:68])[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([C:45]4[CH:46]=[C:47]5[C:52](=[C:53]([CH3:55])[CH:54]=4)[N:51]=[CH:50][C:49]([C:56](=[O:58])[NH2:57])=[C:48]5[NH:59][C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH3:67])[CH:61]=4)(=[O:44])=[O:43])[CH:37]=3)=[CH:30][CH:29]=2)[S:27][CH2:26][CH2:25][S:24]1)C(=O)OC(C)(C)C)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:8][C@H:9]([C:69]1[CH:78]=[CH:77][C:76]([OH:79])=[C:75]2[C:70]=1[CH:71]=[CH:72][C:73](=[O:80])[NH:74]2)[CH2:10][NH:11][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35]([C:36]3[CH:37]=[C:38]([S:42]([C:45]4[CH:46]=[C:47]5[C:52](=[C:53]([CH3:55])[CH:54]=4)[N:51]=[CH:50][C:49]([C:56]([NH2:57])=[O:58])=[C:48]5[NH:59][C:60]4[CH:65]=[CH:64][CH:63]=[C:62]([O:66][CH3:67])[CH:61]=4)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=3)=[O:68])=[CH:32][CH:33]=2)[S:24][CH2:25][CH2:26][S:27]1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C6(CCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(O)c8[nH]c(=O)ccc78)C(=O)OC(C)(C)C)SCCS6)cc5)c4)cc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(C6(CCCCNC[C@H](O)c7ccc(O)c8[nH]c(=O)ccc78)SCCS6)cc5)c4)cc23)c1
Reaction time: 0.5 h

Procedure:
Intermediate 158 (90 mg, 0.08 mmol) was taken up in dichloromethane and treated with trifluoroacetic acid (0.50 mL). After 30 minutes of stirring, the mixture was concentrated to a residue under reduced pressure, taken up in tetrahydrofuran (1 mL) and treated successively with TBAF solution (1.0 M in THF, 1 mL) and glacial acetic acid (0.50 mL). The mixture was left overnight at room temperature and then concentrated under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (RP-HPLC, acetonitrile/water/0.1% TFA) to provide, after concentration, the trifluoroacetic acid salt of the title compound as a bright yellow foam (22 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([O:23][Si](C)(C)C)C#N)=[C:16]([F:28])[CH:15]=1.[C:29]([N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)(=[O:31])[CH3:30]>C1COCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:35]2([OH:38])[CH2:36][CH2:37][N:32]([C:29](=[O:31])[CH3:30])[CH2:33][CH2:34]2)=[O:23])=[C:16]([F:28])[CH:15]=1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)OC(C#N)c1ccc(Cl)cc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCC(O)(C(=O)c2ccc(Cl)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
To a solution of diisopropylamine (4.42 mL, 31.59 mmol) in THF (20 mL) at 0° C. under Ar, was added n-BuLi (12.63 mL, 31.59 mmol, 2.5 M solution in hexane). The mixture was stirred at 0° C. for 30 min. After cooling to −78° C., (4-chloro-2-fluoro-phenyl)-trimethylsilanyloxyacetonitrile (8.12 g, 31.59 mmol) was added. After stirring at −78° C. for 1.5 h, 1-acetyl-piperidin-4-one (4.45 g, 31.59 mmol) was added. The final mixture was stirred at −20° C. for overnight. After concentration, EtOAc (100 mL) was added. The organic phase was washed with Sat. NH4OAc solution, Sat. NaHCO3 solution and concentrated. The residue was dissolved in MeOH (30 mL). 1N HCl solution (20 mL) was added. The mixture was stirred at RT for 2 h. After concentrating the mixture, EtOAc (50 mL) was added. The organic layer was basified with Sat. NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (Ethyl acetate) to give the desired product (4 g, 42% yield) as a white solid. MS: (ESI), M/Z, 300 (M+1). Retention time: 0.87 min (FA-standard).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:19]=[O:20]>>[CH:19]([C:8]1[C:7]([O:9][CH3:10])=[CH:6][C:5]([OH:11])=[CH:4][C:3]=1[O:2][CH3:1])=[O:20]
Reactant: CN(C)C=O
Reactant: COc1cc(O)cc(OC)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(O)cc(OC)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
To a solution of 3,5-dimethoxyphenol (50 g, 320 mmol) in phosphorous oxychloride (60 mL, 650 mmol) at 0° C. was added dimethylformamide (37 mL, 490 mmol) over a period of 30 min and the mixture was warmed to room temperature and stirred overnight. The mixture was added to icewater (600 mL) and the mixture was washed with ether (3×200 mL). Then an 32% aqueous solution of sodium hydroxide was added until pH was 5.5 and the compound precipitated. The precipitate was separated and washed with water (100 mL) and ether (100 mL) and dried in vacuo. The precipitate was recrystallized from ethanol (600 mL) to give 22.6 g of 4-formyl-3,5-dimethoxyphenol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl.C(OCC)(=O)C>[Cl:24][CH2:25][C:26]([NH:18][NH:17][C:15]([C:14]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:23])=[C:10]([Cl:22])[C:11]2[N:12]([CH:19]=[CH:20][N:21]=2)[CH:13]=1)=[O:16])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CCl)NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
7-(4-Bromo-2-fluorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid hydrazide (100 mg, 0.25 mmol) of Step A, Example 35 was suspended in dichloromethane (2 mL) and 4-Me morpholine (0.040 mL, 0.36 mmol) was added. The mixture was cooled to 0° C. and then chloroacetyl chloride (0.029 mL, 0.36 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour under N2. Rinsed reaction mixture into a separatory funnel with a small amount of tetrahydrofuran and methanol and then diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous NaCl, dried over Na2SO4 and concentrated. Purification of the crude product was achieved by flash column chromatography (20:1 dichloromethane/methanol) to yield the desired product (64 mg, 54%) as a yellow solid. MS ESI (+) m/z 474, 476 (M+, Cl, Br pattern) detected.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:12]([C@@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[OH:31])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:41]([C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([O-:43])=[O:42].O>N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]([C@H:12]([C@@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[OH:31])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([C:48](=[O:49])[C:47]1[CH:46]=[CH:45][C:44]([N+:41]([O-:43])=[O:42])=[CH:52][CH:51]=1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(C(=O)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.5 %

Procedure:
First, 59 g (109 mmol) of 2,3,4,6-tetra-O-benzyl glucose, from Sigma Chemical Company, was dissolved in 200 ml of pyridine and 22.3 g (120 mmol) of p-nitrobenzoyl chloride was added. The mixture was stirred at room temperature for 72 hours, poured into 750 ml of water, and the solid was isolated by filtration and recrystallized from 95% ethanol to produce 68.8 g (91%) of 2,3,4,6-tetra-O-benzyl-1-p-nitrobenzoyl glucose.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]1([CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(N(CCCC)CCCC)CCC>[C:7]1([C:13]2[C:14]([OH:15])=[N:1][C:2]3[N:3]([N:4]=[CH:5][CH:6]=3)[C:19]=2[OH:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: Nc1cc[nH]n1
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2ccnn2c(O)c1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 9 g 3-amino pyrazole and 25.6 g diethyl phenylmalonate in N,N-dibutylbutan-1-amine was stirred at 185° C. over night. The reaction mixture consisted of two layers after cooling to room temperature. The top layer was removed and the lower layer was diluted with dichloromethane and methanol. The resulting solution was concentrated and extracted with a mixture of diethyl ether and 10% w/w NaOH solution. The organic layer was discarded and aqueous layer acidified with concentrated HCl. The precipitated product was collected by filtration.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)C.N1C(C)=CC=CC=1C.[CH2:16]([O:23][C:24]1[S:28][N:27]=[C:26]([S:29](C)=O)[N:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>>[CH2:16]([O:23][C:24]1[S:28][N:27]=[C:26]([S:29][CH2:1][O:4][C:5](=[O:7])[CH3:6])[N:25]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)c1nsc(OCc2ccccc2)n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Product: CC(=O)OCSc1nsc(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
Into 1.5 g of acetic anhydride were added 620 mg of 2,6-lutidine and 500 mg of 5-benzyloxy-3-methylsulfinyl-1,2,4-thiadiazole under ice-cooling. After stirring for 15 hours at room temperature, the reaction mixture was added to saturated sodium hydrogen carbonate aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 376 mg of 5-bezyloxy-3-acetoxymethythio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (44)).
Reaction SMILES: CCOCC.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:19])=[CH:9][C:8]=1[C:20]([F:23])([F:22])[F:21].C([Li])CCC.[CH:29]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)=[O:30]>O1CCCC1>[CH3:19][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH:29]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[OH:30])=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:9]=2)[C:17]([CH3:18])=[CH:16][CH:15]=1
Reactant: Cc1ccc(C)n1-c1ccc(Br)c(C(F)(F)F)c1
Reactant: O=Cc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(C)n1-c1ccc(C(O)c2ccncc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To 12 mL of an anhydrous ether solution of 1.08 g (3.4 mmol) of 1-(4-bromo-3-trifluoromethyl-phenyl)-2,5-dimethyl-1H-pyrrole, 1.4 mL of n-butyllithium (a tetrahydrofuran solution, 2.44 M) was added at one time at −60° C. and the mixture solution was stirred for one hour. Then, 5 mL of a tetrahydrofuran solution of 350 mg (3.27 mmol) of 4-formylpyridine was added thereto at −60° C. and the mixture solution was stirred while raising the temperature to room temperature over one hour. The reaction solution was partitioned between a saturated ammonium chloride aqueous solution and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The obtained residue was purified by a silica gel column (n-hexane:ethyl acetate=1:1) to obtain 754 mg (66%) of a target product as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>C(#N)C.CCOC(C)=O>[OH:9][CH2:8][C:7]1[C:2]([CH3:1])=[N+:3]([O-:19])[C:4]([C:10]([F:11])([F:13])[F:12])=[CH:5][CH:6]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1c(CO)ccc(C(F)(F)F)[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a stirring solution of (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (2.70 g, 14.1 mmol) in acetonitrile (20 mL) at room temperature was added dropwise a solution of 3-chloroperoxybenzoic acid (77% pure, 3.8 g, 16.9 mmol) in acetonitrile. The reaction mixture was stirred at room temperature for 16 h before concentration under reduced pressure. The residue was diluted with EtOAc, and the EtOAc solution was washed with 5% aqueous Na2S2O3, water, then saturated aqueous NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (40 g) eluted with a gradient of EtOAc (30-100%) in hexanes to afford 730 mg (25%) of the title compound as a white solid. HPLC/MS: retention time=0.92 min, [M+H]+=208.0. In addition, (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (1.90 g) was recovered.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH2:5][S:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].[Cl:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:11][O:10][C:8](=[O:9])[CH:7]([S:6][CH2:5][CH2:4][C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[Br:1])[Cl:16]
Reactant: COC(=O)CSCCc1ccccc1Br
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Cl)SCCc1ccccc1Br
Reaction time: 2.5 h
Yield: 97 %

Procedure:
A mixture of methyl 2-((2-bromophenethyl)thio)acetate (4.4 g), 1-chloropyrrolidine-2,5-dione (2 g) and carbon tetrachloride (2.4 g) was stirred on ice-bath for 2.5 hrs, filtrated and evaporated to yield the title compound (4.7 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O>[CH:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Methyl 2-isopropoxy-5-nitrobenzoate (6.92 g, 28.95 mmol) was taken up in THF/H2O (35 ml of each) and LiOH (1.39 g, 57.9 mmol) was added. The mixture was stirred at RT overnight then the pH was lowered to 1 by the addition of concentrated HCl and the product extracted in ethyl acetate (50 ml). The organic layer was dried (MgSO4) and evaporated to give 2-isopropoxy-5-nitrobenzoic acid (6.02 g, 92.5%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O>CO.[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]
Reactant: COC(=O)c1ccc(OC)cc1Oc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: COC(=O)c1ccc(OC)cc1Oc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-1 (7.360 g, 21.87 mmol) in methanol (200 mL) was added to a suspension of 10% palladium on carbon in ethanol (100 mL). The mixture was stirred under hydrogen gas pressure at room temperature for 3 hours. The reaction mixture was filtered through celite and the filtrate evaporated in vacuo to afford the title compound 1-2 as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:47]1[CH:48]=[N:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][C:51]=12.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:47]1[CH:48]=[N:49][N:50]2[CH2:55][CH2:54][N:53]([C:4]([C:3]3[CH:7]=[C:8]([CH2:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[NH:14][N:13]=4)[CH:9]=[CH:10][C:2]=3[F:1])=[O:6])[CH2:52][C:51]=12
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: c1nc2n(n1)CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2ncnc2C1
Reaction time: 20 h
Yield: 21 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (360 mg, 1.20 mmol) was dissolved in 10 mL of N,N-dimethylformamide, followed by addition of O-(1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (600 mg, 1.80 mmol), 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine 16a (150 mg, 1.20 mmol, prepared according to a known method disclosed by “patent application WO2009090055”) and N,N-diisopropylethylamine (0.4 mL, 2.40 mmol). After stirring for 20 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[3-(6,8-dihydro-5H-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-4-fluoro-phenyl]methyl]-2H-phthalazin-1-one 16 (100 mg, yield 21.0%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]([CH3:19])([CH3:18])[C:15]([CH3:17])=[CH:16][C:11]=2[CH:10]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C=O>[Si:27]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][C:14]([CH3:18])([CH3:19])[C:15]([CH3:17])=[CH:16][C:11]=2[CH:10]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC1=Cc2cc(Sc3ccccc3O)ccc2OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC1=Cc2cc(Sc3ccccc3O[Si](C)(C)C(C)(C)C)ccc2OC1(C)C
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
6-(2-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (1.1 g) (see Preparation 10) was dissolved in dry dimethylformamide (2 ml) and imidazole (0.55 g) and tert-butyidimethylsilyl chloride (0.61 g) were added. The flask was fitted with a calcium chloride drying tube and the mixture stirred at 40° C for 90 minutes. Water was added and the mixture was extracted with diethyl ether. The organic extract was washed with aqueous sodium hydrogen carbonate solution (×2), dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the crude product was chromatographed on silica using 4:1 hexane:dichloromethane as the eluent to yield 6-(2-tert-butyldimethylsilyloxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (1.43 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH3:30][NH:31][CH3:32]>>[CH3:30][N:31]([CH3:32])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1cc2c(N(C)C)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI): predicted mass calcd. for C21H18ClN5O2, 407.9