Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:18](/[CH2:31][CH3:32])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([O:26]CC)=[O:25])=[CH:6][C:7]2[C:8]([CH2:16][CH3:17])=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[C:5](/[C:18](/[CH2:31][CH3:32])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([OH:26])=[O:25])=[CH:6][C:7]2[C:8]([CH2:16][CH3:17])=[CH:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CC=C2CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc2c(cc1/C(CC)=C(F)\C=C\C(C)=C\C(=O)O)C(CC)=CCC2(C)C

Procedure:
Following General Procedure J-1, ethyl (2E,4E,6E)-7-(3-ethoxy-8-ethyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-6-fluoro-3-methyl-nona-2,4,6-trienoate (Compound A-69, 34 mg, 0.077 mmol) in ethanol (2 mL) was hydrolyzed with 1M NaOH to yield the title compound as a yellow solid after purification by flash column chromatography (silica gel, 3% to 50% ethyl acetate in hexane).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1>>[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:40](=[O:41])[CH2:39][CH2:38][NH:37][C:35]([CH:33]1[C:32]([CH3:43])([CH3:44])[CH2:31][O:30][C:29]([CH3:45])([CH3:28])[O:34]1)=[O:36])(=[O:27])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCCCN
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCCCCCNC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 47 %

Procedure:
N-(6-Aminohexyl)oleamide (3.81 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 1 to obtain 2.92 g of the title compound (yield: 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12](=O)[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[CH:7][C:8]=1[OH:9].O.[NH2:23][NH2:24]>>[CH2:18]([O:17][C:15]([C:14]1[NH:24][N:23]=[C:12]([CH:11]=[CH:10][C:5]2[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:13]=1)=[O:16])[CH3:19]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)C=Cc1ccc(O)c(OC)c1
Solvent: O
Product: CCOC(=O)c1cc(C=Cc2ccc(O)c(OC)c2)n[nH]1
Yield: 51 %

Procedure:
According to the procedure of Example 1, ethyl 6-(3-methoxy-4-hydroxyphenyl)-2,4-dioxo-5-hexenoate is reacted with hydrazine hydrate to afford ethyl-3-[β-(3-methoxy-4-hydroxyphenyl)ethenyl]-1H-pyrazole-5-carboxylate in 51% yield, mp=99°-101° C.
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][NH+:5]=1.[CH3:12][C:13]1[NH:20][C:18](=[S:19])[NH:17][C:15](=[O:16])[CH:14]=1>>[CH2:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][S:19][C:18]2[NH:17][C:15](=[O:16])[CH:14]=[C:13]([CH3:12])[N:20]=2)=[N:5][CH:6]=1)[CH3:11]
Reactant: CCc1ccc(CCl)[nH+]c1
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Agent: [Cl-]
Product: CCc1ccc(CSc2nc(C)cc(=O)[nH]2)nc1
Yield: 51 %

Procedure:
The title compound is prepared from 2-chloromethyl-5-ethylpyridinium chloride (m.p.: 126°-128° C.) and 6-methyl-2-thiouracyl by using the process described in Example 12. After recrystallization from ethanol the title compound is obtained as a white crystalline product in a yield of 51%, m.p.: 127°-128° C.
Reaction SMILES: [CH3:1][CH:2]([CH:5]([CH3:15])[CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])[CH:3]=[O:4].[BH4-].[Na+].Cl>C(O)C>[CH3:1][CH:2]([CH:5]([CH3:15])[CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:13])[CH3:14])[CH2:3][OH:4]
Reactant: CC1=CCC(CC(C)C(C)C=O)C1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1=CCC(CC(C)C(C)CO)C1(C)C
Yield: 77.9 %

Procedure:
A solution of 18.0 g (86 mmol) of 2,3-dimethyl-4-(2,2,3-trimethylcyclopent-3-enyl)butanal in 50 ml of ethanol was added dropwise at 0° C. to 45.0 g (0.11 mol) of sodium borohydride suspended in 200 ml of the same solvent. After 18 hours of stirring at room temperature 100 ml of 1.0 N aqueous hydrochloric acid was added dropwise at 0° C. The reaction mixture was extracted with 200 ml of MTBE, the extract washed with with 3×100 ml of brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled at 82-86° C./0.1 Torr to give 14.1 g (78% yield) of 2,3-dimethyl-4-(2,2,3-trimethylcyclopent-3-enyl)butan-1-ol.
Reaction SMILES: [O:1]=[C:2]([CH:8]=[N+:9]=[N-])[C:3]([O:5]CC)=[O:4].C#N.[C-]#N.O=[C:16]([CH:20]=[N+]=[N-])[C:17]([O-])=O>[Cu]>[CH2:16]([C:20]1[O:1][C:2]([C:3]([OH:5])=[O:4])=[CH:8][N:9]=1)[CH3:17]
Reactant: CCOC(=O)C(=O)C=[N+]=[N-]
Reactant: [N-]=[N+]=CC(=O)C(=O)[O-]
Agent: [Cu]
Agent: C#N
Agent: [C-]#N
Product: CCc1ncc(C(=O)O)o1
Reaction time: 3 h

Procedure:
If one is unable to obtain 5-formyloxazole from commercial sources, one may prepare the compound under the procedure disclosed by J. Ratusky and F. Sorm, Chem. Listy, 51, 1091 (1957), or by following the steps in Scheme III. In the first step of Scheme III, an equimolar mixture of ethyl oxalyl chloride (which is commercially available, e.g., from Aldrich Chemical Co.), diazomethane, and triethylamine in diethyl ether is allowed to react at 20° C. for 4 hours to produce ethyl 2-oxo-3-diazopropionate (15). In the second step, the 2-oxo-3-diazopropionate (15) is pyrolyzed in the presence of hydrogen cyanide to generate a carbene intermediate, which then adds to the cyanide in a 1,3-dipolar addition. For example, 2-oxo-3-diazopropionate is heated at 80°-100° C. in digylme in the presence of a catalytic amount of copper powder. After a few minutes, an equimolar amount of hydrogen cyanide is slowly bubbled into the solution, and hating continued for an additional three hours. The product is isolated and purified by conventional means to yield ethyl 5-carboxyoxazole (16). The ethyl 5-carboxyoxazole is converted to 5-formyloxazole in the same manner as ethyl 4-carboxyoxazole (12) is converted to 4-formyloxazole (see Scheme II, steps 5-7).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:11]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([F:32])=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CCc2cccc(N)c2)ccn1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cc(CCc2cccc(Nc3nc(Cl)ncc3F)c2)ccn1
Yield: 41.1 %

Procedure:
To a solution of tert-butyl {4-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate (160 mg, 0.51 mmol) (prepared in Example C15, step C) and 2,4-dichloro-5-fluoropyrimidine (89.5 mg, 0.54 mmol) in N,N-dimethylformamide (2.3 mL) was added potassium carbonate (212 mg, 1.53 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered first to remove K2CO3, followed by quenching with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product as an off-white solid (93 mg, 41%). LCMS for C22H24ClFN5O2 (M+H)+: m/z=444.1.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[S:13][C:14]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[CH:15][C:5]=2[N:4]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=1)(=[O:23])=[O:22])[CH3:2].C(=O)(O)[O-].[Na+].B(Br)(Br)Br.C(Cl)Cl>C1CCCCC=1>[CH2:1]([CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[S:13][C:14]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)=[CH:15][C:5]=2[N:4]1[S:21]([C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)(=[O:23])=[O:22])[CH3:2]
Reactant: CCC1c2ccccc2-c2sc(-c3ccsc3)cc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CCC1c2ccccc2-c2sc(-c3ccsc3)cc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: -78 °C
Yield: 289.4 %

Procedure:
A suspension of 5-ethyl-4-[(4-methoxyphenyl)sulfonyl]-2-thien-3-yl-4,5-dihydrothieno[3,2-c]isoquinoline (0.73 g, 1.6 mmol) in cyclohexene (11 mL) was treated with sodium bicarbonate (4.0 g, 48 mmol) and the mixture was cooled to −78° C. A solution of boron tribromide in methylene chloride (1.0 M, 6.4 mL, 6.4 mmol) was added dropwise during ca. 10 min. At this time the cooling bath was removed and the reaction mixture was warmed to 23° C. After 4 h the mixture was poured into saturated aqueous sodium bicarbonate (75 mL) and extracted with ethyl acetate (50 mL). The extract was washed with brine (75 mL), dried (Na2SO4), and concentrated in vacuo to give a dark oil (2.1 g) which was taken up in methylene chloride (ca. 5 mL) and pre-adsorbed on silica gel (5 g). Flash chromatography on silica (50 g) eluting 1.25-, and then 2.5% ethyl acetate-benzene gave the product (0.26 g) as a yellow solid. Recrystallization from hot ethyl acetate-hexane gave the title compound (0.15 g, 21%, m.p. 195-96° C.) as shiny tan needles.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:24]N1C(=O)CCC1=O>CN(C)C=O>[Br:24][C:10]1[N:9]=[C:8]([C@H:11]2[CH2:12][CH2:13][C@H:14]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH2:15][CH2:16]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: Cc1nccn2c1cnc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (2.086 mmol, 654 mg) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (2.295 mmol, 408 mg) and the mixture was stirred at room temperature for one hour. The reaction mixture was evaporated to dryness. The residue was dissolved in dichloromethane/methanol 9/1 (100 mL) and this solution was washed with a mixture of water (2 ml), of saturated aqueous sodium hydrogencarbonate (2 mL) and a few drops of 2 N sodium hydroxide, the organic layer dried (sodium sulfate) and evaporated to dryness to yield crude 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (1.04 g)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH:3]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[O:4][C:5]1[N:10]=[C:9]2[CH:11]=[N:12][CH:13]=[CH:14][C:8]2=[N:7][C:6]=1[NH2:15].[CH2:24]([S:27](Cl)(=[O:29])=[O:28])[CH2:25][CH3:26].[H-].[Na+].O>C1COCC1.C(OCC)(=O)C>[F:23][C:2]([F:1])([F:22])[CH:3]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[O:4][C:5]1[N:10]=[C:9]2[CH:11]=[N:12][CH:13]=[CH:14][C:8]2=[N:7][C:6]=1[NH:15][S:27]([CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1nc2ccncc2nc1OC(c1cccnc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCCS(=O)(=O)Nc1nc2ccncc2nc1OC(c1cccnc1)C(F)(F)F
Temperature: 80 °C
Yield: 30.2 %

Procedure:
3-[2,2,2-Trifluoro-1-(pyridin-3-yl)ethoxy]-pyrido[3,4-b]pyrazin-2-amine (100 mg, 0.310 mmol) obtained in Step 2 was dissolved in THF (2.50 mL). To this, propane-1-sulfonyl chloride (0.094 mL, 0.840 mmol) and 60% sodium hydride (in oil) (23.0 mg, 0.560 mmol) were added, and the mixture was stirred with heat at 80° C. for 4 hours. The reaction was stopped by addition of water to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and purification by silica gel column chromatography (chloroform/methanol=1/0 to 16/1) was performed to give Compound 361 (40.0 mg, yield: 30%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH2:20]>C(O)C>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH:20][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NCc1ccco1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Solvent: CCO
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NCc1ccco1

Procedure:
A solution of 14.7 g of 2-fluoro-5-nitrobenzoic acid and 23.1 g of 2-furylmethylamine in 250 ml of ethanol is boiled under a reflux condenser for 6 hours. After the solvent has been removed by distillation under reduced pressure, the residue is dissolved in 150 ml of water, the pH is adjusted to approximately 2 with 2 N HCl, and the precipitate is filtered off. After the precipitate has been washed several times with water, it is dried in a stream of air. Pale yellow crystals, melting point 190°-192° C. (from isopropanol).
Reaction SMILES: [CH:1]([C:4]1[CH:23]=[CH:22][C:7]([N:8]=[CH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CC1C=CC(NCC2C=C(OC)C(OC)=C(OC)C=2)=CC=1>>[CH:1]([C:4]1[CH:23]=[CH:22][C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COc1cc(C=Nc2ccc(C(C)C)cc2)cc(OC)c1OC
Agent: COc1cc(CNc2ccc(C)cc2)cc(OC)c1OC
Product: COc1cc(CNc2ccc(C(C)C)cc2)cc(OC)c1OC
Yield: 90.2 %

Procedure:
From 108f (8.2 g, 26.0 mmol), a similar procedure as described for 109a gave 109f (7.4 g, 89.8%) as an oil. 1H NMR (200 MHz, CDCl3) δ7.06 (d, J=8 Hz, 2H), 6.61 (d, J=8 Hz, 2H), 6.61 (s, 2H), 4.24 (s, 2H), 3.84 (s, 9H), 2.81 (h, J=8 Hz, 1H, 1.21 (d, J=8 Hz, 6H). EIMS 315 (M+, 100).
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[CH2:3][CH:4]=[O:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O.CC(C)=CCO.[N+]([O-])(O)=O>O>[CH3:6][C:2]([CH3:1])=[CH:3][CH2:4][O:5][CH2:10][CH:9]=[C:8]([CH3:12])[CH3:7]
Reactant: C=C(C)CC=O
Reactant: CC(C)=CC=O
Agent: CC(C)=CCO
Solvent: O
Solvent: O=[N+]([O-])O
Product: CC(C)=CCOCC=C(C)C
Reaction time: 16 h

Procedure:
700 g of a mixture containing 90.2% by weight of 3-methyl-but-3-en-1-al and 5.3% by weight of 3-methyl-but-2-en-1-al, 2,780 g of 3-methyl-but-2-en-1-ol and 6 g of 51% strength aqueous nitric acid are boiled under 100 mm Hg in a 4 liter flask surmounted by a packed column (filled with 5 mm Raschig rings). The bottom temperature assumes a value of from 86 to 93° C. The column has a diameter of 45 mm and has 30 theoretical plates. The water formed in the reaction is taken off at the top of the column and the organic materials which separates from the water is returned continuously into the column. With a reflux of 600 g/hour, quantitative conversion of the aldehyde is achieved in 16 hours. After distilling off the excess alcohol, a mixture consisting of 74.5% by weight of 1,1-bis-(3-methyl-but-2-en-1-yloxy)-3-methyl-but- 3-ene and 10.6% by weight of 1,1-bis-(3-methyl-but-2-en-1-yloxy)-3-methyl-but-2-ene, together with the by-products 3-methyl-butadien-1-yl-3-methyl-but-2-en-1-yl-ether (5.9% by weight) and di-(3-methyl-but-2-en-1-yl)-ether is obtained. The selectivity of the acetals obtained is 86.5% based on the sum of the aldehydes employed and 72.5% based on 3-methyl-but-2-en-1-ol.
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH3:27])=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:16]=1[CH3:41])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH3:27])=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:16]=1[CH3:41])#[N:14]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)CC(=O)N(C)C)nc2c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(=O)N(C)CC(=O)N(C)C)nc2c1C#N
Reaction time: 0.83 h
Yield: 14.4 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (52 μl, 408 μmol) was added at 150° C. to a dimethyl sulfoxide (6 ml) solution of 4-cyano-N-[2-(dimethylamino)-2-oxoethyl]-7-fluoro-N,5-dimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-125) (134 mg, 340 μmol) and triethylamine (62 μl, 442 μmol), followed by stirring at the same temperature for 50 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (20:1, v/v) gave the entitled compound (24 mg, 14%) as an amorphous substance.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:17]([OH:20])[C:18]#[CH:19].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]([C:19]#[C:18][CH2:17][OH:20])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)c(NC2CCCCCC2)n1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC#Cc1cnc(Cl)nc1NC1CCCCCC1
Yield: 56 %

Procedure:
To a yellow solution of 5-bromo-2-chloro-N-cycloheptylpyrimidin-4-amine (18.1 g, 55.5 mmol) in THF (200 mL) were added propargyl alcohol (4.5 mL, 1.4 equiv) and a solution of tetrabutylammonium fluoride in THF (1 M, 130 mL, 2.3 equiv) and the resulting brown mixture was treated with a stream of nitrogen for 15 min (bubble in the solution). The mixture was then treated with bis(triphenylphosphine)palladium(II) chloride (2.09 g, 0.054 equiv) and heated to reflux for 5 h. After cooling, the reaction mixture was filtered through a pad of celite (rinsed with EtOAc ˜350 mL). The filtrate was concentrated to remove THF, further diluted with EtOAc (total volume 250 mL), washed with sat. NaHCO3 (2×150 mL) and water (150 mL), dried over Na2SO4, filtered and concentrated. Titration of the residue in acetone and CH2Cl2 provided 3-(2-chloro-4-(cycloheptylamino)pyrimidin-5-yl)prop-2-yn-1-ol (8.65 g) in 56% yield. 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 4.45 (s, 2H), 4.19 (septet, J=4.5 Hz, 1H), 1.95 (m, 2H), 1.77-1.52 (m, 10 Hz); MS m/z 280.4 (M+
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)([OH:11])[C:5]=2[CH:6]=1.O1CCOCC1.C[Sn](C)(C)[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=1.ClCCl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2([OH:11])[C:5]3[CH:6]=[C:2]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:28]=4)[S:3][C:4]=3[CH2:10][CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: OC1(c2ccc(Cl)cc2)CCCc2sc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(-c2cc3c(s2)CCCC3(O)c2ccc(Cl)cc2)ccn1
Temperature: 25 °C
Yield: 9.8 %

Procedure:
In a 100 mL round bottomed flask were placed 2-bromo-4-(4-chlorophenyl)-4,5,6,7-tetrahydro-1-benzothiophene-4-ol (640 mg, 1.9 mmol) and 1,4-dioxane (10 mL). To the mixture were added N-[4-(trimethylstannyl)pyridin-2-yl]acetamide (925 mg, 3.09 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (198 mg, 0.242 mmol). The mixture was refluxed for 16 hr with vigorous stirring. The mixture was allowed to cool to rt and then diluted with EtOAc (100 mL). The resulting solution was washed with H2O (50 mL×2). The combined aqueous phases were extracted with EtOAc (50 mL×2). The combined organic phases were washed with brine (50 mL) and dried over MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (40 g) column chromatography, eluting with a 30% to 100% EtOAc/hexane to obtain crude title compound (ca 500 mg). About 100 mg of this material was purified by HPLC (AA) to obtain pure title compound (74 mg; 10%). LCMS: (AA) ES+ 399, 401; 1H NMR (400 MHz, d6-DMSO) δ ppm 10.51 (br s, 1H), 8.23 (s, 1H), 8.20 (d, 1H), 7.36 (d, 2H), 7.30 (d, 2H), 7.19 (dd, 1H), 7.14 (s, 1H), 5.85 (s, 1H), 2.83-2.90 (m, 2H), 2.07 (s, 3H), 1.85-2.01 (m, 3H), 1.65-1.70 (m, 1H).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH3:9][C:10]1([CH3:38])[C@@H:15]([OH:16])[C@H:14]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[C:13]2[CH:27]=[C:28]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH:29]=[CH:30][C:12]=2[O:11]1>C(Cl)Cl.O>[N+:7]([O-:8])([O:16][C@H:15]1[C@H:14]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[C:13]2[CH:27]=[C:28]([S:31]([C:34]([F:37])([F:35])[F:36])(=[O:33])=[O:32])[CH:29]=[CH:30][C:12]=2[O:11][C:10]1([CH3:38])[CH3:9])=[O:6]
Reactant: O=[N+]=O
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.6 %

Procedure:
116 mg of nitronium tetrafluoroborate were added to a solution of 300 mg of trans-3,4-dihydro-2,2-dimethyl-4-(1-oxoisoindolin-2-yl)-6-trifluoromethylsulfonyl-2H-1-benzopyran-3-ol (prepared as described in Preparation 13) in 5 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time, the reaction mixture was diluted with 20 ml of water and extracted with 15 ml of methylene chloride. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:4 by volume mixture of ethyl acetate and cyclohexane as the eluent, to afford 88 mg of the title compound as crystals, melting at 189.5°-190° C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[C:8]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)=[O:9])[CH2:34][CH2:33]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2ccccc2C(=O)Nc2cccc3[nH]ccc23)CC1

Procedure:
1.6 g of 2-[(2-oxiranyl)-methoxy]-N-[(1H-indol-4-yl)]-benzamide in 36 ml of ethanol as refluxed for 4 hours with 1.82 ml of (methoxyphenyl)piperazine and the solvent was eliminated under reduced pressure. The residue was purified by chromatography over silica (eluent:chloroform--ethyl acetate--triethylamine, 6-3-1) to obtain 1.85 g of 2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide