Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([NH:7][CH3:8])=[CH:5][CH:4]=1)#[N:2].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[N:13]=1.CC([O-])=O.[Na+]>C1COCC1.O>[CH3:8][N:7]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[N:13]=1)[C:6]1[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CNc1ccc(C#N)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N(C)c2ccc(C#N)cc2)c2ccccc2n1
Temperature: 23 °C
Reaction time: 96 h
Yield: 1 %

Procedure:
To a solution of formic acid 30 mL and acetic anhydride 30 mL stirred at room temperature for 1 h was added a solution of 4-aminobenzonitrile 2.36 g (20.0 mmol) in CH2Cl2 150 mL dropwise at 0° C. The reaction mixture was stirred at room temperature for 4 h (EMI-mass: 146 [M]+). After concentration, the crude intermediate was dissolved in THF 50 mL, and was added BH3 in Me2S 15 mL. The reaction mixture was then stirred for 5 h under reflux. The crude product was extracted with EtOAc, washed with water, sat. Na2CO3 aqueous solution and dried on anhydrous MgSO4. After removal of solvents, 4-cyano-N-methylaniline was obtained in 80% purity based on GC/MS (EMI-mass: 132 [M]+). A mixture of crude 4-cyano-N-methylaniline 0.40 g (ca. 2 mmol) and 4-chloro-2-methylquinazoline 0.357 g (2.0 mmol) with NaOAc 0.2 g (2.3 mmol) in THF 20 mL and H2O 12 mL was stirred at 23° C. for 4 days. After removing solvents, the crude product was purified with preparative HPLC to give the titled compound in 1% yield (10 mg). 1H NMR (CD3OD, 400 MHz): δ 7.94 (d, 2H, J=8.8 Hz), 7.91-7.86 (m, 1H), 7.76-7.73 (m, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.34-7.30 (m, 1H), 6.99-6.96 (m, 1H), 3.87 (s, 3H), 2.81 (s, 3H). m/e: 275.1420 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.Cl.[C:12]([C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[NH2:19])([CH3:15])([CH3:14])[CH3:13].CCN(C1C=CC=CC=1)CC>C1(C)C=CC=CC=1>[C:12]([C:16]1[CH:17]=[C:18]([NH:19][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[CH:4][CH:3]=2)[CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])([CH3:15])([CH3:14])[CH3:13]
Reactant: Clc1ccnc2ccnn12
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(Nc2ccnc3ccnn23)cc(C(C)(C)C)c1O
Temperature: 120 °C
Yield: 40.4 %

Procedure:
A suspension of 7-chloropyrazolo[1,5-a]pyrimidine (1.0 g), 3,5-di-t-butyl-4-hydroxyaniline hydrochloride (1.8 g) and diethylaniline (2.3 ml) in toluene (50 ml) is heated at 120° C. for 30 minutes. After cooling, the solvent is distilled off, and the residue is purified by silica gel column chromatography (solvent; CHCl3) to give 7-(3,5-di-t-butyl-4-hydroxyphenyl)aminopyrazolo[1,5-a]pyrimidine (890 mg) as colorless crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:14])=[C:6]([CH:9]=[C:10]([CH2:12][CH3:13])[CH:11]=1)[CH:7]=[O:8])[CH3:2].[C-:15]#[N:16].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]1[C:5]([F:14])=[C:6]([CH:7]([OH:8])[C:15]#[N:16])[CH:9]=[C:10]([CH2:12][CH3:13])[CH:11]=1)[CH3:2]
Reactant: CCOc1cc(CC)cc(C=O)c1F
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(CC)cc(C(O)C#N)c1F
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To 118D (630 mg, 3.46 mmol) in ethyl acetate (10 mL) was added a solution of KCN (676 mg) and NaHSO3 (1.08 g) dissolved in H2O (10 mL). It was left stirring overnight before extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried and concentrated. The crude producte was purified by column chromatography to give 118E (685 mg, 92% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.69 Hz, 3H) 1.44 (t, J=7.03 Hz, 3H) 2.62 (q, J=7.76 Hz, 2H) 4.11 (q, J=7.03 Hz, 2H) 5.75 (s, 1H) 6.85 (dd, J=7.91, 2.20 Hz, 1H) 6.96 (dd, J=5.93, 1.98 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:18])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1.C(O)C.Cl.[CH2:23]([O:25][C:26](=[O:34])[CH:27](N)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24]>N1C=CC=CC=1>[CH2:23]([O:25][C:26](=[O:34])[CH:27]([N:18]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[OH:17])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24]
Reactant: COc1ccc(C(=N)c2ccc(Cl)cc2)c(O)c1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C(N=C(c1ccc(Cl)cc1)c1ccc(OC)cc1O)C(=O)OCC

Procedure:
10.5 G. of 4'-chloro-2-hydroxy-4-methoxy-benzophenone imine in 60 ml. of ethanol is reacted with 12.6 g. of aminomalonic acid diethyl ester hydrochloride and 5.0 ml. of pyridine in accordance with the procedure described in Example 2. After a single recrystallization of the crude product from ethanol, there is obtained {[2-hydroxy-4-methoxy-α-(4-chlorophenyl)benzyliden]amino}malonic acid diethyl ester, having a melting point of 73°-75° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][O:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].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.O>[CH3:9][O:8][CH2:7][C:5]1[O:6][C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3][C:4]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COCc1oc(Br)cc1C(=O)OC
Reactant: OB(O)c1ccccc1
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: O
Solvent: COCCOC
Product: COCc1oc(-c2ccccc2)cc1C(=O)OC
Yield: 87.5 %

Procedure:
A mixture of methyl 5-bromo-2-(methoxymethyl)-3-furancarboxylate (3.7 g), phenylboronic acid (2.2 g), tetrakis(triphenylphosphine)palladium(0) (0.9 g), 2N aqueous sodium carbonate solution (18 mL) and 1,2-dimethoxyethane (30 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give the title compound (3.2 g, 87%) as an oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)([CH3:3])[CH3:2].[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[OH:17]>>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[O:17][CH2:5][CH:6]([OH:8])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: CC(C)N1CC(O)C1
Product: CC(C)NCC(O)COc1cccc(Cl)c1Cl
Yield: 54 %

Procedure:
1-(iso-propyl)-3-azetidinol and 2,3-dichlorophenol were reacted in the same manner as in Example 6 to yield 1-(2',3'-dichlorophenoxy)-3-(iso-propylamino)-2-propanol melting at 94°-96° C. The yield was 54%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](C=O)=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19](/[CH:19]=[CH:17]/[C:16](=[O:15])[CH2:22][CH3:21])=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc([N+](=O)[O-])c(C=O)c3O2)cc1
Solvent: Cc1ccccc1
Product: CCC(=O)/C=C/c1c([N+](=O)[O-])ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5.00 g (12.2 mmol) of [(2R)-8-formyl-7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate in 200 mL of toluene was added 5.10 g (15.3 mmol) of 1-triphenylphosphorylidene-2-butanone. The mixture was stirred at room temperature under nitrogen for 5 hours, after which time the solvent was removed in vacuum and the crude residue was column chromatographed on silica gel with methylene chloride as eluant to give 5.0 g of the (R)-enantiomer of the title compound as a yellow solid (m.p. 114° C.).
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]=1.[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([C:32](O)=[O:33])[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)(=[O:19])=[O:18]>>[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:22]([C:32]([N:9]2[CH2:8][CH2:7][C:6]3[N:5]=[C:4]([C:3]([F:2])([F:14])[F:15])[CH:13]=[CH:12][C:11]=3[CH2:10]2)=[O:33])[CH:21]=1)(=[O:18])=[O:19]
Reactant: FC(F)(F)c1ccc2c(n1)CCNC2
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCc3nc(C(F)(F)F)ccc3C2)c1

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine hydrochloride (CA [741736-98-1]; WO2004069162) and 4-methanesulfonyl-biphenyl-2-carboxylic acid (example 2.5). MS (m/e): 461.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[F:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[H-].[Na+].O>CN(C=O)C.C(OCC)(=O)C>[C:28]([Si:25]([O:24][CH2:23][CH2:22][CH:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[C:12]1[C:13]([F:20])=[CH:14][CH:15]=[C:16]([F:19])[C:17]=1[F:18])([CH3:27])[CH3:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=S(=O)(Cc1c(F)ccc(F)c1F)c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-Chloro-benzenesulfonylmethyl)-1,3,4-trifluoro-benzene (4.0 g, 12.5 mmol) was dissolved in 40 mL dry DMF. (2-Bromo-ethoxy)-tert-butyl-dimethylsilane (4.1 g, 17.1 mmol) and NaH (2.28 g, 95.0 mmol) were added respectively. The solution was stirred at room temperature overnight. 200 mL of water and 200 mL of EtOAc were added. The aqueous layer washed with 100 mL of EtOAc. The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated. The product was purified using column chromatography (hex./EtOAc 100/0 to 90/10 in 45 min, 1.7 g, 28%). 1H NMR (CDCl3 400 MHz) δ 7.65 (m, 2H), 7.46 (m, 2H), 7.14 (m, 1H), 6.84 (m, 0.5H), 6.73 (m, 0.5H), 4.87 (m, 1H), 4.79 (m, 1H), 4.37 (m, 1H), 2.55 (m, 2H), 2.04 (s, 9H), −0.13 (d, J=22.7 Hz, 6H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2].[CH3:35][C@@H:36]1[CH2:40][O:39][C:38](=[O:41])[NH:37]1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:37]3[C@H:36]([CH3:35])[CH2:40][O:39][C:38]3=[O:41])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:34])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Reactant: C[C@@H]1COC(=O)N1
Product: CC(=O)N1CCN(c2cc(N3C(=O)OC[C@H]3C)ccc2C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)C1=O
Yield: 15.4 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (344 mg) described in Preparation Example 196 and (R)-4-methyloxazolidin-2-one (61.8 mg) described in Preparation Example 25, the title compound (51.3 mg) was obtained.
Reaction SMILES: [C:1]([OH:20])(=[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][CH2:15][C:16]([OH:18])=[O:17].C(O[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O>CCCCCCCC>[CH2:24]([O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=COCc1ccccc1
Reactant: O=C(O)CCCCCCCCCCCCCCC(=O)O
Solvent: CCCCCCCC
Product: O=C(O)CCCCCCCCCCCCCCC(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 50 h

Procedure:
Hexadecanedioic acid (20.0 g, 69.8 mmol) and Dowex® were suspended in n-octane and heated to reflux. Benzyl formate (22.0 g, 162 mmol) was added. After 6 hours additional benzyl formate (22.0 g, 162 mmol) was added. The heating was continued for 50 hours. The reaction mixture was filtered at 80° C. The filtrate was cooled to 20° C., and the precipitate was collected by filtration. The crude product (20.2 g) was suspended in dichloromethane (220 ml) at 20° C. for 4 hours. The suspension was filtered, and the filtrate was evacuated to dryness at 20-30° C. The resulting solid (13.9 g) was recrystallised from 2-propanol (140 ml). The product was isolated by filtration, and dried to constant weight under reduced pressure at 30-40° C. Yield: 10.2 g (39%) of white material.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.C[O:22][C:23](=[O:29])[C@H:24]([CH2:26][CH2:27][CH3:28])[NH2:25].C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:3][CH2:2]1.[NH2:25][C@H:24]([C:23]([OH:29])=[O:22])[CH2:26][CH2:27][CH3:28]
Reactant: CCC[C@H](N)C(=O)OC
Agent: O=C(O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 0.62 g N-(Morpholinocarbonyl)-L-phenylalanine-L-norvaline methyl ester in 40 mL methanol and 20 mL water was added 1.2 g potassium carbonate. The resulting mixture was stirred at ambient temperature for 60 h, afterwhich it was concentrated in vacuo to an aqueous solution and washed (3×50 mL) ether. The aqueous phase was acidified with 10 mL 4N hydrochloric acid solution and was extracted (3×25 mL) with methylene chloride. The combined extracts were dried over magnesium sulfate, filtered and concentrated to afford 0.46 g crude acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9]CC)=O.[CH:12]1([C:15]([CH3:17])=[O:16])[CH2:14][CH2:13]1.C[O-].[Na+]>C1C=CC=CC=1>[CH:12]1([C:15](=[O:16])[CH2:17][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH2:14][CH2:13]1
Reactant: CC(=O)C1CC1
Reactant: CCOC(=O)c1ccccn1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C(CC(=O)C1CC1)c1ccccn1

Procedure:
A stirred mixture of 24 g. of ethyl picolinate, 18 g. of cyclopropylmethyl ketone and 11 g. of sodium methoxide in 250 ml. of benzene is heated under reflux for 6 hours. The mixture is diluted with 200 ml. of water and the water phase is removed. The aqueous solution is made weakly acidic with dilute hydrochloric acid. A solid precipitates and is collected by filtration. Recrystallization from cyclohexane provided colorless crystals, melting point 77°-78° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.S(OCC)(OCC)(=O)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30].Cl.[I-].[Na+].Cl[Si](C)(C)C>[Cu](I)I.ClC1C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([C:4](=[O:5])/[CH:3]=[CH:2]/[C:1]([OH:6])=[O:7])[CH:26]=[CH:25][C:24]=1[O:29][CH3:30]
Reactant: COc1ccccc1OC
Reactant: O=C1C=CC(=O)O1
Agent: I[Cu]I
Agent: CCOS(=O)(=O)OCC
Agent: C[Si](C)(C)Cl
Solvent: Clc1ccccc1
Product: COc1ccc(C(=O)/C=C/C(=O)O)cc1OC
Temperature: 10 °C
Reaction time: 24 h
Yield: 54.1 %

Procedure:
Into a 500 ml four-neck flask were charged 66.9 g (0.682 mol) of maleic anhydride, 150 ml of chlorobenzene, 71.6 ml (0.546 mol) of diethyl sulfate, and 0.186 g (0.975 mmol) of copper iodide under a nitrogen atmosphere. Then, the whole was cooled to 10° C. or lower and 67.6 g (0.507 mol) of aluminum chloride was added thereto. While temperature was maintained at 10 to 15° C., 25 ml (0.195 mol) of 1,2-dimethoxybenzene was added dropwise, followed by 2 hours of reaction. After termination of the reaction was confirmed by HPLC analysis, the reaction solution was added dropwise to 200 ml of a 1N hydrochloric acid aqueous solution cooled to 0° C. to decompose excess aluminum chloride. After liquid separation, the organic layer was washed with 200 ml of a 10% sodium bicarbonate aqueous solution to remove excess maleic anhydride. Then, 42.9 g (0.286 mol) of sodium iodide and 31.1 g (0.286 mol) of chlorotrimethylsilane were added to the organic layer, followed by heating and refluxing. After completion of the reaction, the organic layer was washed with 100 ml of a 5% sodium thiosulfate aqueous solution and 100 ml of a saturated sodium hydrogen carbonate aqueous solution to extract (E)-4-(3,4-dimethoxyphenyl)-4-oxo-2-butenoic acid into the aqueous layer, followed by adjusting the aqueous layer to pH 2.0. After 24 h of stirring at 5° C., filtration was conducted to obtain 24.9 g (yield 54.2%) of the aimed compound as light yellow crystals. As a result of HPLC analysis, the purity was found to be 98.5%.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH:10]([O:14]CC)OCC)=O)=[CH:4][CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C([O-])(O)=O.[Na+].[NH4+].[OH-]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:14][CH:10]=[CH:9][N:8]=2)=[CH:17][CH:18]=1
Reactant: CCOC(CNC(=O)c1ccc(Br)cc1)OCC
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: Brc1ccc(-c2ncco2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
4-Bromo-N-(2,2-diethoxyethyl)benzamide was dissolved in concentrated sulfuric acid at 0° C. To phosphorus pentoxide (5.2 g, 18.3 mmol) was added the sulfuric acid solution, and the mixture was heated at 180° c. for 30 minutes. The reaction mixture was cooled down to room temperature, and poured into ice. The whole was made basic by addition of NaHCO3 and ammonia aqueous solution. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give title compound (1.23 g, 70% yield).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[CH3:34][O:35][CH2:36][CH2:37]Br>>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:22]([NH:24][N:25]([S:26]([CH3:29])(=[O:27])=[O:28])[CH2:37][CH2:36][O:35][CH3:34])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: COCCBr
Product: COCCN(NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NO)S(C)(=O)=O

Procedure:
The starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide and 2-bromoethyl methyl ether.
Reaction SMILES: [CH3:1][N:2](N=O)[C:3]([NH:5][N+:6]([O-:8])=[O:7])=[NH:4].[Cl:11][C:12]1[CH:13]=C([CH:16]=[C:17]([Cl:20])[C:18]=1[Cl:19])N.[OH-].[Na+]>C(O)C>[N+:6]([NH:5][C:3]([NH:2][C:1]1[CH:13]=[C:12]([Cl:11])[C:18]([Cl:19])=[C:17]([Cl:20])[CH:16]=1)=[NH:4])([O-:8])=[O:7]
Reactant: CN(N=O)C(=N)N[N+](=O)[O-]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(Nc1cc(Cl)c(Cl)c(Cl)c1)N[N+](=O)[O-]
Temperature: 40 °C
Yield: 21.9 %

Procedure:
To a slurry of N-methyl-N-nitroso-N'-nitroguanidine 3.3 g (0.0225 mol) in 200 ml of a 50% aqueous ethanol mixture is added 5.0 g (0.025 mol) of 3,4,5-trichloroaniline. This mixture is heated to 40° C. for 72 hours and then treated with one equivalent of NaOH to decompose excess N-methyl-N-nitroso-N'-nitroguanidine. The mixture is then filtered and acidified with concentrated HCl to given 1.6 g of a yellow solid which, when recrystallized, gives 1.4 g of the desired product. The melting point of the product is 209.5° C. dec.
Reaction SMILES: [Cl:1][C:2]([Cl:14])=[CH:3][CH2:4][CH:5]([CH:11]([CH3:13])[CH3:12])[C:6]([O:8]CC)=[O:7].C(=O)([O-])[O-].[K+].[K+].CO>O>[Cl:1][C:2]([Cl:14])=[CH:3][CH2:4][CH:5]([CH:11]([CH3:12])[CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(CC=C(Cl)Cl)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)C(CC=C(Cl)Cl)C(=O)O
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A mixture of 67.0 g (0.28 mol) of ethyl 5,5-dichloro-2-isopropyl-4-pentenoate, 77.35 g (0.56 mol) of anhydrous potassium carbonate, 2128 ml of methanol, and 708 ml of water was refluxed 4 days under nitrogen. The reaction mixture was then cooled to room temperature and about two-thirds of the solvent removed on the rotary evaporator. The residue was taken up in three times its volume of water, extracted twice with ether, and acidified with conc. HCl. The acidified reaction mixture was extracted into ether, the ether solution washed with water, dried (MgSO4), and removed. The residue was vacuum distilled to give 52.5 g (89% yield) of 5,5-dichloro-2-isopropyl-4-pentenoic acid, b.p. 91°-96° C./0.30 mm.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)[CH3:14].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)[CH3:14]
Reactant: COc1ccc2c(c1)C(=C(C)c1ccc[nH]1)C(=O)N2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=C1C(=O)Nc2ccc(O)cc21)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-methoxy-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; (0.12 g, 0.5 mmol) in dichloromethane (5 mL) was treated with BBr3 solution (1.5 mL of a 1M solution in dichloromethane, 1.5 mmol, 3.0 eq.). After stirring overnight at ambient temperature, the reaction was quenched by water (10 mL). The organic layer was separated. The aqueous layer was neutralized with saturated NaHCO3 solution and extracted with ethyl acetate (2×20 mL). The combined organic layers were concentrated. Reverse phase HPLC using acetonitrile/water afforded 5-hydroxy-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; (0.04 g); 1H NMR (400 MHz, DMSO-d6) δ 2.74 (s, 3H), 6.38 (m, 1H), 6.62 (m, 1H), 6.70 (m, 1H), 7.08 (m, 1H), 7.20 (m, 1H), 7.32 (m, 1H), 8.96 (s, 1H), 10.78 (s, 1H) ppm.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:21]=[C:22]2[C:28]([CH2:29][CH2:30][NH:31][C:32]([C:34]3[CH:38]=[C:37]([CH2:39][C:40]4[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=4[F:47])[O:36][N:35]=3)=[O:33])=[C:27]([Si](CC)(CC)CC)[NH:26][C:23]2=[N:24][CH:25]=1.C1C[O:58]CC1>>[Cl:19][C:20]1[CH:21]=[C:22]2[C:28]([CH2:29][CH2:30][NH:31][C:32]([C:34]3[CH:38]=[C:37]([C:39](=[O:58])[C:40]4[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=4[F:47])[O:36][N:35]=3)=[O:33])=[CH:27][NH:26][C:23]2=[N:24][CH:25]=1
Reactant: C1CCOC1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(NCCc1c[nH]c2ncc(Cl)cc12)c1cc(C(=O)c2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
A solution of tetrabutylammonium fluoride 1M in THF (1 mL; 1 mmol) was added to a solution of N-(2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide (0.105 g, 0.198 mmol) in THF (5 mL). The mixture was stirred overnight at room temperature and was evaporated. The residue was dissolved in dichloromethane, and the organic solution was washed with water and was concentrated under reduced pressure. The crude material was purified twice by flash chromatography on silica gel (eluent: 0 to 40% of ethyl acetate in dichloromethane) to give 0.019 g (22%) of N-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-5-(2,5-difluorobenzoyl)isoxazole-3-carboxamide as a white solid.