Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH2:10](Cl)Cl>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH3:10])[CH:7]=1
Reactant: COc1cncc(Br)c1
Reactant: ClCCl
Product: CCOc1cncc(Br)c1
Reaction time: 8 h

Procedure:
As shown in step 2-iii of Scheme 2,3-chloroperoxybenzoic acid (9.426 g, 42.06 mmol) was added to 3-bromo-5-methoxypyridine (4.25 g, 21 mmol) in 200 mL of DCM at RT. The reaction was stirred overnight and the mixture was washed with 200 mL of 2 N NaOH and 2×200 mL brine. The organic phase was dried over MgSO4, filtered and the volatiles removed under reduced pressure to provide 3-bromo-5-ethoxypyridine, 1-oxide (Compound 1002, 4.4 g): 1H NMR (CDCl3): δ 8.05 (s, 1H), 7.9 (s, 1H), 7.0 (s, 1H), 4.12 (q, 2H), 1.45 (t, 3H).
Reaction SMILES: Cl.C([NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:14])[CH:9]=[CH:8][N:7]=1)(=O)C>>[NH2:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[CH:9]=[CH:8][N:7]=1
Reactant: CC(=O)Nc1cc(NC(=O)Nc2ccccc2)ccn1
Agent: Cl
Product: Nc1cc(NC(=O)Nc2ccccc2)ccn1
Reaction time: 6 h
Yield: 67.1 %

Procedure:
15 ml of 6 N hydrochloric acid was added to 173 mg (0.64 mmol) of N-(2-acetamido-4-pyridyl)-N'-phenylurea. The mixture was then stirred for 6 hrs. on a boiling water bath. After cooling, the crystals which deposited were removed by filtration and a small amount of water added thereto to dissolve the crystals while warming. An aqueous sodium carbonate solution was then added to the solution to neutrallize the same. The crystals which deposited were collected by filtration and recrystallized from methanol to give 98 mg. of the objective compound; yield 67.1%; m.p. above 290° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15]O)[CH3:13])[CH3:8])[CH3:3].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:41]I>C1(C)C=CC=CC=1.CCCCCC>[CH3:13][CH:12]([CH2:11][CH2:10][CH2:9][CH:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH2:14][CH2:15][I:41]
Reactant: CC(C)CCCC(C)CCCC(C)CCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)CCCC(C)CCCC(C)CCI
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a stirring solution of 44 (1.5 g, 6.6 mmol), imidazole (1.13 g, 16.6 mmol, 2.5 equ) and triphenylphosphine (4.40 g, 16.8 mmol, 2.5 equ) in toluene (250 ml) under nitrogen was added iodine (3.26 g, 12.8 mmol, 1.9 equ). The reaction mixture was stirred for one hour then filtered. The filtrate was washed with 8% sodium thiosulphate solution (250 ml) and brine (100 ml) then dried (Na2SO4) and concentrated in vacuo to give a white solid. This solid was taken up in hexane, cooled and filtered. The filtrate was then concentrated in vacuo to give 46 (1.1 g, 61%) as a colourless oil.
Reaction SMILES: [N+](C1C=CC=CC=1)([O-])=O.[C:10]([CH2:13][C:14]1C2[C:18](=[CH:19]C=CC=2)[CH:17]=[CH:16][CH:15]=1)(=O)[CH3:11]>>[CH3:11][CH2:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(=O)Cc1cccc2ccccc12
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCCCC

Procedure:
A crude isomer mixture weighing 33.71 grams and containing 59.4 weight 2,6-AMN, 12.8 weight percent nitrobenzene and 27.8 weight percent of other materials which were believed to be mainly other isomers of acetylmethylnaphthalene was used for the present evaluation.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.O>C1COCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:7]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3cc(Cl)ncn3)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
0.34 mL (2.43 mmol) TEA are added to a mixture of 181 mg (1.22 mmol) 4,6-dichloropyrimidine and 300 mg (1.22 mmol) (S)-N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) in 3 mL THF. The mixture is stirred for 5 min at 80° C. and for 2 h at rt. After that time, water is added and the mixture is extracted with dichloromethane (2×). The combined organic layers are dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silica gel; dichloromethane/methanol, gradient 98:2-95:5) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:13]([OH:19])=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1>N1C=CC=CC=1>[Cl:11][C:12]1[C:13]([O:19][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:14][C:15]([O:18][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:16][CH:17]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Oc2cc(OC(=O)c3ccc(C)cc3)c(Cl)cn2)cc1
Reaction time: 6 h

Procedure:
A 2.66 g quantity of 4-methylbenzoyl chloride was added dropwise to 50 ml of a solution of 1.00 g of 5-chloro-4-hydroxy-2-pyridone in pyridine. The mixture was subjected to reaction at room temperature overnight. The pyridine was distilled off and the residue was stirred in ether for 6 hours. The solids thus precipitated were dried, giving 1.71 g of the title compound. The ether was concentrated and the residue was applied to silica gel column chromatography using as an eluent petroleum ether-chloroform (1:2), affording 0.85 g of the same compound (total amount 2.56 g, total yield 97%).
Reaction SMILES: P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C.[C:18]([C:21]1[N:30]=[C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]3[O:39][CH2:40][O:41][C:35]=3[CH:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:42])[CH:27]=2)[N:22]=1)(O)=[O:19].[NH2:43][CH2:44][CH2:45][S:46]([O-:49])(=[O:48])=[O:47].[Na+].Cl>CN(C)C=O.O>[ClH:42].[S:46]([CH2:45][CH2:44][NH:43][C:18]([C:21]1[N:30]=[C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]3[O:39][CH2:40][O:41][C:35]=3[CH:34]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:42])[CH:27]=2)[N:22]=1)=[O:19])([OH:49])(=[O:48])=[O:47]
Reactant: O=C(O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reactant: NCCS(=O)(=O)[O-]
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCCS(=O)(=O)O)c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Yield: 173.8 %

Procedure:
0.60 ml (3.8 mmol) of diethyl cyanophosphate and 0.90 ml (6.4 mmol) of triethylamine were dropped, in this order, into a solution of 0.50 g (1.4 mmol) of 2-carboxy-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline and 0.28 g (1.9 mmol) of sodium 2-aminoethanesulfonate in 15 ml of dimethylformamide under cooling with ice and stirring. The obtained mixture was stirred at room temperature for several days, followed by the addition of 10 ml of 1N hydrochloric acid and water. The crystals thus precipitated were recovered by filtration, washed with water and air-dried to give 0.61 g of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[CH:12]=[C:13]([CH2:21]O)[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[Cl:3][CH2:21][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2ccccc2)cc2ccccc12
Solvent: ClC(Cl)Cl
Product: ClCc1cc(-c2ccccc2)cc2ccccc12
Reaction time: 15 h

Procedure:
Thionyl chloride (0.78 cc) is added in the course of 10 minutes to a stirred solution, cooled beforehand to 0° C., of 3-phenyl-1-naphthalenemethanol (1 g) in chloroform (20 cc), and the temperature is then allowed to rise to room temperature (approximately 20° C.). The mixture is stirred for 15 hours at this temperature and the solvent evaporated under reduced pressure. 1-Chloromethyl-3-phenylnaphthalene (1.1 g) is obtained, the proton NMR spectrum of which, in deuterated chloroform, shows the following characteristics:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([CH:15]=O)=[C:12]([CH2:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NO.C([N:24](CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C1(C)C=CC=CC=1.CCCCCC.CO>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]#[N:24])=[C:12]([CH2:17][CH3:18])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NO
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: CCc1cc(CO[Si](C)(C)C(C)(C)C)sc1C#N
Temperature: 25 °C
Yield: 69 %

Procedure:
To a suspension of 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethylthiophene-2-carboxaldehyde (1.3 g, 4.8 mmol) that was obtained in Example 10 (10b) and hydroxylamine hydrochloride (0.37 g, 5.3 mmol) in dichloromethane (20 ml) were added successively methanol (2 ml) and triethylamine (1.3 ml, 9.6 mmol) with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After removing the solvent in vacuo, toluene (10 ml) was added to the residue and the resulting mixture was evaporated azeotropically in vacuo. Subsequently, the residue obtained and N,N′-dicyclohexylcarbodiimide (1.1 g, 5.3 mmol) were suspended in toluene (20 ml) and stirred at 90° C. for 15 hours. After cooling to room temperature, hexane (20 ml) was added to the reaction mixture, and the resulting mixture was filtered with Celite. The filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 5:95) as the eluent to afford the title compound (0.94 g) in a yield of 69% as a pale yellow oily product.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].O.[NH2:18][NH2:19].O>CO>[NH:18]([C:3](=[O:2])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])[NH2:19]
Reactant: NN
Reactant: COC(=O)COc1cccc(C(=O)OC)c1
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(OCC(=O)NN)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of methyl 3-(2-methoxy-2-oxoethoxy)benzoate (887 mg, 3.96 mmol) in MeOH (50 mL) was added hydrazine hydrate (1.92 mL). After stirring for 0.5 h at rt, water (50 mL) was added and the reaction mixture was filtered. Washing with water (3×5 mL) and drying under vacuo at 70° C. overnight gave 713 mg of the title compound (80%) as a white solid in 98.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][C@@H:5]([CH:7]=O)[C@H:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.Cl.[CH2:16]([NH:23][C:24]([N:26]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:27][CH2:28][CH3:29])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]=[C:2]1[CH2:3][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]([CH2:7][N:33]2[CH2:32][CH2:31][CH:30]([N:26]([C:24]([NH:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:25])[CH2:27][CH2:28][CH3:29])[CH2:35][CH2:34]2)[CH2:6]1
Reactant: CCCN(C(=O)NCc1ccccc1)C1CCNCC1
Reactant: C=C1C[C@@H](C=O)[C@H](c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: C=C1CC(CN2CCC(N(CCC)C(=O)NCc3ccccc3)CC2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To a solution of (+−)-trans-4-methylene-2-phenylcyclopentanecarboxaldehyde from Step C (880 mg, 4.7 mmol) in 1,2-dichloroethane (50 mL) was added 4-(N-(benzylaminocarbonyl)-(N-prop-1-yl)amino)piperidine hydrochloride (1.62 g, 5.2 mmol) and DIPEA (1.0 mL, 5.7 mmol). After 15 min, sodium triacetoxyborohydride (2.0 g, 9.5 mmol) was added and the reaction was stirred at rt for 4 h. The reaction was diluted with methylene chloride, quenched with aq. sodium carbonate and extracted 3 times with methylene chloride. The organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC eluting with 60% ethyl acetate in hexanes to give the title product (1.8 g) as the free amine. MS (NH3/ESI): m/z 448 (M +1).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.OB(O)[C:26]1[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:23][C:9]1[N:8]=[CH:7][C:6]2[C:2]([C:26]3[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=3)=[CH:3][O:4][C:5]=2[C:10]=1[O:11][C@@H:12]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=1[Cl:22])[CH3:13]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](Oc1c(N)ncc2c(-c3ccc(C(=O)O)s3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
A mixture of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridine-6-ylamine (100.0 mg, 0.238 mmol), 5-(dihydroxyboryl)thiophene-2-carboxylic acid (205 mg, 1.19 mmol), Pd(PPh3)4 (10.0 mg, 0.01 mmol), potassium carbonate (98.7 mg, 0.714 mmol) and 4:1 dioxane:water (4 mL) was heated in a microwave reactor at 100° C. for 6 h. The material was dry-loaded onto silica gel for column chromatography. The crude product was eluted with 20% MeOH/DCM. The fractions containing the product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.90 (d, J=6.8 Hz, 3H), 6.54 (q, J=6.9 Hz, 1H), 7.22 (t, J=8.6 Hz, 1H), 7.31 (d, J=3.8 Hz, 1H), 7.41 (dd, J=9.0, 4.9 Hz, 1H), 7.53 (d, J=3.8 Hz, 1H), 7.92 (s, 1H), 8.27 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][C:7]([C:16]#[N:17])(O[Si](C)(C)C)[C:6]=2[CH:18]=1.P(Cl)(Cl)(Cl)=O.Cl>N1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]=[C:7]([C:16]#[N:17])[C:6]=2[CH:18]=1
Reactant: C[Si](C)(C)OC1(C#N)CCOc2ccc(F)cc21
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC1=CCOc2ccc(F)cc21
Temperature: 25 °C
Yield: 76.6 %

Procedure:
To a solution of 32 g (0.12 mole) of the crude 6-fluoro-2,3-dihydro-4-cyano-4-[(trimethylsilyl)oxy]-4H-benzopyran in 170 ml of dry pyridine was added 60 ml (0.6 mole) of phosphorous oxychloride. The reaction was heated to reflux for 5 hours then cooled to room temperature. The resulting solution was added dropwise to a solution of 300 cc of concentrated HCl in 1 L of water. This aqueous layer was extracted with EtOAc and the EtOAc layer was dried over Na2SO4, filtered and evaporated to give 16.1 g of product m.p. 114°-115° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])=[O:10])[CH:2]=1.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:14]=[CH:15][C:16]=2[O:17][CH3:18])=[O:10])[CH:2]=1
Reactant: COC(=O)CCc1ccc(OC)c(C(=O)NCc2cccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCC(=O)O)cc1C(=O)NCc1cccnc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
Methyl 3-[3-[N-(3-pyridylmethyl)carbamoyl]-4-methoxy-phenyl]propionate (200 mg, 0.609 mmol), 10 mL of methanol and 10 mL of 1 mol/L aqueous solution of sodium hydroxide were mixed and, after stirring for 4 hours at 60° C., the reaction mixture was concentrated under reduced pressure. The residue was neutralized with. 2 mol/L hydrochloric acid under cooling with ice. The precipitates produced were filtered and dried to obtain 90.0 mg (47%) of the title compound as colorless powder.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[N:18]=[C:19]([CH3:22])[O:20][CH:21]=3)[N:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+]>CCO.O.ClCCl.[Fe]>[CH:1]1([C:4]2[C:12]3[C:11]([NH2:13])=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]([CH2:16][C:17]3[N:18]=[C:19]([CH3:22])[O:20][CH:21]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)co1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cc1nc(Cn2nc(C3CC3)c3c(N)cccc32)co1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a suspension of 4-((3-cyclopropyl-4-nitro-1H-indazol-1-yl)methyl)-2-methyloxazole (88 mg, 0.295 mmol) in EtOH/H2O (4:1; 2 mL) was added iron powder (0.33 g, 5.9 mmol) and ammonium chloride (15.8 mg, 0.295 mmol). The reaction mixture was heated at reflux for three hours. The reaction mixture was cooled to ambient temperature, diluted with excess dichloromethane, and the resulting suspension was dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was dissolved in dichloromethane, passed through a silica plug, eluting with 10% MeOH/DCM, and concentrated to afford the product (60.8 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)=O>C(O)C>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([C:17]2[N:1]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[S:14][CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Yield: 91.8 %

Procedure:
To a solution of the compound (2.99 g, 14.0 mmol) obtained in Example 1b in ethanol (30 mL) was added 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (3.74 g, 14.0 mmol), and the mixture was heated under reflux for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed successively with diluted aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (4.90 g, 91%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:18]=1)[CH:7]=[C:8]1[C:12]([CH3:14])([CH3:13])[O:11][C:10]([CH3:16])([CH3:15])[C:9]1=[O:17].[OH:21]O.[OH-].[Li+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:19][CH3:20])=[C:6]([CH:7]2[C:8]3([C:9](=[O:17])[C:10]([CH3:15])([CH3:16])[O:11][C:12]3([CH3:13])[CH3:14])[O:21]2)[CH:18]=1
Reactant: CCc1ccc(Br)cc1C=C1C(=O)C(C)(C)OC1(C)C
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(Br)cc1C1OC12C(=O)C(C)(C)OC2(C)C
Temperature: 35 °C
Yield: 87.2 %

Procedure:
To a solution of 4-(5-bromo-2-ethylbenzylidene)-2,2,5,5-tetramethyldihydrofuran-3-one (32.07 g, 95.15 mmol) in methanol (1570 ml) at 35° C. is added 50% aqueous hydrogen peroxide (8.10 ml, 142.73 mmol), followed immediately by a solution of 2M aqueous lithium hydroxide (9.51 ml, 19.03 mmol). This reaction mixture is stirred at 35° C. for exactly 1 hour, then quenched with saturated sodium metabisulfite (340 ml) and distilled water (340 ml). After stirring at room temperature for 15 minutes solvents are then concentrated in vacuo (to approximately 500 ml), over which time the product precipitates as a yellow solid. To this suspension is added distilled water (500 ml), and the product is isolated by filtration. After additional washing with distilled water the solid is dried under vacuum overnight to afford 2-(5-bromo-2-ethylphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (29.30 g) as a yellow solid which is used without purification in the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(CC(=O)C(C)(C)C)(=O)C(C)(C)C.Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>CN1CCCC1=O.[Cu]Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([O:11][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:33](=[O:34])[CH3:32])[CH:2]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Oc1cnc2ccccc2c1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccccc1Oc1cnc2ccccc2c1
Temperature: 130 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
0.73 g of 3-quinolinol, 1.8 g of cesium carbonate, 0.18 g of dipivaloylmethane, 2.0 g of 2-bromoacetophenone, and 0.50 g of copper (I) chloride were dissolved in 10 ml of N-methylpyrrolidone, and the mixture was stirred for 3 hours at 130° C. The resultant was purified by silica gel column chromatography, and 0.82 g of 1-[2-(quinolin-3-yloxy)-phenyl]-ethanone (Compound Number 1) was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10][C@H:5]2[C@H:4]([C:22]([OH:24])=O)[O:3]1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:22]([C@H:4]2[C@H:5]3[N:6]([C:7]4[CH:14]=[CH:13][C:12]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][C:16]5=[O:21])=[CH:11][C:8]=4[O:9][CH2:10]3)[C:2](=[O:1])[O:3]2)=[O:24])=[N:30][CH:31]=1
Reactant: O=C(O)[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Reactant: Nc1ccc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Yield: 52.65 %

Procedure:
Using compound (3R,3aS)-1-oxo-7-(3-oxomorpholin-4-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-carboxylic acid (the product of step (b) in Example 36) (90 mg, 0.24 mmol), 5-chloropyridine-2-amine (37 mg, 0.287 mmol), HATU (137 mg, 0.36 mmol), and TEA (48.4 mg, 0.48 mmol) as starting materials, preparation following the method as described in Example 11 (g) afforded white solid 56 mg, yield: 52.65%.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C([O-])(C)C.[K+].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=1[C:23](=[CH2:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CS(C)=O>[CH3:22][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[C:16]=1[C:23]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:29]1
Reactant: C=C(C(=O)OCC)c1c(OC)cccc1OC
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2c(OC)cccc2OC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To trimethylsulfoxonium iodide (32 g, 1.2 equiv) in DMSO (250 ml) was added ground KOt-Bu (17.62 g, 1.3 equiv) and this mixture was stirred at r.t. for 30 min. A solution of the styrene 17 (28.53 g, 121 mmol) in DMSO (55 ml) was then added and this mixture was stirred at r.t. for 3 h. The reaction was poured into water (1.0 L) mixed with sat. NHCl (350 ml). The product was extracted into hexane (2×300 ml) and this solution was washed with water and brine, dried over Na2SO4 and filtered through silica (400 ml). The product was then eluted with EtOAc/hexane 15 and 20% to yield 18 (21.1 g, 70%) as a colorless oil.