Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(O)(=O)C>CCO>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:19]([C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:18][CH:17]=2)[N:20]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(N)n(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of 4,4-dimethyl-3-oxopentanenitrile (20.4 g, 163 mmol) and 4-nitrophenylhydrazine (25.0 g, 163 mmol) in anhydrous EtOH (300 mL) was added acetic acid (3.4 mL, 60 mL) dropwise. The reaction was stirred at reflux under N2 for 18 h. The reaction mixture was cooled to room temperature and concentrated at reduced pressure. The residue was partitioned between EtOAc (500 mL) and aqueous saturated NaHCO3 solution (300 mL). The organic layer was washed with water and brine, dried over Na2SO4, and concentrated at reduced pressure. The crude residue was purified by MPLC (eluting with 80:20 hexanes/EtOAc) to give 36.0 g (85%) of the desired product. 1H-NMR (DMSO-d6) δ 8.28 (d, J=6.9 Hz, 2H), 7.93 (d, J=6.9 Hz, 2H), 5.55 (s, 2H), 5.46 (s, 1H), 1.20 (s, 9H); MS LC-MS [M+H]+=261, RT=2.74 min.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:20](O)[CH2:21][OH:22].COC(OC)OC.C([O-])(O)=O.[Na+]>ClCCl>[C:14]1([C:7]2([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[O:22][CH2:21][CH2:20][O:6]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCO
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: COC(OC)OC
Product: O=C(O)CCCC1(c2ccccc2)OCCO1
Reaction time: 16 h
Yield: 17.3 %

Procedure:
Step AAH (1): Concentrated sulfuric acid (0.200 mL, 3.75 mmol) was added to a mixture of 5-oxo-5-phenylpentanoic acid (4.0 g, 20.81 mmol), ethylene glycol (6.96 mL, 125 mmol), and trimethylorthoformate (6.90 mL, 62.4 mmol) in dichloromethane (40 mL) at it under nitrogen. The mixture was stirred at it for 16 h. Solid NaHCO3 (2.0 g) was carefully added. The resulting mixture was concentrated in vacuo. The residue was taken up in methanol (50 mL) and the vessel was placed in a it water bath. Aqueous 50% NaOH (5 mL) was slowly added and the mixture was stirred at for 16 h. The mixture was concentrated in vacuo (to remove methanol) and the resulting aqueous layer was neutralized to pH 2. The aqueous layer was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was crystallized from diethyl ether to afford 4-(2-phenyl-1,3-dioxolan-2-yl)butanoic acid (850 mg, 17% yield) which was contained with a significant portion of 5-oxo-5-phenylpentanoic acid. LC-MS (M+H)+ 235.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[C:21]([CH2:29][C:30](=O)[CH3:31])(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:30]([CH3:31])=[CH:29][C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Reactant: CC(=O)CC(=O)c1ccccc1
Product: Cc1cc(-c2ccccc2)nn1-c1nc(Nc2ccc(Cl)cc2)c2ncn(C)c2n1

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and benzoylacetone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:15])=[CH:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]3([CH3:15])[O:25][CH:9]3[C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=Cc2cc([N+](=O)[O-])ccc2OC1(C)C
Solvent: ClCCl
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2C2OC21C
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a solution of 6-nitro-2,2,3-trimethyl-2H-1-benzopyran (10.0 g, 0.0457 mol) in dichloromethane (200 ml) at 0° C. was added m-chloroperbenzoic acid (13.5 g, 70%, 0.0548 mol). After stirring for eighteen hours at room temperature the mixture was washed successively with water, aqueous sodium hydrogen carbonate, water and then aqueous sodium hydroxide solution. The organic phase was separated and evaporated under reduced pressure to give 9.96 g (93%) of 6-nitro-2,2,3-trimethyl-3,4-dihydro-3,4-epoxy-2H-1-benzopyran, 1H NMR (CDCl3): δ1.3 (s,3H), 1.55 (s,3H), 1.60 (s,3H), 3.8 (s,1H), 6.9 (d,1H), 8.15 (d,1H), 8.30 (s,1H).
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([Cl:19])[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:20])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[C:6]=2[CH:5]=1)[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[Cl:19][C:16]1[C:15]2[O:14][C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([F:20])[C:8]=3[C:7](=[O:21])[C:6]=2[CH:5]=[C:4]2[CH2:1][CH:2]([C:37]([OH:38])=[O:40])[O:18][C:17]=12
Reactant: O=C([O-])[O-]
Reactant: C=CCc1cc2c(=O)c3c(F)cccc3oc2c(Cl)c1O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C1Cc2cc3c(=O)c4c(F)cccc4oc3c(Cl)c2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.5 %

Procedure:
A mixture of 2-allyl-4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene (2.8 g), m-chloroperbenzoic acid (4.7 g) and chloroform (100 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (10 g) and water (200 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (500 ml) and, to the stirred solution, a mixture of chromium trioxide (2.8 g), water (16 ml) and concentrated sulfuric acid (4.8 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.0 g of 11-chloro-6-fluoro-2,3-dihydro-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 300° C. This compound showed a mass spectrum having a molecular ion peak at m/e 334.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([C:7]1[C:8](=[O:15])[NH:9][C:10]([CH2:13][CH3:14])=[CH:11][CH:12]=1)=[O:6].C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClC(Cl)C.CN(C)C1C=CN=CC=1>[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([O:15][C:8]2[C:7]([C:5](=[O:6])[C:4]3[CH:16]=[CH:17][CH:18]=[C:2]([Cl:1])[CH:3]=3)=[CH:12][CH:11]=[C:10]([CH2:13][CH3:14])[N:9]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CCc1ccc(C(=O)c2cccc(Cl)c2)c(=O)[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1ccc(C(=O)c2cccc(Cl)c2)c(OS(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
3-(3-Chlorobenzoyl)-6-ethyl-2-pyridone (95.8 g, 366 mmol) was dissolved in 1,000 ml of dichloroethane, 56.4 ml (403 mmol) of triethylamine, 4.52 g (366 mmol) of 4-dimethylaminopyridine and 76.7 g (403 mmol) of p-toluenesulfonyl chloride were added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was washed with water, 1 N hydrochloric acid-brine and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration and then the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was recrystallized from ethyl acetate-hexane to give 139.90 g of 3-(3-chlorobenzoyl)-6-ethyl-2-pyridyl p-toluenesulfonate in the form of crystals. The yield was 91.9%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)=[CH:3][CH:2]=1.[NH2:17][C@@H:18]([CH3:42])[C:19]([N:21]([C@@H:33]([CH3:41])[CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:39]([O:38][CH:34]([O:35][CH2:36][CH3:37])[C@@H:33]([N:21]([CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[C:19](=[O:20])[C@@H:18]([NH:17][C:13](=[O:15])[CH2:12][O:11][NH:10][C:9]([NH:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:16])[CH3:42])[CH3:41])[CH3:40]
Reactant: O=C(O)CONC(=O)NCc1ccncc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetic acid VI-10) 94 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)-propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([S:9]([NH:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH2:28])[C:18](=[O:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:30]([C:32](=[O:39])[CH:33](Cl)[CH2:34][CH2:35][CH2:36][CH3:37])[CH3:31].[N+](C1C=CC=CC=1)([O-])=O>CO>[CH2:1]([S:9]([NH:12][C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:28][CH:33]([CH2:34][CH2:35][CH2:36][CH3:37])[C:32]([CH2:30][CH3:31])=[O:39])[C:18](=[O:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1)(=[O:10])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCS(=O)(=O)Nc1cccc2c1C(=O)c1c(N)cccc1C2=O
Reactant: CCCCC(Cl)C(=O)CC
Solvent: CO
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCCCS(=O)(=O)Nc1cccc2c1C(=O)c1c(NC(CCCC)C(=O)CC)cccc1C2=O

Procedure:
1-(n-octylsulfonylamino)-8-aminoanthraquinone (0.25g), 1-ethylhexanoyl chloride (0.5g) and nitrobenzene (5ml) were heated at reflux for 10 mins. After addition of methanol (10ml), the mixture was heated on a steam bath for a further 10 mins to destroy excess acid chloride. 0n evaporation of low-boiling material, the remaining liquid was diluted with toluene (100ml) and separated by chromatography on a silica gel column. Nitrobenzene eluted first, and the material eluted with a 50:50 mixture of toluene:ethyl acetate was collected. The solvent was evaporated and ethanol was added to the residue, which upon trituration afforded the product as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][C@H:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.Cl>ClCCl>[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([O:19][CH2:18][C@@H:9]2[CH2:10][C@@H:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OC(C)(C)C)cc1
Yield: 92 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (12.0 g) in dichloromethane (180 ml) stirring under ice cooling, triethylamine (6.23 ml), p-toluenesulfonyl chloride (8.52 g) and N,N-dimethylaminopyridine (993 mg) are successively added. The mixture is heated to reflux for 3 hours, supplemented with triethylamine (0.57 ml) and p-toluenesulfonyl chloride (775 mg), and heated to reflux for 1 hour. The reaction mixture is acidified with dilute hydrochloric acid. The organic layer is taken, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography and recrystallized from n-hexane to give (2S,4R)-1-t-butoxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (16.8 g). Yield: 92%. mp. 65° to 66° C. NMR δ(CDCl3) ppm: 1.42(s, 9H), 2.15 to 2.55(m, 2H), 2.45(s, 3H), 3.03(s, 3H), 3.3 to 4.5(m, 5H), 5.1 to 5.25(m, 1H), 7.35(d, J=8.0 Hz, 2H), 7.76(d, J=8.0 Hz, 2H). IR ν (CHCl3) cm-1 : 1693.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].[CH:12]([NH:15][OH:16])([CH3:14])[CH3:13]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N+:15]([CH:12]([CH3:14])[CH3:13])[O-:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(C)NO
Reactant: CCOc1ccc(C=O)cc1
Product: CCOc1ccc(C=[N+]([O-])C(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 4-ethoxybenzaldehyde and N-isopropylhydroxylamine. The title compound was isolated in 41.2% yield as a solid, m.p. 115.1° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:6]=1)[C:2]#[CH:3].[N:27]([CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[N+:28]=[N-:29].C1CCN2C(=NCCC2)CC1>CO.[Cu]I>[N:32]1([CH2:31][CH2:30][N:27]2[CH:3]=[C:2]([CH2:1][NH:4][C:5]3[C:10]([C:11]([NH2:13])=[O:12])=[CH:9][N:8]=[C:7]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([CH:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:17][CH:16]=4)[CH:6]=3)[N:29]=[N:28]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: [N-]=[N+]=NCCN1CCCCC1
Reactant: C#CCNc1cc(Nc2ccc(C3CCOCC3)cc2)ncc1C(N)=O
Agent: [Cu]I
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: NC(=O)c1cnc(Nc2ccc(C3CCOCC3)cc2)cc1NCc1cn(CCN2CCCCC2)nn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Compound 4-(prop-2-ynylamino)-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)nicotinamide (Example 184) (20 mg, 0.057 mmol) was dissolved in 6 mL MeOH. To it were added 1-(2-azidoethyl)piperidine (18 mg, 0.11 mmol), DBU (26 μL, 0.17 mmol) and finally powder CuI (13 mg, 0.068 mmol). The mixture was stirred at RT for 5 h, filtered and subjected to reverse phase prep HPLC to isolate the title compound. MS found for C27H36N8O2 as (M+H)+ 505.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.14 (1H, s), 8.12 (1H, s), 7.39 (2H, dt, J=8.4; 2.0 Hz), 7.24 (2H, dt, J=8.4; 2.0 Hz), 6.20 (1H, s), 4.60 (2H, s), 4.05 (2H, m), 3.73 (2H, m), 3.59 (4H, m), 3.04 (2H, m), 2.87 (1H, m), 1.95 (2H, m), 1.86-1.75 (8H, m) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[NH:22][CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[CH:13][C:14]=2[O:16][CH2:17][C@H:18]2[N:22]([C:31](=[O:32])[CH2:30][OH:33])[CH2:21][C@H:20]([OH:23])[CH2:19]2)[N:9]=[CH:8][N:7]=1
Reactant: O=C(O)CO
Reactant: COc1cc(OC[C@@H]2C[C@@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Product: COc1cc(OC[C@@H]2C[C@@H](O)CN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Yield: 53 %

Procedure:
The procedure described in Example 20 was repeated using (3R,5S)-5-[({4-[3-chloro-4-fluoroanilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol (209 mg) with glycolic acid (42 mg) to give the title compound as a white solid in 53% yield; NMR spectrum (DMSO-d6) 10.17 (s, 1H), 8.53 (s, 1H), 8.14 (dd, 1H), 7.74-7.69 (m, 1H), 7.47 (t, 1H), 6.92 (d, 1H), 6.83 (d, 1H), 5.14-5.10 (m, 1H), 4.71-4.67 (m, 1H), 4.50-4.44 (m, 1H), 4.40-4.38 (m, 1H), 4.28-4.23 (m, 1H), 4.06-4.03 (m, 2H), 3.95 (s, 3H), 3.53-3.48 (m, 3H), 2.05-2.02 (m, 2H); Mass spectrum MH+ 477.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[O:40]1[C:44]2[CH:45]=[CH:46][C:47](B(O)O)=[CH:48][C:43]=2[O:42][CH2:41]1>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[C:24]([C:47]3[CH:46]=[CH:45][C:44]4[O:40][CH2:41][O:42][C:43]=4[CH:48]=3)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc([N+](=O)[O-])c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc([N+](=O)[O-])c2)c1CCC(=O)OCC
Yield: 73.4 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-nitro-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (6.6 g, 10.07 mmol) and benzo[1,3]dioxol-5-yl-boronic acid (3.45 g, 20.14 mmol) to afford 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-nitro-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (4.8 g, 73%) as a light yellow oil: EI(+)-HRMS m/e calculated for C36H43NO10 (M+Na)+ 672.2779, found 672.2773.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].C1(C)C=CC=CC=1.C[O:33]CCOCCOC.[OH-].[Na+]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:33])[CH3:2]
Reactant: COCCOCCOC
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 120 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
To a 100 mL volume four-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (6.57 g), toluene (16.7 g), diethylene glycol dimethylether (3.6 g), and sodium hydroxide (2.86 g) were added under a nitrogen atmosphere, and stirred at 120° C. for 15 hours. Then, water (24.2 g) was added at room temperature. The organic layer was removed, and then the aqueous layer was mixed with 3.5 w/w % of hydrochloric acid (25 g) at the same temperature, and filtered. The residue was washed with water (12 g) and dried to give 4.7 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][OH:18])[CH2:13][C:12]=2[CH:11]=[CH:10][C:9]=1[F:19].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:18][CH2:17][CH:14]2[CH2:13][C:12]3[CH:11]=[CH:10][C:9]([F:19])=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:16]=3[O:15]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2ccc(F)c(-c3ccccc3Cl)c2O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Yield: 35.8 %

Procedure:
Treatment of 1-bromo-2-chlorobenzene (5.63 g, 29.4 mmol) with (2-fluoro-6-methyoxyphenyl)boronic acid (5.0 g, 29.42 mol) generally according to the procedure described for Intermediate 37 afforded 2.0 g (29%) of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether. Treatment of 6-fluoro-2′-chlorobiphenyl-2-yl methyl ether with hydrogen bromide (50 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded a brown oil. The oil was reacted with sodium hydride (0.34 g, 14.35 mmol) and allyl bromide (1.74 g, 14.35 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 to provide 3-allyl-6-chloro-2′-chlorobiphenyl-2-ol. Treatment of 3-allyl-6-fluoro-2′-methylbiphenyl-2-ol (1.2 g, 4.56 mmol) with m-chloroperoxybenzoic acid (2.36 g, 13.68 mmol, 77%) and potassium carbonate (1.575 g, 11.4 mmol) generally according to the procedure described for Intermediate 9 afforded 0.7 g (55%) of (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanol (1.5 g, 5.81 mmol) with p-toluenesulfonyl chloride (1.66 g, 8.71 mol) generally according to the procedure described for Intermediate 10 gave 0.9 g (82%) of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.50 g, 1.15 mmol) with sodium azide (0.4 g, 6.15 mmol) generally according to the procedure described for Intermediate 98 afforded 0.35 g, (99%) of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-chlorophenyl)-6-fluoro-2,3-dihydro-1-benzofuran (0.35 g, 1.15 mmol) in tetrahydrofuran (10 mL) with polymer-supported triphenylphosphine (0.60 g, 2.3 mmol) generally according to the procedure described for Example 154 provided 0.170 g (47%) of (±)-{[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 248-250° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[O:3][CH2:4][CH2:5][CH2:6][C:7]([NH2:9])=[O:8].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:23]([O:25][C:26]([CH3:28])=[CH2:27])=[O:24]>C1COCC1>[F:1][C:2]([F:10])([F:11])[O:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:23](=[O:24])[O:25][C:26]([CH3:28])=[CH2:27])=[O:8]
Reactant: NC(=O)CCCOC(F)(F)F
Reactant: C=C(C)OC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)CCCOC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A −78° C. mixture of 4-(trifluoromethoxy)butanamide (175 mg, 1.023 mmol) in THF (5 mL) was treated drop wise with LiHMDS (1.0M in THF, 1.33 mL, 1.33 mmol), stirred for 0.5 h, then treated drop wise with a solution of isopropenyl chloroformate (0.129 mL, 1.176 mmol) in THF (1 mL). The mixture was allowed to warm to RT, treated with satd. NaHCO3 and extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated to afford prop-1-en-2-yl (4-(trifluoromethoxy)butanoyl)carbamate (100% yield assumed).
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CC(C)=O>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:12])[N:21]=[C:13]([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[S:20][CH:2]3[CH2:10][C:9]=2[CH:8]=1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Reactant: NC(=S)c1ccncc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: OC12N=C(c3ccncc3)SC1Cc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.98 g of 2-bromo-5-chloroindan-1-one and 0.55 g of thioisonicotinamide are dissolved in 40 ml of dry acetone at room temperature and treated with 0.55 ml of triethylamine. The mixture is stirred at room temperature for 2 days. The reaction mixture is concentrated, and the residue is taken up with ethyl acetate and washed twice with water and then twice with satd sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated, and the residue is chromatographed on silica gel using ethyl acetate/n-heptane 10/1. 6-Chloro-2-pyridin-4-yl-8,8a-dihydro-indeno[1,2-d]thiazol-3a-ol of melting point 155-160° C. (dec.) is obtained.