Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.C([Mg]Cl)(C)C.[B:16](OC)([O:19]C)[O:17]C>>[F:1][CH:2]([F:10])[C:3]1[CH:8]=[CH:7][C:6]([B:16]([OH:19])[OH:17])=[CH:5][CH:4]=1
Reactant: COB(OC)OC
Reactant: FC(F)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Product: OB(O)c1ccc(C(F)F)cc1

Procedure:
In a departure from the procedure described above the compound is prepared from 4-difluoromethyl-1-iodo-benzene (prepared from 4-iodobenzaldehyde using diethylaminosulfurtrifluoride (DAST) in dichloromethane) using iPrMgCl to generate the arylmetal compound and trapping this intermediate with trimethyl borate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[Cl-].[OH:13][NH3+:14].N1C=CC=CC=1>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=[N:14][OH:13]
Reactant: [NH3+]O
Reactant: O=Cc1cc2ccccc2o1
Agent: [Cl-]
Solvent: CO
Solvent: c1ccncc1
Product: ON=Cc1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 96.9 %

Procedure:
To a solution of 2-benzofuran carbaldehyde (1.00 g, 6.85 mmol) in methanol (20 ml) were added hydroxylammonium chloride (530 mg, 7.63 mmol) and pyridine (2.8 ml), followed by stirring at room temperature for 6.5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, followed by washing sequentially with a 5% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogen carbonate solution and then a saturated aqueous sodium chloride solution. The resulting organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford the title compound (1.07 g) as a white solid. (Yield: 97%)
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].[Cl:6][C:7]1[CH:8]=[C:9]([S:15][C:16]2[CH:17]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([F:22])[CH:21]=2)[CH:10]=[CH:11][C:12]=1[CH2:13]Cl>>[Cl:6][C:7]1[CH:8]=[C:9]([S:15][C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=2)[CH:10]=[CH:11][C:12]=1[CH2:13][O:5][N:4]=[C:2]([CH3:3])[CH3:1]
Reactant: COC1(c2cc(F)cc(Sc3ccc(CCl)c(Cl)c3)c2)CCOCC1
Reactant: CC(C)=NO
Product: COC1(c2cc(F)cc(Sc3ccc(CON=C(C)C)c(Cl)c3)c2)CCOCC1
Yield: 50 %

Procedure:
Using an analogous procedure to that described in Example 1, acetone oxime was reacted with 4-[3-(3-chloro-4-chloromethylphenylthio)-5-fluorophenyl]-4-methoxytetrahydropyran to give acetone O-{2-chloro-4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]benzyl}oxime as a gum in 50% yield.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[OH:8][C@@H:9]1[CH2:13][N:12]([CH2:14][C:15]2[CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:11](=[O:32])[CH2:10]1.O>ClCCl>[CH3:22][O:21][C:18]1[C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)=[CH:16][C:15]([CH2:14][N:12]2[C:11](=[O:32])[CH2:10][C@H:9]([O:8][C:6](=[O:7])[NH2:5])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1ccc(CN2C[C@@H](O)CC2=O)cc1-c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN2C[C@@H](OC(N)=O)CC2=O)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 20 mL vial with a stir bar was added chlorosulfonyl isocyanate (42 mg, 0.30 mmol), 1 mL dichloromethane, then P-248 (51.3 mg, 0.15 mmol) in 2 mL of dichloromethane. The reaction was stirred at room temperature for 18 hours after which 2 mL of water was added and the mixture was stirred at room temperature for 30 minutes. The layers were separated and the aqueous was extracted with dichloromethane. The combined organics were concentrated and then purified by preparative layer TLC using 50% acetone/dichloromethane to obtain P-253 (12.4 mg, 21%) as an off-white semi-solid. 1H NMR (400 MHz, DMSO-d6) 8.30 (s, 1H), 8.20 (dd, J=2.1, 8.6 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.33-7.26 (m, 2H), 7.16 (d, J=9.0 Hz, 1H), 6.59 (br. s., 2H), 5.04 (t, J=5.8 Hz, 1H), 4.49-4.30 (m, 2H), 3.80 (s, 3H), 3.46-3.38 (m, 1H), 3.21 (d, J=11.4 Hz, 1H), 2.78 (dd, J=6.9, 17.5 Hz, 1H), 2.23 (d, J=18.1 Hz, 1H) ppm. LC/MS=100.0%, 386.1 (APCI+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH2:9]([CH2:11][NH2:12])[OH:10]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH2:11][CH2:9][OH:10])=[N:6][CH:7]=1
Reactant: NCCO
Reactant: Fc1ccc(Br)cn1
Product: OCCNc1ccc(Br)cn1
Yield: 13.2 %

Procedure:
Prepared from 5-bromo-2-fluoropyridine (2.5 g, 14 mmol) and ethanolamine (4.34 g, 70 mmol) as described in example B.45. Obtained as a colorless oil (400 mg, 13%). MS (ISP) 217.2 [(M+H)+], 219.1 [(M+2+H)+].
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:39])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[O:23][CH:22]3[CH:24]([N:31]4[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]4=[O:38])[O:25][CH:26]([CH2:27][N:28]=[N+:29]=[N-:30])[CH:21]3[O:20]2)=[CH:15][CH:14]=1)C.Cl>O.CCO>[N:28]([CH2:27][CH:26]1[CH:21]2[CH:22]([O:23][CH:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:39])=[O:5])=[CH:14][CH:15]=3)[O:20]2)[CH:24]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[O:25]1)=[N+:29]=[N-:30]
Reactant: CCOC(=O)CCCCCOc1ccc(C2OC3C(CN=[N+]=[N-])OC(n4ccc(=O)[nH]c4=O)C3O2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=NCC1OC(n2ccc(=O)[nH]c2=O)C2OC(c3ccc(OCCCCCC(=O)O)cc3)OC12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of sodium hydroxide (NaOH, 20.8 g, 522 mmol) in H2O (125 mL) was added to a suspension of 7 (89.8 g, 174 mmol) in EtOH (400 mL) and stirred for 4 h at room temperature. The solvent was removed and the resulting residue was diluted with H2O (300 mL). The suspension was then treated dropwise with 1M aqueous HCl (522 mmol, 522 mL) to afford a white precipitate, which was subsequently partitioned with EtOAc (1.5 L). The organic layer was then washed with H2O (2×1 L), dried (MgSO4), filtered and concentrated in vacuo to give a white foam (8, 80.2 g, 164 mmol, 95%) as a mixture of two diastereomers: 1H-NMR (400 MHz, (CD3)2SO3) δ=12.01 (s, 1H, 1H′), 11.49 (s, 1H, 1H′), 7.78 (d, J=8.0, 1H), 7.74 (d, J=8.0, 1H′), 7.43 (d, J=8.5, 2H), 7.37 (d, J 8.5, 2H′), 6.96 (d, J=8.5, 2H), 6.93 (d, J=8.5, 2H′), 6.07 (s, 1H′), 5.93 (s, 1H), 5.91 (s, 1H, 1H′), 5.67 (d, J=8.0, 1H), 5.66 (d, J=8.0, 1H′), 5.20-4.81 (m, 2H, 2H′), 4.31 (m, 1H, 1H′), 3.96 (m, 2H, 2H′), 3.62 (m, 2H, 2H′), 2.22 (m, 2H, 2H′), 1.70 (m, 2H, 2H′), 1.54 (m, 2H, 2H′), 1.41 (m, 2H, 2H′); 13C-NMR (400 MHz, (CD3)2SO3) δ=175.3, 175.3, 164.1, 164.0, 160.7, 160.6, 151.2, 151.2, 144.3, 143.7, 129.3 (2C), 129.3 (2C), 128.6, 128.6, 115.1 (2C), 115.0 (2C), 107.6, 103.5, 103.1, 102.8, 93.5, 92.5, 85.9, 85.1, 83.2, 82.8, 82.6, 81.5, 68.3, 68.3, 52.7, 52.5, 34.5, 34.5, 29.2, 29.1, 26.0, 25.9, 25.1, 25.1; IR (film) ν=3354, 3183, 2941, 2101, 1684, 1245, 1069, 1050, 1023, 995, 824; HRMS (MALDI-FTMS) mn/z 510.1600 (510.1595 calculated for C22H25N5O8Na (M+Na)+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[N:10]=[C:11]=S.[NH:13]([C:15](=[O:38])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)=[O:17])[NH2:14].CCN=C=NCCCN(C)C.O>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]1[O:38][C:15]([C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH:31]([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[O:17])=[N:13][N:14]=1
Reactant: Fc1cc(F)c(N=C=S)cc1F
Reactant: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4,5-Trifluorophenyl isothiocyanate (252 mg, 1.33 mmol) was added in one portion to a suspension of trans-ethyl 2-[4-(4-{[hydrazino(oxo)acetyl]amino}phenyl)cyclo-hexyl]propanoate (Intermediate 99, 400 mg, 1.11 mmol) in DMA (6 mL) and the reaction mixture was stirred at room temperature for 2 h. EDCI (319 mg, 1.66 mmol) was added in one portion and the reaction mixture was heated to 90° C. for 10 mins in the microwave. The mixture was then cooled to room temperature and H2O (20 mL) was added. The mixture was filtered to leave a solid, which was washed with H2O (10 mL) to give the title compound (550 mg, 95%) as a solid; 1H NMR δ 1.1 (3H, d), 1.12-1.28 (2H, m), 1.2 (3H, t), 1.35-1.51 (2H, m), 1.52-1.64 (1H, m), 1.65-1.75 (1H, m), 1.77-1.9 (3H, m), 2.22-2.32 (1H, m), 2.38-2.51 (1H, m), 4.01-4.16 (2H, m), 7.2 (2H, d), 7.65-7.78 (1H, m), 7.69 (2H, d), 8.1-8.25 (1H, m), 10.95 (1H, s), 11.05 (1H, s); MS m/e MH+ 517.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH:9]([F:27])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].N.CO>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[C@H:9]([F:27])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC(F)C2NC(=O)Nc1cccc2[nH]ncc12
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)C[C@@H](F)[C@H]2NC(=O)Nc1cccc2[nH]ncc12

Procedure:
The title compound was prepared by chiral separation of the corresponding racemic compound N-(5-tert-butyl-2-fluoro-2,3-dihydro-1H-inden-1-yl)-N′-1H-indazol-4-ylurea (Ex. 39) using a chiral column ChiralCel OD. 1H NMR (300 MHz, d6-DMSO) 13.01 (broad s, 1H), 8.87 (s, 1H), 8.08 (s, 1H), 7.71 (d, 1H), 7.33 (s, 1H), 7.30 (d, 1H), 7.21 (m, 2H), 7.09 (d, 1H), 6.87 (d, 1H), 5.33-5.46 (m, 2H), 3.05-3.27 (m, 2H), 1.27 (s, 9H). MS (DCI/NH3) m/e 367 (M+H)+. [α]D +2.67° (c=0.935, 1:1 MeOH:CH2Cl2). Structure is cis by ROESY NMR, absolute stereochemistry assigned arbitrarily. Contains 17% of trans (−) diastereomer.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[Br:19][CH2:20][C:21](Br)=[O:22]>ClCCl>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:1][C:21](=[O:22])[CH2:20][Br:19])[CH:3]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of methyl 3-aminobenzoate (4.53 g, 30.0 mmol) and triethylamine (3.54 g, 4.88 mL, 35.0 mmol) in dichloromethane (100 mL), at 0° C. while stirring, was added bromoacetyl bromide (6.66 g, 2.9 mL, 33.0 mmol) dropwise. After the addition, the mixture was stirred at room temperature overnight and passed through a short silica pad. The crude product, 3-(2-bromoacetylamino)benzoic acid methyl ester (8.09 g, 99.1%), obtained after the removal of the solvent (>99% by LC/MS, MS (ES+) m/z: 272, 274) was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@H:10]([CH3:11])[CH2:9][N:8]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)(=[O:14])=[O:13])[CH2:7][C@@H:6]1[CH3:25])=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40]>C(#N)C.O>[CH3:25][C@H:6]1[CH2:7][N:8]([S:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)(=[O:13])=[O:14])[CH2:9][C@@H:10]([CH3:11])[N:5]1[C:3](=[O:4])[CH2:2][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][CH3:32]
Reactant: COc1ccccc1O
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc3ccccc3c2)C[C@H](C)N1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccccc1OCC(=O)N1[C@H](C)CN(S(=O)(=O)c2ccc3ccccc3c2)C[C@@H]1C
Reaction time: 4 h

Procedure:
2-Chloro-1-((2S,6R)-2,6-dimethyl-4-(naphthalene-2-ylsulfonyl)piperazin-1-yl)ethanone (200 mg, 0.52 moles) was dissolved in 20 mL of acetonitrile. Dry K2CO3 (106 mg, 0.79 moles) was added to the reaction mixture under nitrogen atmosphere and allowed to stir for about ten minutes. 2-methoxyphenol (97 mg, 0.78 moles) was slowly added to the reaction at room temperature and allowed the reaction to continue for another 4 h. The reaction was monitored by TLC and after product formation was observed, the reaction mixture was diluted with cold water (10 mL) and extracted with ethyl acetate (25 mL×2). The combined organic layers were washed with bicarbonate followed by brine & then dried over sodium sulphate. The solvent was evaporated on reduced pressure to afford crude product which was purified by column chromatography to yield the title compound as an off-white solid.
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:9](=[O:19])[O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[OH:18])#[N:7].[H-].[Na+].[C:22]([O:25][CH2:26][CH2:27][CH2:28]Br)(=[O:24])[CH3:23]>O>[C:6]([C:8]1[C:9](=[O:19])[O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[O:18][CH2:28][CH2:27][CH2:26][O:25][C:22](=[O:24])[CH3:23])#[N:7]
Reactant: CC(=O)OCCCBr
Reactant: N#Cc1cc2cccc(O)c2oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCCOc1cccc2cc(C#N)c(=O)oc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25 %

Procedure:
In 150 ml. of dry dimethylformamide was dissolved 9.35 g. of 3-cyano-8-hydroxycoumarin. To the resulting solution was added 2.5 g. of about 60% sodium hydride with agitation and ice-cooling, and after raising to room temperature, the solution was agitated for 20 minutes. After adding dropwise 9.05 g. of 3-acetoxypropyl bromide at a temperature of 80° to 90° C. with agitation, the reaction was carried out for 5 hours with agitation. After the completion of the reaction, the reaction mixture was poured into 200 ml. of water added with ice, and extracted with three 200 ml. portions of methylene chloride. The obtained extract was dried with magnesium sulfate, and the solvent was then distilled away under reduced pressure. The residue was purified by a silica-gel column chromatography (silica-gel: 350 g., eluent: methylene chloride) to give 3-cyano-8-(3-acetoxypropoxy)coumarin (yield: 25%). The product was further recrystallized from ethyl acetate to give light yellow needles having a melting point of 132° to 135° C.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[C:27]1([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.CCCCC>[C:27]1([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][I:25])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: II
Reactant: OCC1CCC(c2ccccc2)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: ICC1CCC(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
Imidazole (4.4 g, 0.065 mol) is added in one portion to a solution of triphenylphosphine (17.0 g, 0.065 mol) in dichloromethane (300 mL) at 25° C. After all of the solids dissolved, iodine (16.5 g, 0.065 mol) is added in four portions. The mixture is stirred for 10 min. then a solution of 4-phenylcyclohexylmethanol (10.5 g, 0.055 mol) is added dropwise and the mixture is stirred at 25° C. for 18 h. The reaction mixture is poured into pentane and the resulting solids filtered. The filtrate is concentrated in vacuo and the residue is dissolved in dichloromethane. This solution is poured into hexanes, the solids were filtered, and the filtrate is concentrated in vacuo. The residue is passed through a pad of silica gel using hexanes as eluent to afford 14.6 g (89%) of 4-phenylcyclohexylmethyl iodide as an oil.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]([CH:31]([CH3:33])[CH3:32])=[CH:9][CH:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:7])[CH2:2][CH2:3][CH3:4]>C1COCC1.C(Cl)(Cl)Cl.[Rh]>[CH2:1]([NH:5][C:6]([CH:8]([CH:31]([CH3:32])[CH3:33])[CH2:9][CH:10]1[O:14][C:13]([CH3:15])([CH3:16])[N:12]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH:11]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C(=CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1)C(C)C
Agent: [Rh]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)C(CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1)C(C)C
Reaction time: 16 h
Yield: 71.8 %

Procedure:
A THF (2.03 mL) solution containing 5-[2-[(butylamino)carbonyl]-3-methyl-1-butenyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylic acid, 1,1-dimethylethyl ester (236 mg, 0.51 mmol) and rhodium on alumina (24 mg, 10% by wt, 5% Rh content) was placed under a hydrogen atmosphere for 16 h. Additional rhodium on alumina (24 mg) in THF (2.03 mL) was added and the reaction continued under H2 atmosphere for 6 h. The mixture was diluted with CHCl3, filtered and concentrated in vacuo. Silica gel chromatography (3:1 to 3:2 hexane:Et2O gradient) of the concentrate afforded the title compound (171 mg, 70%). MS (ESI) m/e 465 (M-H)-MS (ESI) m/e 467 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:25][C:26]1[S:30][C:29]([CH2:31]Cl)=[CH:28][CH:27]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3SC(Cl)=CC=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][C:29]3[S:30][C:26]([Cl:25])=[CH:27][CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(Cl)s3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3ccc(Cl)s3)c3c2CCNCC3)cc1
Yield: 38.3 %

Procedure:
The title compound (0.029 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 5-chloro-thiophen-2-ylmethyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(5-chloro-thiophen-2-ylmethyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C18H17Cl2N3S, 377.05; found, m/z 378.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.54-7.51 (m, 2H), 7.49-7.46 (m, 2H), 3.91 (d, J=3.8 Hz, 1H), 6.86 (d, J=3.8 Hz, 1H), 5.51 (s, 2H), 3.45-3.44 (m, 2H), 3.38-3.61 (m, 2H), 3.27-3.25 (m, 2H), 3.07-3.05 (m, 2H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.O[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH2:22][C:23](O)=[O:24]>O>[OH:24][CH2:23][CH2:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:13][CH:14]=2)[NH:18][CH:17]=1
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1c[nH]c2ccccc12
Reaction time: 3 h

Procedure:
LiAlH4 (1.99 g, 52.3 mmol) was placed in abs. THF (60 ml), under argon, and (5-hydroxy-1H-indol-3-yl)-acetic acid (5.00 g, 26.2 mmol) in abs. THF (100 ml) was added in the course of 30 min. The mixture was boiled for 3 h under reflux. For working up, THF (10 ml) and H2O (4 ml) were added to the mixture, while cooling with ice, and stirring was carried out for 30 min. The mixture was filtered over Celite and rinsed with dichloromethane (150 ml), and the filtrate was concentrated in vacuo.
Reaction SMILES: O.NN.[C:4]([O:8][C:9](=[O:27])[CH2:10][N:11]1[CH:15]=[CH:14][C:13]([N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[N:12]1)([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9](=[O:27])[CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)Cn1ccc(N2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Cn1ccc(N)n1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
Hydrazine hydrate (0.27 ml, 6.69 mmol) is added to a stirred solution of [3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pyrazol-1-yl]-acetic acid tert-butyl ester (2.18 g, 6.69 mmol) in ethanol (12 ml). The reaction is stirred at 90° C. for 2.5 hours. When cool, the reaction is diluted with ethanol (50 ml) and the white precipitate is removed by filtration, washing with more ethanol (250 ml). The combined filtrate is evaporated to dryness and dichloromethane (100 ml) is added. After filtering again, the filtrate is evaporated to give the titled compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=CC2C(=O)N3OC(C)CC3O[C:4]=2[CH:3]=1.[Cl:17][C:18]1[CH:27]=[C:22]([C:23]([NH:25][OH:26])=[O:24])[C:21]([OH:28])=[CH:20][CH:19]=1.C(=O)/C=C/C.Cl>C(O)(=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:28][CH:4]([CH2:3][CH:2]([Cl:1])[CH3:16])[N:25]([OH:26])[C:23](=[O:24])[C:22]=2[CH:27]=1
Reactant: CC1CC2Oc3cc(Cl)ccc3C(=O)N2O1
Reactant: O=C(NO)c1cc(Cl)ccc1O
Agent: C/C=C/C=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(Cl)CC1Oc2ccc(Cl)cc2C(=O)N1O

Procedure:
Prior to the present invention, 6-chloro-2-methyl-3,3a-dihydro-2H,9H-isoxazolo (3,2-b) (1,3) benzoxazin-9-one has been prepared by the reaction of 5-chlorosalicylhydroxamic acid (made from 5-chlorosalicylate and hydroxylamine) and crotonaldehyde in the presence of hydrogen chloride and glacial acetic acid to obtain 6-chloro-2-(2-chloropropyl)-2,3-dihydro-3-hydroxy-4H-1, 3-benzoxazin-4-one. The latter compound was then cyclized to 7-chloro-2-methyl-3,3a-dihydro-2H,9H-isoxazolo (3,2-b) (1,3) benzoxazin-9-one. Said cyclization can be carried out using organic or inorganic bases in the appropriate solvent. U.S. Pat. No. 3,598,814 discloses and claims 7-chloro-2-methyl-3, 3a-dihydro-2H,9H-isoxazolo (3,2b) (1,3) benzoxazin-9-one and several methods for its manufacture.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][C:10](OC)=[CH:11][CH:12]=2)[N:7]1[C:17]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[NH:19][C:18]1=[O:27])=[O:5])[CH3:2].C(C1C(=O)C([Cl:46])=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:17]2([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:46])[CH:9]=2)=[O:5])[CH3:2]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCOC(=O)C1Cc2ccc(OC)cc2N1C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2ccc(Cl)cc2n1C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 92.2 %

Procedure:
The solution of rac-6′-Chloro-3′-(3-chloro-benzyl)-6-methoxy-2′-oxo-2,3,2′,3′-tetrahydro-1′H-[1,3′]biindolyl-2-carboxylic acid ethyl ester (1.0 g, 1.9 mmol) and DDQ (0.73 g, 3.2 mmol) in toluene (50 mL) was heated to 90° C. for 4 h. Then the mixture was cooled to room temperature and washed with NaOH solution (10%) and water. The organic layer was dried with Na2SO4, concentrated in vacuo to give 0.9 g rac-6,6′-Dichloro-3′-(3-chloro-benzyl)-2′-oxo-2′,3′-dihydro-1′H-[1,3′]biindolyl-2-carboxylic acid ethyl ester as yellow solid. MS: [M+H]+=513
Reaction SMILES: [OH:1][CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][CH:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+].CO.OO>O>[OH:1][CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=[C:3]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1c2ccccc2NC(c2ccccc2)C1O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2N=C(c2ccccc2)C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
To a solution of 0.23 g (0.96 mmol) 3-hydroxy-2-phenyl-2H, 3H, 4H-1-benzopyridin-4-one, 0.94 g NaOH (in 4 mL water) and 35 mL MeOH was added 15 mL of H2O2 over ice bath. The yellow solution was then stirred at room temperature for 4 hours before the mixture was poured into 300 mL of water. The resulting mixture was extracted with CH2Cl2 and the solvent was removed from the organic phase. The resulting residue was recrystallized form toluene which gave the desired product in 17% yield. MP: 260°-262° C. Quantum yield (relative to 3-hydroxyflavone in CH2Cl2) 1.4. Extinction coefficient εmax (M-1 cm-1) 10,000. λmax (abs)=343 nm and λmax (em)=510 nm.