Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)[C:7](=[O:19])[C:6]3([CH3:24])[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1.[CH3:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)=[O:28].C(=O)(O)[O-].[Na+].O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]4[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=4)[C:7](=[O:19])[C:6]4([CH3:24])[CH2:20][O:21][CH2:22][CH2:23][N:5]4[C:4]=3[N:3]=2)=[CH:32][CH:31]=1)=[O:28]
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cn1ccc(CN2C(=O)C3(C)COCCN3c3nc(Cl)ncc32)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CO
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCOCC2(C)C(=O)N3Cc2ccn(C)n2)cc1
Temperature: 100 °C
Yield: 23 %

Procedure:
A mixture of 2-chloro-6a-methyl-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (118 mg), PdCl2(dppf) (43.6 mg), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (124 mg, 0.447 mmol), saturated sodium bicarbonate solution (1.5 mL), and 1,4-dioxane (3 mL) was heated by microwave irradiation at 100° C. for 45 minutes. The reaction mixture was diluted with 2 mL of methanol, filtered then purified by mass-triggered preparative HPLC eluted with 20-30% of ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column to give the title compound (36 mg) as a pale yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.72 (s, 3H) 2.80 (s, 3H) 3.57 (m, 1H) 3.70 (m, 1H) 3.85 (s, 3 H) 3.89 (d, J=12 Hz, 1H) 4.15 (dd, J=12, 4 Hz, 1H) 4.19 (d, J=12 Hz, 1H) 4.71 (m, 1H) 4.95 (d, J=12 Hz, 1H) 5.30 (d, J=12 Hz, 1H) 6.24 (d, J=4 Hz, 1H) 7.55 (d, J=4 Hz, 1H) 7.63 (d, J=8 Hz, 2H) 8.07 (d, J=8 Hz, 2H) 8.12 (s, 1H). MS [M+H] Found 463.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]([O:17]C)=[O:16])[C:5]2[O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]3[C:4]=2[CH:3]=1>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:5]2[O:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]3[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc(Cl)cc2c1OC1CCCCC21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cl)cc2c1OC1CCCCC21
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 1.6 g of methyl 2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate in 10 ml of methanol and 20 ml of 1N sodium hydroxide is stirred at 50° C. for 6 hours. This is cooled, the methanol is removed under vacuo, diluted with 30 ml water and filtered. The aqueous solution is acidified with acetic acid, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness to give crystalline product which is used directly in the next step.
Reaction SMILES: [Cl-].[C:2]([C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][NH+:14]([CH3:16])[CH3:15])[CH:8]=[CH:7][C:6]=1[Cl:17])([OH:4])=O.[NH2:18][C:19]1[CH:41]=[CH:40][C:22]2[CH2:23][CH2:24][C:25]3[C:26]([C:37]([NH2:39])=[O:38])=[N:27][N:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:29]=3[C:21]=2[CH:20]=1>>[Cl:17][C:6]1[C:5]([C:2]([NH:18][C:19]2[CH:41]=[CH:40][C:22]3[CH2:23][CH2:24][C:25]4[C:26]([C:37]([NH2:39])=[O:38])=[N:27][N:28]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[C:29]=4[C:21]=3[CH:20]=2)=[O:4])=[N:10][C:9]([S:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=1
Reactant: C[NH+](C)CCSc1ccc(Cl)c(C(=O)O)n1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Agent: [Cl-]
Product: CN(C)CCSc1ccc(Cl)c(C(=O)Nc2ccc3c(c2)-c2c(c(C(N)=O)nn2-c2ccc(F)cc2)CC3)n1

Procedure:
The title compound was synthesized from 0.355 g of the title compound of Step 1 and the title compound of Example 244 (0.32 g) by the same procedure used in Example 255. The title compound is a white solid (0.49 g, 87%). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (CD3CN): δ 2.18 (s, 6H), 2.57 (m, 2H), 2.85 (m, 4H), 3.00 (m, 4H), 3.26 (m, 2H), 5.88 (s, 1H), 6.94 (d, 1H), 7.27-7.38 (m, 5H), 7.47-7.62 (m, 3H), 7.69 (d, 1H, J=9 Hz), 9.40 (s, 1H). ESI mass spectrum for C28H27ClFN6O2S+: 565 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:14])[C:5]=1[OH:15])[CH:2]=[CH2:3].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:14])[C:5]=1[OH:15])[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(C(=O)OC)c(C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCc1ccc(C(=O)O)c(C)c1O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the methyl 4-allyl-3-hydroxy-2-methylbenzoate (6.5 g, 31.6 mmol) in a mixture of THF:MeOH (3:1 ratio, 80 ml) at room temperature was added 25.3 g (316 mmol) of 50 w/w % aqueous NaOH solution, and the reaction mixture was stirred at 50° C. for 4 h. LCMS showed it as a clean reaction. The reaction mixture was cooled to room temperature and the methanol was removed on a rotovapor and diluted with ethyl acetate. The crude reaction mixture was acidified with 1N HCl. Some of the product precipitated out. It was diluted with water and extracted using ethyl acetate. The organic fractions were collected, dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified using an ISCO system (80 g silica column, hexane/EtOAc gradient. The product eluted ˜30% EtOAc in hexane, and the product fractions were collected and concentrated. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.12-5.78 (m, 1H), 5.30-5.08 (m, 2H), 3.45 (d, J=6.3 Hz, 2H), 2.54 (d, J=3.7 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:34]Br>CN(C=O)C.C(OCC)(=O)C>[CH3:29][O:30][C:31](=[O:44])[CH:32]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:34][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])=[CH:23][CH:24]=1
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Reactant: COC(=O)C(CCBr)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(CCOc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
Potassium carbonate (935 mg, 6.77 mmol) was added in one portion to a solution of 4-[4-(benzyloxycarbonylamino)butyl]phenol (506 mg, 1.69 mmol) and N-Boc bromide 30 (501 mg, 1.69 mmol) in anhydrous DMF (10 mL). The reaction mixture was stirred at 70° C. (oil bath) for 14 h, cooled to room temperature, and diluted with ethyl acetate (100 mL) and hexanes (20 mL). The mixture was washed with water (4×20 mL) and brine (40 mL) and concentrated under reduced pressure. Flash silica gel column chromatography using ethyl acetate/CH2Cl2 (1:25, 1:20, v/v) gave the desired product 31 as a thick yellow oil (718 mg, 83% yield). 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 9H), 1.48-1.68 (m, 4H), 2.12-2.38 (m, 2H), 2.48-2.60 (m, 2H), 3.10-3.24 (m, 2H), 3.75 (s, 3H), 3.97-4.06 (m, 2H), 4.41-4.52 (m, 1H), 4.70 (br s, 1H), 5.09 (s, 2H), 5.25-5.37 (m, 1H), 6.70-6.80 (m, 2H), 6.95-7.09 (m, 2H), 7.30-7.38 (m, 5H). m/z (ESI) 515 [C28H38N2O7+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:27]([O:30][C:31]1[C:36]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:35][C:34]([CH3:41])=[CH:33][C:32]=1[Si:42](Cl)([CH2:46][CH2:47][CH3:48])[CH2:43][CH2:44][CH3:45])[CH:28]=[CH2:29].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.CCCCCC.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:27]([O:30][C:31]1[C:36]([C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:35][C:34]([CH3:41])=[CH:33][C:32]=1[Si:42]([CH:8]1[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=2)([CH2:43][CH2:44][CH3:45])[CH2:46][CH2:47][CH3:48])[CH:28]=[CH2:29]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](Cl)(CCC)CCC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](CCC)(CCC)C1c2cc(C(C)(C)C)ccc2-c2ccc(C(C)(C)C)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 20.8 %

Procedure:
There was dissolved 2.28 g (8.19 mmol) of 2,7-di-tert-butylfluorene in 37 mL of THF, and the obtained solution was cooled down to 0° C. To the solution, 5.19 mL of a 1.58 M-concentration hexane solution of n-butyllithium was added slowly, 5.19 mL of said hexane solution containing 8.20 mmol of n-butyllithium. Temperature of the resultant mixture was raised up to a room temperature, and the mixture was stirred for 1 hour at a room temperature. The mixture was cooled down to 0° C., and a solution of 2.89 g (8.17 mmol) of (2-allyloxy-3-tert-butyl-5-methyl phenyl)chlorodi-n-propylsilane in 9 mL of THF was added to the mixture. Temperature of the resultant mixture was raised up to a room temperature, and the mixture was stirred for 3 hours, thereby obtaining a reaction solution. A mixture of 50 mL of a 10% aqueous solution of sodium hydrogen carbonate and 50 mL of a 10% aqueous solution of sodium carbonate was added to the reaction solution at 0° C. To the obtained mixture, 58 mL of toluene was added, and the mixture was separated to the toluene solution and the aqueous solution. The toluene solution was dried over sodium sulfate, and the mixture was filtered. The obtained filtrate was concentrated under a reduced pressure. The concentrated filtrate was treated according to silica gel-column chromatography using, as a developing solvent, a 0.5% concentration-solution of triethylamine in a mixed solvent of 10 parts by volume of hexane and 1 part by volume of ethyl acetate, thereby obtaining 1.01 g (yield: 20.7%) of (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,7-di-tert-butylfluoren-9-yl)di-n-propylsilane.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4](=O)[CH2:5][Br:6].[NH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([Cl:17])=[CH:12][C:11]=1[NH2:18]>>[Br:1][CH2:2][C:3]1[C:4]([CH2:5][Br:6])=[N:9][C:10]2[C:11](=[CH:12][C:13]([Cl:17])=[C:14]([Cl:16])[CH:15]=2)[N:18]=1
Reactant: O=C(CBr)C(=O)CBr
Reactant: Nc1cc(Cl)c(Cl)cc1N
Product: Clc1cc2nc(CBr)c(CBr)nc2cc1Cl

Procedure:
Following the procedure of Example 1, condensation of 1,4-dibromo-2,3-butanedione with 1,2-diamino-4,5-dichlorobenzene yielded 2,3-bis(bromomethyl)-6,7-dichloro-quinoxaline, m.p. 154°-156° C.; 1H NMR (CDCl3, 200 MHz): δ4.86 (s, 4H, CH2), 8.18 (s, 2H, ArH).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[S:21])[NH2:20])[C:3]=1[S:22]([CH3:24])=[O:23].[CH2:25]1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].CI>O1CCCC1.C(=O)=O>[CH3:25][S:21][C:19]([C:4]1[C:3]([S:22]([CH3:24])=[O:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)=[NH:20]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CS(=O)c1c(C(N)=S)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CSC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reaction time: 0.28 h
Yield: 99.2 %

Procedure:
To a stirred solution of 1.00 gram (0.0024 mole) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbothioamide, (Compound 4, prepared as described in applicants' copending U.S. patent application Ser. No. 08/418,680, entitled "PESTICIDAL 1-ARYLPYRAZOLE-3-THIOCARBOXAMIDES", filed concurrently herewith, incorporated by reference herein in its entirety and relied upon) and a few crystals of 18-crown-6 in 30 milliliters of dry tetrahydrofuran, was added 0.27 gram (0.00244 mole) of potassium tertiary-butoxide, and the mixture was strirred for a few minutes. A 0.16 milliliter (0.00264 mole) portion of methyl iodide was then injected into the reaction mixture, followed by stirring for a two-hour period. An additional 0.08 milliliter (0.0013 mole) portion of methyl iodide and 0.09 gram of potassium tertiary-butoxide were added and stirring was continued for a period of 17 minutes. The mixture was neutralized by passing in gaseous CO2 for about 10 minutes and volatiles were then removed under reduced pressure. The residue was taken up in dichloromethane and filtered, and the filtrate was evaporated to give the product as a crude residue. This was chromatographed on silica, eluting with 2:1 ethyl acetate/hexane, followed by a second chromatography employing 4:1 chloroform/acetone as the solvent, resulting in 0.67 gram (0.00155 mole) of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidothioic acid methyl ester (99.2% purity) having a melting point of 206.5° C. This compound is referred to hereinafter as Compound 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[NH:7][CH3:8].[H-].[Na+].[Cl-].[Cl-].[Ca+2].[CH3:18][O:19][CH2:20][C:21](Cl)=[O:22]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([N:7]([CH3:8])[C:21](=[O:22])[CH2:20][O:19][CH3:18])[CH:9]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Reactant: COCC(=O)Cl
Agent: [Ca+2]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COCC(=O)N(C)c1cc(Br)ccc1[N+](=O)[O-]

Procedure:
To a solution of 5-bromo-N-methyl-2-nitroaniline (500 mg) in THF (10 ml) was added NaH (40% oil dispersion, 104 mg) at 0° C. The mixture was stirred at 0° C. under a dry atmosphere (CaCl2 tube) for 30 min. After being stirred, methoxyacetyl chloride (0.237 ml) was added to the reaction mixture. The mixture was stirred at 60° C. under a dry atmosphere (CaCl2 tube) for 3 h and then at room temperature overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc). The resulting solid was washed with Et2O to give the title compound (478 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][N:13]1[C:17]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:16]([CH:27]([CH3:29])[CH3:28])[N:15]=[C:14]1[CH3:30])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[C:31]([O:37][CH2:38]I)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[C:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][N:13]1[C:17]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:16]([CH:27]([CH3:28])[CH3:29])[N:15]=[C:14]1[CH3:30])(=[O:7])[CH2:2][CH2:3][C:4]([O:6][CH2:38][O:37][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:5]
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC(=O)CCC(=O)[O-]
Reactant: CC(C)(C)C(=O)OCI
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC(=O)CCC(=O)OCOC(=O)C(C)(C)C
Yield: 84.5 %

Procedure:
The compound 76 (250 mg, 0.526 mmol) was converted to the ester with pivaloyloxymethyl iodide (140 mg, 0.578 mmol) under potassium carbonate (50.9 mg, 0.368 mmol) in the same manner as the example 61 to give the compound 78 (262 mg, 84%) as oil. Rf 0.18 (1:1 EtOAc - hexane).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:28]4[C:23](=[C:24]([CH3:29])[CH:25]=[CH:26][CH:27]=4)[N:22]=[N:21][C:20]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:14]=2)=[CH:7][CH:6]=1.O.[OH-].[Li+].C(O)(=O)C>C1COCC1.CO.O>[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[N:22]=[N:21][C:20]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:19]2[C:15]1[CH:14]=[C:13]([NH:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:36])=[O:2])=[CH:6][CH:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc(CNc2cccc(-c3c(-c4ccccc4)nnc4c(C)cccc34)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1cccc2c(-c3cccc(NCc4ccc(CC(=O)O)cc4)c3)c(-c3ccccc3)nnc12
Temperature: 40 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a stirred solution of (4-{[3-(8-methyl-3-phenyl-cinnolin-4-yl)-phenylamino]-methyl}-phenyl)-acetic acid methyl ester in THF/methanol/water (2:1:1, 10 mL) was added lithium hydroxide monohydrate (0.1 g). The reaction was stirred at 40° C. for 1 hour. The reaction mixture was made acidic (pH 6) with glacial acetic acid, and the solid was collected and dried over P2O5 to give the title compound as an orange solid (0.02 g, 43% for Step 5 and Step 6). MS (ESI) m/z 460; HRMS (ESI, [M+H]+) 460.2012.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(N=CC)(C)(C)C.P(Cl)(OCC)([O:22][CH2:23][CH3:24])=O.O=[C:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][CH2:31]1.C(O)(=O)C(O)=O>CCCCCC.O1CCCC1.C1(C)C=CC=CC=1.O>[O:22]=[CH:23][CH:24]=[C:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][CH2:31]1
Reactant: CCOP(=O)(Cl)OCC
Reactant: COC(=O)C1CCC(=O)CC1
Agent: CC=NC(C)(C)C
Agent: O=C(O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: COC(=O)C1CCC(=CC=O)CC1
Temperature: 3 °C
Reaction time: 0.25 h
Yield: 55.8 %

Procedure:
A mixture of 729 ml of dry tetrahydrofuran and 76.4 ml of dry diisopropylamine was cooled to 3° C. with an ice-water bath. Then 340.6 ml of n-butyllithium in hexane was added dropwise over 45 minutes, followed by an additional 15 minutes of stirring. The solution was then cooled to -75° C. and 26.9 g of acetaldehyde t-butylimine was added dropwise with a syringe over 20 minutes, followed by an additional 30 minutes of stirring. With the temperature still at -75° C., 47.0 g of diethyl chlorophosphate was added with a dropping funnel over 1 hour. The reaction was allowed to stir for an additional hour at -75° C., warmed to -11° C. over 2 hours and cooled again to -75° C. Then, 28.4 g of methyl 4-oxocyclohexanecarboxylate in 50 ml of tetrahydrofuran was added with a dropping funnel over 1 hour. The reaction was allowed to warm to room temperature overnight. It was then poured into a mixture of 49.0 g of oxalic acid in 1.8 1 of water and 1.8 1 of toluene. This was stirred vigorously for 24 hours and the aqueous layer was then separated and extracted with ether (2×500 ml). The combined toluene and ether extracts were washed with aqueous 5% oxalic acid (2×500 ml), 500 ml of saturated sodium bicarbonate and 500 ml of saturated sodium chloride. The organic layer was then dried over anhydrous potassium carbonate, filtered and concentrated under vacuum. The resulting oil was purified on the Prep LC (25% ethyl acetate/hexane, 300 ml/min., 2 min./cm, 2 columns, Rt =7.5 min.) to give 18.5 g of methyl 4-(oxoethylidene)cyclohexanecarboxylate. 1H NMR (CDCl3, 60 MHz) δ 10.05 (d, 1 H); 5.85 (d, 1 H); 3.70 (s, 3 H); 2.8-1.5 (9 H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:12]([C:34]([OH:36])=[O:35])=[C:13]([C:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)=[CH:27][CH:28]=2)[O:14][CH:15]2[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37]>>[ClH:37].[NH:17]1[CH2:18][CH:15]([O:14][C:13]2[C:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)=[CH:27][CH:28]=[C:11]([CH2:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[C:12]=2[C:34]([OH:36])=[O:35])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2c(-c3ccoc3)ccc(CS(=O)(=O)c3ccccc3)c2C(=O)O)C1
Agent: Cl
Product: O=C(O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1OC1CNC1

Procedure:
Prepared by proceeding in a similar manner to Example 38, starting from t-butyl 3-[3-(benzenesulphonylmethyl)-2-carboxy-6-(furan-3-yl)phenoxy]-azetidine-1-carboxylate (Intermediate 167). The crude product was dissolved in HCl (4M in dioxane, 0.5 ml) and then evaporated to dryness. The residue was triturated with diethyl ether and the solid was collected by filtration to give 2-(azetidin-3-yloxy)-6-(benzenesulphonylmethyl)-3-(furan-3-yl)benzoic acid hydrochloride salt.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)([O-])=O.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH:15]=O.[NH4+].[Cl-]>CS(C)=O>[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[C:15]1[NH:11][C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][C:7]=2[N:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: Nc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-benzene-1,2-diamine (1.5 g) and 2,6-dichloro-benzaldehyde (1.7 g) in DMSO (20 mL) was added a catalytic amount of FeCl3 and the mixture was stirred in an open flask at ambient temperature overnight. Resulting solution was diluted by aqueous NH4Cl and extracted twice with ethyl acetate. Combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up in THF (10 mL) and mixed with conc NH4OH (5 mL). To the solution was added Na2S2O4 (2 g) as a solid and the mixture was stirred at ambient temperature for 24 h. After usual aqueous workup, the crude product obtained was purified by column chromatography on silica gel to give aerobically unstable 2-(2,6-dichloro-phenyl)-3H-benzoimidazol-5-ylamine: 1H NMR (CDCl3, 400 MHz) 7.4 (app d, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 7.1 (app d, 1H), 6.7 (br, 1H), 3.7 (br, 2H).
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:18][S-:19].[Na+].O>CN(C)C=O>[CH3:15][C:3]1[C:2]([S:19][CH3:18])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: C[S-]
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(C(F)(F)F)ccc(C(=O)O)c1C
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
300 mg (1.35 mmol) of 3-fluoro-2-methyl-4-trifluoromethylbenzoic acid were initially charged in 5 ml of N,N-dimethylformamide, and 59 mg (purity 60% by weight, 1.49 mmol) of NaH were added. The mixture was stirred for 10 min, and 199 mg (purity 95% by weight, 2.70 mmol) of sodium thiomethoxide were then added. The mixture was stirred at RT for 1.5 h and then heated at 80° C. for 16 h. The reaction mixture was cooled and, for workup, poured into water and extracted with ethyl acetate, and the aqueous phase was then acidified with concentrated HCl. The mixture was extracted twice with t-butyl methyl ether, dried and concentrated. This gave 310 mg of the product.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[CH3:11])[CH2:3]1.[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1>>[CH3:11][C:10]1[N:13]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[C:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][C:4]=2[CH:9]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)CC1CC(C)CCC1=O
Product: Cc1cc2c(n1-c1ccc(C(=O)O)cc1)CCC(C)C2
Yield: 66 %

Procedure:
Following the general methods as outlined under Intermediate 7, starting from 4-methyl-2-(2-oxopropyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated, in 66% yield (98% purity by HPLC). MS(ESI+): 270.5; MS(ESI−): 268.4.