Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:21])([F:20])[F:19])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:25]=1.N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C>[CH3:31][O:30][C:28]1[CH:29]=[C:24]([O:23][CH3:22])[N:25]=[C:26]([NH:32][C:33]([NH:1][S:2]([C:5]2[CH:14]=[C:13]([NH:15][N:16]=[CH:17][C:18]([F:19])([F:20])[F:21])[CH:12]=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:3])=[O:4])=[O:34])[N:27]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(N)(=O)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(NN=CC(F)(F)F)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At room temperature, 166 mg (0.5 mmol) of methyl 2-(aminosulfonyl)-4-[(2,2,2-trifluoroethlidene)hydrazino]-benzoate and 137.5 mg (0.5 mmol) of phenyl (4,6-dimethoxy-pyrimidin-2-yl)carbamate were dissolved in 1.5 ml of N,N-dimethylacetamide. Then, 86.1 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene were added, followed by stirring for 5 minutes. The resultant mixture was allowed to stand for 15 hours. Thereafter, 0.2 ml of 35% hydrochloric acid was added to 20 ml of ice water, followed by the addition of the reaction mixture in 0.2 ml portions under stirring. After the reaction mixture was stirred for 20 minutes, the resulting precipitate was collected by filtration and dried in air. Using dichloromethane as an eluent, the crude product was purified by chromatography on a column of silica gel ("WAKO GEL C-300", trade name; product of Wako Pure Chemical Industries, Ltd.). The title compound was obtained as a white solid. Yield: 162 mg (64%). Melting point: 201°-202° C. Its physicochemical properties are shown in Table 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.CN(C)C(=O)C.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Cl:19])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: ClCCc1ccc(Cl)cc1
Temperature: 67.5 °C
Reaction time: 2 h

Procedure:
Into a 250-mL round-bottom flask equipped with magnetic stirring, a thermocouple, a condenser, and a nitrogen bubbler vented to caustic scrubber, was charged 2-(4-chlorophenyl)ethanol (25.011 g, 160 mmol), N,N-dimethylacetamide (0.748 mL, 7.99 mmol), and toluene (73 mL). The mixture was heated to 65 to 70° C. and then thionyl chloride (12.24 mL, 168 mmol) was added over 1 h. The reaction was stirred at 60 to 68° C. for 2 h to give a dark-brown solution. This solution was cooled to 45° C., washed with water (2×27 mL) and saturated aqueous sodium bicarbonate (3×27 mL) at 40 to 45° C., and then cooled room temperature and allowed to stir overnight.
Reaction SMILES: [Na].[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=1)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:21][CH:20]=1.[CH2:33]([O:35][C:36](=[O:39])CBr)[CH3:34].[CH2:40](O)C>>[CH3:40][CH2:34][CH2:33][O:35][C:36]([N:27]1[N:26]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:16]3[CH:30]=[CH:31][CH:32]=[C:14]([O:13][CH2:12][C:3]4[CH:4]=[CH:5][C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[N:2]=4)[CH:15]=3)=[CH:20][CH:21]=2)[N:29]=[N:28]1)=[O:39]
Reactant: CCO
Reactant: c1cc(OCc2ccc(-c3nnn[nH]3)cc2)cc(OCc2ccc3ccccc3n2)c1
Reactant: CCOC(=O)CBr
Agent: [Na]
Product: CCCOC(=O)n1nnc(-c2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2)n1
Reaction time: 16 h

Procedure:
To a solution of 0.2 g sodium in 30 ml ethanol is first added 1 g of 5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazole and then after 30 minutes 0.6 g of ethylbromoacetate and stirring is continued at 80° C. for 16 hours. The solvent is then removed, diluted with water, filtered, washed with ether and dried to give the desired compound, also referred to as ethyl 5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazol-3-yl acetate.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].O1CCOCC1.O.C(N(CC)CC)C.[C:24](=O)([O:30]C(Cl)C(Cl)(Cl)Cl)[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>O>[C:26]([O:25][C:24]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)OC(Cl)C(Cl)(Cl)Cl
Reactant: N[C@@H](CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)O
Yield: 60 %

Procedure:
To a solution of 1.33 g (10 mmol) of L-aspartic acid in a dioxane/water (1:1) mixture (30 ml), 4.2 ml (30 mmol) of triethylamine are added, and the mixture is stirred until solution is complete (approximately 10 min). 2.85 g (10 mmol) of tert-butyl 1,2,2,2-tetrachloroethyl carbonate are then added and the mixture is stirred for 6 hours at 20° C. 50 ml of water are then added and the mixture is extracted with 2×20 ml of ethyl acetate. The aqueous phase is acidified (pH 2-3) with NHCl, and then extracted with 3×30 ml of ethyl acetate. The extract is washed with saturated NaCl solution, dried over MgSO4 and evaporated. The product obtained is crystallised in ethyl acetate and petroleum ether. 1.4 g (60% yield) of the expected acid is obtained. ##STR60##
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][N:18]2[CH:22]=[N:21][N:20]=[CH:19]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[C:5]([N:17]([N:18]1[CH:22]=[N:21][N:20]=[CH:19]1)[C:14]1[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Solvent: c1ccncc1
Product: CC(=O)N(c1ccc([N+](=O)[O-])cc1)n1cnnc1
Reaction time: 2 h

Procedure:
2.8 Milliliters of acetic anhydride was added to 15 ml of a pyridine solution containing 0.62 g of 4-[(4-nitrophenyl)amino]-4H-1,2,4-triazole at room temperature and the mixture was stirred for about 2 hours. After completion of reaction, the solvent was removed by distillation under reduced pressure, and a proper amount of an aqueous sodium hydrogencarbonate solution was added to the residue obtained, which was then extracted several times each with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography to give 0.52 g of 4-[N-acetyl-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole from the chloroform/methanol (100/1) eluate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[N:6][CH:7]=1.[OH:14][C:15]([CH3:48])([CH3:47])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH3:25])[CH2:19][CH2:18]1>>[OH:14][C:15]([CH3:47])([CH3:48])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:27]=[CH:28][C:29]([C:2]3[CH:3]=[N:4][C:5]([N:8]4[CH2:12][CH2:11][CH2:10][C:9]4=[O:13])=[N:6][CH:7]=3)=[CH:30][CH:31]=2)[CH3:25])[CH2:19][CH2:18]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=C1CCCN1c1ncc(Br)cn1
Product: C[C@@H](c1ccc(-c2cnc(N3CCCC3=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 1-(5-bromopyrimidin-2-yl)pyrrolidin-2-one and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one following a procedure analogous to that described in Example 28. LC (method 4): tR=1.02 min; Mass spectrum (ESI+): m/z=515 [M+H]+; 1H NMR (CD3OD) δ 0.81 (s, 3H), 1.17 (s, 3H), 1.47 (d, 3H), 2.09 (m, 3H), 2.13 (m, 2H), 2.41 (m, 2H), 2.57 (m, 2H), 2.96 (m, 1H), 4.08 (m, 2H), 5.52 (m, 1H), 7.02 (d, 2H), 7.23 (m, 5H), 7.38 (m, 2H), 8.78 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13](=[O:23])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:5]=1.O.[OH-].[Li+]>CO.O.Cl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][C:13]([NH:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:3]([OH:24])=[O:2])=[O:23]
Reactant: COC(=O)c1ccc(OC)c(NC(=O)Cc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)O)cc1NC(=O)Cc1ccc(Cl)cc1Cl

Procedure:
To a solution of 400 mg 3-[2-(2,4-Dichloro-phenyl)-acetylamino]-4-methoxy-benzoic acid methyl ester in 5 ml MeOH/H2O 2:1 56 mg lithium hydroxide monohydrate were added and the mixture was stirred over night. The suspension was diluted with 5 ml concentrated HCl to precipitate the acid. After filtration the filter cake was washed twice with water and then dried to yield the acid as a white powder.
Reaction SMILES: [B].CCO[Si](OCC)(OCC)OCC.C([O:17][B:18]([O:22]CC)[O:19]CC)C.[N:25]([CH2:32][CH2:33]O)([CH2:29][CH2:30]O)[CH2:26][CH2:27]O>>[B:18]([OH:22])([OH:19])[OH:17].[CH2:26]([N:25]([CH2:32][CH3:33])[CH2:29][CH3:30])[CH3:27]
Reactant: CCOB(OCC)OCC
Reactant: OCCN(CCO)CCO
Agent: CCO[Si](OCC)(OCC)OCC
Agent: [B]
Product: CCN(CC)CC
Product: OB(O)O

Procedure:
The reaction of the MCR with the boron impurities in the TEOS feedstock produces a chelated organoborane reaction product in the reaction vessel 16. For example, the TEOS feedstock may illustratively contain 550 parts per billion of triethylborate (TEB) or other boron impurity containing from about 2 to about 10 percent elemental boron, based on the molecular weight thereof. The TEB impurity reacts with triethanolamine (TEA) as the MCR, to form triethylamine borate (TEAB) as the organoborate reaction product. Some ethanol is formed as a side-product of the reaction, but ethanol is low boiling (bp=78° C.) and easily separated from the distilling TEOS. The MCR co-reactant desirably is added in stoichiometric excess to ensure maximal reaction of the boron impurity species in the TEOS feedstock. The reaction volume in this illustrative embodiment will then include TEOS, TEA, TEB and TEAB, as well as by-product alcohol.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1cccc(CN2C(=O)CN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CC(=O)N(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution containing the product from Example 23S (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 46E (0.020 g, 0.046 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.021 g, 67% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.88 (s, 9 H), 1.55 (m, 2 H), 2.29 (m, 1 H), 2.39 (s, 3H), 2.75 (m, 3 H), 3.15 (d, J=18.38 Hz, 1 H), 3.52 (s, 3 H), 3.61 (m, 1 H), 3.94 (m, 2 H), 4.19 (m, 3 H), 4.68 (d, J=10.30 Hz, 2 H), 4.89 (d, J=5.52 Hz, 1 H), 6.83 (d, J=9.93 Hz, 1 H), 7.00 (m, 6 H), 7.13 (d, J=7.72 Hz, 1 H), 7.31 (m, 3 H), 7.64 (m, 2 H), 7.88 (m, 4 H), 8.09 (d, J=9.19 Hz, 1 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].Br[CH:16]([C:22]1[CH:27]=[CH:26][C:25]2[O:28][CH2:29][O:30][C:24]=2[CH:23]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CCOCC>[C:6]([C:5]1[CH:10]=[CH:11][C:2]([O:1][CH:16]([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([CH2:12][CH2:13][CH3:14])[CH:4]=1)([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)C(Br)c1ccc2c(c1)OCO2
Reactant: CCCc1cc(C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCCc1cc(C(=O)OC)ccc1OC(C(=O)OCC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a nitrogen flushed 5 L three neck round bottom flask fitted with a mechanical stirrer, condenser, and a nitrogen inlet was charged 326 g (1.68 mol) of methyl 4-hydoxy-3-n-propylbenzoate, 507.6 g (1.73 mol) of ethyl α-bromo-3,4-methylenedioxyphenylacetate from above, 235 g (1.70 mol) of anhydrous potassium carbonate, and 1.7 L of acetone. The mixture was refluxed with vigorous stirring for 9 hr. The suspension was allowed to cool to ambient temperature and stirred overnight. The mixture diluted with 2 L of ether, cooled to 0° C. and filtered through Super-CelR. The cake washed with ether and the combined filtrate concentrated. The residue was redissolved in ether and the organic layer washed with once with 1N HCl, saturated sodium bicarbonate solution, 10% sodium bisulfite solution, brine, dried with magnesium sulfate, treated with charcoal and filtered through a plug of silica. The pale yellow solution was concentrated to 697.3 g (theoretical 678 g) of a thick yellow oil which was used without purification in the next step. NMR was consistent with the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[CH:11]=2)[CH:5]=1.OO>C(O)(=O)C.C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][O:17][C:3](=[O:2])[CH3:4])[CH:11]=2)[CH:5]=1
Reactant: COC(=O)c1cccc(-c2ccnc(C)c2)c1
Agent: OO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cccc(-c2ccnc(COC(C)=O)c2)c1
Yield: 161.2 %

Procedure:
Oxidation of 3-(2-methyl-pyridin-4-yl)-benzoic acid methyl ester (26.2 g, 0.11 mol; example K12) with H2O2 (30%, 31.5 ml, 0.31 mol) in acetic acid (117 ml) at 70° C. for 27 h and subsequent reaction of the N-oxide in acetic acid anhydride (22 ml) at 135° C. for 30 min yielded after aqueous work-up 3-(2-acetoxymethyl-pyridin-4-yl)-benzoic acid methyl ester (25.3 g, 82%) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[Cl:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1.C(=NO)C1C(=CC=CC=1)O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[Cl:29][C:30]1[CH:31]=[N:32][N:33]([C:6]2[CH:5]=[CH:4][C:3]([N:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:21]=[CH:20][CH:19]=4)=[N:10]3)=[C:2]([F:1])[CH:7]=2)[CH:34]=1
Reactant: Clc1cn[nH]c1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: COc1cn(-c2ccc(-n3cc(Cl)cn3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 14.7 %

Procedure:
A suspension of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (488 mg, 1.0 mmol), 4-chloro-1H-pyrazole (103 mg, 1.0 mmol), Cu2O (14.3 mg, 0.1 mmol), salicylaldoxime (54.9 mg, 0.4 mmol), and Cs2CO3 (652 mg, 2.0 mmol) in CH3CN (10 mL) was refluxed overnight under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was subjected to basic silica gel column chromatography eluting with AcOEt followed by purification by preparative HPLC. Recrystallization from MeOH/H2O gave the title compound (68.1 mg, 15% yield) as a pale yellow powder: mp 190-192° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.92 (3H, s), 6.43 (1H, t, J=9.0 Hz), 7.23 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.35 (1H, d, J=1.9 Hz), 7.36-7.48 (5H, m), 7.57 (1H, dd, J=2.6, 12.4 Hz), 7.68 (1H, s), 7.79 (1H, d, J=1.9 Hz), 7.82 (1H, d, J=2.3 Hz), 7.92 (1H, d, J=0.8 Hz). LC-MS (ESI) m/z 463 [M+H]+. Anal. Calcd for C23H16ClFN6O2: C, 59.68; H, 3.48; N, 18.16. Found: C, 59.81; H, 3.50; N, 18.14.
Reaction SMILES: [CH3:1][O:2][C:3](/[C:5](/NC(=O)OC(C)(C)C)=[CH:6]/[C:7]1[CH:15]=[C:14]([CH3:16])[C:13]2[C:9](=[CH:10][N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:12]=2)[CH:8]=1)=[O:4].FC(F)(F)C(O)=[O:36].C([BH3-])#N.[Na+].O1CCCC1>ClCCl.C(OCC)(=O)C>[CH3:22][Si:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][O:18][CH2:17][N:11]1[CH:10]=[C:9]2[C:13]([C:14]([CH3:16])=[CH:15][C:7]([CH2:6][CH:5]([OH:36])[C:3]([O:2][CH3:1])=[O:4])=[CH:8]2)=[N:12]1
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)/C(=C/c1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C(O)Cc1cc(C)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (Z)-1-(methoxycarbonyl)-2-(2-((2-(trimethylsilyl)ethoxy)methyl)-7-methyl-2H-indazol-5-yl)vinylcarbamate (200 mg, 0.43 mmol) in dichloromethane (2 mL) at 0° C. was added trifluoroacetic acid (1 mL). The ice bath was removed. After 30 min, the reaction was poured into a separatory funnel containing ethyl acetate and water, neutralized with solid sodium bicarbonate, and the layers were separated. The organic phase was washed with saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. The yellow residue was treated with sodium cyanoborohydride (200 mg, 7.4 equiv) and tetrahydrofuran (2 mL). The reaction was stirred at room temperature overnight, diluted with ethyl acetate, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography on silica gel (25% ethyl acetate/hexanes) gave 20.4 mg (13%) as a light yellow oil. Mass spec.: 365.40 (MH)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29](=[O:31])[CH:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](OC(F)(F)F)[CH:33]=2)O1.C(O)([C:46]([F:49])([F:48])[F:47])=O>C(Cl)Cl>[C:16]1([C:15]#[C:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:46]([F:49])([F:48])[F:47])[CH:33]=4)[CH2:28][C:29](=[O:31])[NH:22][C:9]=3[CH:10]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC1(C)OC(=O)C=C(c2cccc(OC(F)(F)F)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Solvent: ClCCl
Product: O=C1CC(c2cccc(C(F)(F)F)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) and 2,2-dimethyl-6-(3-trifluoromethoxy-phenyl)-[1,3]dioxin-4-one (Example J8) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (157 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:22]#[C:23][Br:24]>C(O)C>[BrH:24].[Cl:1][C:2]1[C:11]2[N:12]=[C:23]([NH2:22])[N:13]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N#CBr
Reactant: C[C@@H](Nc1c(N)c(Cl)nc2ccccc12)c1ccccc1
Solvent: CCO
Product: Br
Product: C[C@H](c1ccccc1)n1c(N)nc2c(Cl)nc3ccccc3c21
Temperature: 80 °C
Reaction time: 8 h
Yield: 101.5 %

Procedure:
A solution of 2-chloro-N4-[(1R)-1-phenylethyl]quinoline-3,4-diamine (10.0 g, 33.6 mmol) in ethanol (100 mL) was heated to 80° C. Cyanogen bromide (3.84 g, 36.9 mmol) was added, and the dark solution was heated at 80° C. for two hours. An analysis by LC/MS indicated the presence of starting material. Additional cyanogen bromide (3.84 g, 36.9 mmol) was added, and the reaction was stirred overnight at 80° C. The solvent was removed under reduced pressure, and the resulting oil was stirred with diethyl ether (300 L), isolated by filtration, washed with diethyl ether, and dried under vacuum to provide 13.77 g of 4-chloro-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-amine hydrobromide as a brown solid.
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[Cl:12][C:13]1[C:14]([N:31]([CH2:36][CH3:37])[C:32]([O:34][CH3:35])=[O:33])=[C:15]([CH:26]=[CH:27][C:28]=1SC)[C:16]([C:18]1[CH:19]=[N:20][O:21][C:22]=1[CH:23]1[CH2:25][CH2:24]1)=[O:17].[S:38](S([O-])=O)([O-:41])(=O)=[O:39].[Na+].[Na+]>ClCCl>[Cl:12][C:13]1[C:14]([N:31]([CH2:36][CH3:37])[C:32]([O:34][CH3:35])=[O:33])=[C:15]([CH:26]=[CH:27][C:28]=1[S:38]([CH3:2])(=[O:41])=[O:39])[C:16]([C:18]1[CH:19]=[N:20][O:21][C:22]=1[CH:23]1[CH2:24][CH2:25]1)=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCN(C(=O)OC)c1c(C(=O)c2cnoc2C2CC2)ccc(SC)c1Cl
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCN(C(=O)OC)c1c(C(=O)c2cnoc2C2CC2)ccc(S(C)(=O)=O)c1Cl
Reaction time: 5 h

Procedure:
m-Chloroperbenzoic acid (1.81 g of a 50% oil dispersion) was added to a stirred solution of 4-[3-chloro-2-(N-ethyl-N-methoxycarbonylamino)-4-(methylthio)benzoyl]-5-cyclopropylisoxazole (compound 35, 0.92 g) in dichloromethane. After 5 hours, a solution of sodium metabisulphite was added and the mixture stirred for 5 minutes. The organic phase was washed with sodium bicarbonate solution and water, dried (anhydrous magnesium sulphate) and evaporated. The residue was triturated (with a hexane/ether solution) to yield 4-[3-chloro-2-(N-ethyl-N-methoxycarbonylamino)-4-methylsulphonylbenzoyl]-5-cyclopropylisoxazole (compound number 48, 0.95 g) as a white solid, m.p. 152-155.5° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]1[C:18](=[O:19])[O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:18]([OH:17])=[O:19])(=[O:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccccc1
Reactant: O=C1CCCCCCCCCCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCCCCCCCCCC(=O)c1ccccc1
Reaction time: 2.5 h

Procedure:
To a stirred suspension of 18 gms AlCl3 (0.135 mole) in 150 ml dry benzene was added 13 gms 1,10-decanedicarboxylic anhydride in small portions over 15 minutes, then the mixture was refluxed for 6 hours. The solid was filtered off, stirred for 2.5 hours in 350 ml 2N HCl, removed by filtration, and stirred in 300 ml 1N NaOH which was then heated to 70° and filtered hot. As the solution cooled, solid material (sodium salt of the product) crystallized out. This salt was dissolved in hot water, acidified to pH 3 with concentrated HCl, filtered after cooling, and dried to give 5.5 gm of the desired 11-benzoylundecanoic acid m.p. 83°-6°.