Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]([CH3:29])=[C:7]([C:23]([O:25][CH2:26][CH2:27][Br:28])=[O:24])[CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11].[CH2:30]([O:32][CH2:33]Cl)[CH3:31].C1(C)C=CC=CC=1>O1CCCC1.O>[CH2:30]([O:32][CH2:33][N:5]1[C:6]([CH3:29])=[C:7]([C:23]([O:25][CH2:26][CH2:27][Br:28])=[O:24])[CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]1[CH3:3])[CH3:31]
Reactant: CCOCCl
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCBr)C1c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOCN1C(C)=C(C(=O)OC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCBr)=C1C
Temperature: 0 °C
Yield: 72.5 %

Procedure:
10.65 g of a 80% suspension of sodium hydride in liquid paraffin are suspended in 300 ml of anhydrous tetrahydrofuran. A solution of 120 g of 3-methyl 5-(2-bromoethyl) (±)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and 28.4 g of chloromethyl ethyl ether in 300 ml of anhydrous tetrahydrofuran is slowly added dropwise in the course of 4 h at -5° to -7° C., while stirring. After the mixture has been stirred for a further hour at 0° C., 600 ml of toluene and 210 ml of water are added in succession. The phases are separated, and the organic phase is washed with water, dried overnight and evaporated in vacuo. The residue is dissolved in 390 ml of warm ethanol and the stirred solution is then cooled. The product crystallises out during this procedure. It is cooled to 0° C., filtered off under suction, washed with ice-cold ethanol and dried. 98.5 g of the title compound of m.p. 72.5°-74° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][N:16](C=O)[CH2:15][CH2:14]2)[N:5]=1)[CH3:2]>[OH-].[K+].C(O)C>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([O:10][CH2:11][CH3:12])[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:5]=1)[CH3:2]
Reactant: CCOc1nc(OCC)nc(N2CCN(C=O)CC2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc(OCC)nc(N2CCNCC2)n1
Yield: 102.5 %

Procedure:
The product from (b) (3.25 g) in potassium hydroxide solution (1N, 20 ml) and ethanol (30 ml) was left at room temperature for 3 hours. Then further potassium hydroxide solution (20 ml) was added. After 45 minutes the reaction mixture was extracted with chloroform (5×30 ml), and the combined chloroform extracts dried (Na2SO4) and evaporated in vacuo to give 4,6-diethoxy-2-piperazino-1,3,5-triazine (3.0 g) as an oil. The product was characterized spectroscopically and used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Li+].[CH3:20][C:21]1[N:26]=[C:25]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32]([O-])=[O:33])[CH:24]=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:20])[N:26]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2ocnc2C(=O)[O-])n1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Agent: [Li+]
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(C)n3)cn2)o1

Procedure:
Following general procedure Z3 followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(6-methyl-pyridin-2-yl)-oxazole-4-carboxylic acid lithium salt. LC-MS-conditions 02: tR=0.75 min; [M+H]+=392.31.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[N:11](S(C3C=CC(C)=CC=3)(=O)=O)[N:10]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[NH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nn(S(=O)(=O)c3ccc(C)cc3)c3nccc(-c4ccsc4)c23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: COc1ccc(-c2n[nH]c3nccc(-c4ccsc4)c23)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of compound 39 (35 mg, 00758 mmol) in methanol (10 mL) and water (5 mL) was added potassium carbonate (20 mg, 0.151 mmol) and the RM heated to 60° C. overnight. After completion of the SM, the RM was completely distilled off, diluted with water and extracted with chloroform twice. The organic layer was dried over sodium sulphate and the solvent was completely distilled off to get the crude product, which was passed through 100-200 mesh silica gel eluting the compound at 28-30% ethyl acetate in hexane as eluent to get the pale yellow colored solid of compound 40. 1H NMR (CDCl3) δ: 10.71 (s, 1H), 8.57 (d, 1H), 7.18 (m, 4H), 7.09 (m, 1H), 6.92 (m,1H), 6.74 (m,1H), 3.81 (s, 3H) and MS m/z=307.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([NH:7][CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=O)[CH3:2].P(Cl)(Cl)(Cl)=O>>[CH2:1]([O:3][C:4]([C:5]1[O:14][C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][N:7]=1)=[O:15])[CH3:2]
Reactant: CCOC(=O)C(=O)NCC(=O)C(C)(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc(C(C)(C)C)o1
Temperature: 105 °C
Reaction time: 2 h

Procedure:
The mixture of N-(3,3-dimethyl-2-oxo-butyl)-oxalamic acid ethyl ester (0.79 g, 3.67 mmol) and phosphorus oxychloride (2.0 mL, 22.0 mmol) was stirred at 105° C. under N2 for 2 h, cooled to RT, quenched slowly with ice-water, extracted with EtOAc. The combined organic portions were washed with brine, dried with Na2SO4, removal of the solvents gave a dark brownish oil which was purified by flash column chromatography to yield the title compound. MS m/z: 197.9 (M+H). Calc'd for C10H15NO3-197.23
Reaction SMILES: C(O[C:6](=[O:23])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[N:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH:11]=1)=O)(C)(C)C.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.C([O-])(O)=O.[Na+].C(OC(=O)[NH:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][C:52]=1[NH2:61])(C)(C)C>CN(C1C=CN=CC=1)C.C1COCC1.C1(C)C=CC=CC=1>[NH2:22][C:19]1[N:18]=[CH:17][C:16]([C:12]2[CH:11]=[C:10]([C:8]3[CH2:7][C:6](=[O:23])[NH:61][C:52]4[CH:53]=[C:54]([C:57]([F:58])([F:59])[F:60])[CH:55]=[CH:56][C:51]=4[N:50]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccc(N)nc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)cn1
Temperature: 23 °C
Reaction time: 26.5 h

Procedure:
The title compound was prepared by the following sequence: 1.) To a solution of 3-[3-(6-Amino-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K25) (1.0 g, 3.2 mmol) and DMAP (8 mg, 0.064 mmol) in THF (6.4 mL) was added Boc2O (699 mg, 3.2 mmol) and mixture was stirred for 26.5 h at 23° C., poured onto sat. NaHCO3-solution (20 mL), extracted with EtOAc (twice 25 mL). The combined organic layers were washed with 0.5 M HCl (20 mL) and brine (20 mL), dried over Na2SO4. Removal of the solvent in vacuum left a light brown foam (1.273 g). 2.) Part of this material (206 mg, 0.5 mmol) and (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (214 mg, 0.75 mmol) were refluxed in toluene (3 mL) for 8 h, then the reaction mixture was cooled to 23° C., the precipitate was filtered off and washed with Et2O (10 mL) to give a light brown solid (96.5 mg). 3.) Part of the obtained material (88.9 mg, 0.145 mmol) was converted into the title compound by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (35.2 mg, 61%).
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:14])[C:10]([N+:11]([O-])=O)=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(O)C.O>[Zn].C(O)(=O)C>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:14])[C:10]([NH2:11])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn2c(Br)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1nn2c(Br)cccc2c1N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a Suspension of 7-bromo-2-methyl-3-nitropyrazolo[1,5-a]pyridine (890 mg) in a mixed solution of ethanol (20 mL), water (10 mL) and acetic acid (2 mL) was added zinc powder (890 mg) at room temperature, and the reaction mixture was heated and stirred for 30 minutes at 60° C. After filtering off the insoluble residue, the filtrate was extracted with ethyl acetate and the organic extract was washed with saturated aqueous sodium bicarbonate and brine. The obtained organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and [7-bromo-2-methylpyrazolo[1,5-a]pyridin-3-yl]amine (371 mg) was obtained as an brown oil from the n-hexane:ethyl acetate (1:1) fraction.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23](Br)=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1.[CH2:31]([Sn](CCCC)(CCCC)C#CC)[CH2:32][CH2:33]C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:31]#[C:32][CH3:33])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(CNc2ncccc2C(=O)Nc2ccc(Br)c(C(F)(F)F)c2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC#Cc1ccc(NC(=O)c2cccnc2NCc2ccc(OC)nc2)cc1C(F)(F)F
Temperature: 100 °C

Procedure:
A stirred solution of 2-[(6-Methoxypyrid-3-yl)methylamino]-N-[4-bromo-3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide (Example 24; 0.96 g, 2.0 mmol) in dry toluene (50 mL) is purged with argon for 20 minutes at 40° C. Tributyl-l-propynylstannane (1.0 g, 2.4 mmol) and tetrakis-(triphenylphosphine)palladium (0) (60 mg) are then added and the resulting mixture is heated at 100° C. for 30 hours under an argon atmosphere. The mixture is then cooled, treated with an aqueous solution of sodium hydroxide (20 mL of 0.1 M) and purged with air for 2 hours. The resulting mixture is then diluted with ethylacetate (200 mL). The orgainic phase is then sequentially washed with water (2×40 mL) and saturated aqueous sodium chloride (1×40 mL), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 50% ethyl acetate in hexane and recrystallised from ether-hexane to give the tite compound as a pale-yellow crystalline solid, m.p. 109-111° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:15].[C:16](Cl)(=[O:18])[CH3:17].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:11][C:10]1[C:2]([NH:1][C:16](=[O:18])[CH3:17])=[C:3]2[C:7](=[CH:8][C:9]=1[O:13][CH3:14])[C:6](=[O:15])[CH2:5][CH2:4]2
Reactant: CC(=O)Cl
Reactant: COc1cc2c(c(N)c1OC)CCC2=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(c(NC(C)=O)c1OC)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
4-Amino-5,6-dimethoxy-indan-1-one (Intermediate U) (0.214 g, 1.0 mmol) was taken up into 5 mL of DMF and acetyl chloride (0.071 mL, 1.0 mmol) and DIEA (0.18 mL, 1.0 mmol) were added. The reaction stirred overnight at room temperature. The reaction was quenched with sat. sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and removed in vacuo. 0.25 g of the crude material was produced (Intermediate V); MS m/z 250.1 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OCC(C)(C)CO2)=[CH:20][CH:19]=1.CCO>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CC1(C)COB(c2ccc(F)cc2)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Temperature: 100 °C
Yield: 46 %

Procedure:
A solution of 6-bromopicolinic acid (Aldrich) (2.02 g, 10 mmol) in DME containing 4 mL of 10% aq Na2CO3 was purged with Ar gas. To this mixture was added Pd(PPh3)4 followed by 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2.40 g, 11.5 mmol, Wako Pure Chemical Industries, Ltd) and EtOH (20 mL), and the mixture was purged with Ar gas. The reaction mixture was heated at 100° C. for 2.5 h in a sealed tube. Additional 2-bromopicolinic acid (900 mg) and Pd (OAc)2 was added, and after purging with Ar gas it was heated at 100° C. for 4.5 h. Trifluoroacteic acid (20 mL) was added to the reaction mixture, concentrated and MeOH (150 mL) was added to the residue. The insoluble material was filtered, and the filtrate solution was concentrated. Purification by flash column on silica gel eluting with EtOAc/MeOH//900:100 followed by EtOAc/MeOH/HOAc//700:1500:50 provided the desired product (1.0 g, 40% based on borinane starting material) as a white solid. 1H NMR (CD3OD) δ 8.01 (d, 1H, J=7.7 Hz), 7.94-7.87 (m, 3H), 7.73 (d, 1H, J=7.7 Hz), 7.13 (t, 2H, 8.8 Hz); MS(ESI+) m/z 234 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[C:24]([C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)#[N:25].CC(C)([O-])C.[K+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:29]1[CH:30]=[C:26]([C:24]#[N:25])[N:27]=[CH:28]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Reactant: N#Cc1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cnc(C#N)c1
Yield: 39.4 %

Procedure:
(2R,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(2methanesulfonyloxyethyl)pyrrolidine (36.1 g) was reacted with 4-cyanoimidazole (10.0 g) and potassium t-butoxide (12.0 g) in substantially the same manner as Preparation 10-3) to give (2R,4R)-1-allyloxycarbonyl-2-[2-(4-cyanoimidazol-1-yl)ethyl]-4-methanesulfonyloxypyrrolidine (14.1 g) as a yellow paste.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([NH2:10])[C:4]=2[O:3][CH2:2]1.[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)C2C(=C(C)C(OC)=CC=2)N=1)[CH3:12]>>[CH2:11]([O:13][C:14]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:42][CH:41]3[CH:27]([C:28](=[O:48])[N:29]([CH3:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH:34]=[CH:35][CH:36]4[C:38]([C:44]([OH:46])=[O:45])([NH:39][C:40]3=[O:43])[CH2:37]4)[CH2:26]2)[C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[C:9]=2[N:10]=1)[CH3:12]
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Reactant: Nc1cccc2c1OCO2
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc3c(c2n1)OCO3

Procedure:
The title compound (14) was prepared from benzo[1,3]dioxol-4-ylamine following the procedure (Steps A-J) reported for synthesis of 17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (2): m/z=566 (M+H)+.
Reaction SMILES: C1(C2C(C(F)(F)F)=C([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=[O:30])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)ON=2)C=CC=CC=1.[C:31]1([C:37]2[O:41][N:40]=[C:39](C3OC4C5C(=CC(C=C)=CC=5)CCC=4N=3)[C:38]=2[C:57]([F:60])([F:59])[F:58])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([C:37]2[O:41][N:40]=[C:39]([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([CH:29]=[O:30])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[C:38]=2[C:57]([F:60])([F:59])[F:58])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Reactant: C=Cc1ccc2c(c1)CCc1nc(-c3noc(-c4ccccc4)c3C(F)(F)F)oc1-2
Product: O=Cc1ccc2c(c1)CCc1nc(-c3noc(-c4ccccc4)c3C(F)(F)F)oc1-2

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 48C employing 2-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[2,1-d]oxazole (Preparation 48E). LC/MS M+1=411.1.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([O:13][CH2:14][CH2:15][NH2:16])[CH3:12].C(=O)([O-])O.[Na+]>C(O)C>[CH2:11]([O:13][CH2:14][CH2:15][NH:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOCCNc1ncccc1[N+](=O)[O-]
Reaction time: 6 h
Yield: 100 %

Procedure:
A mixture of 19 parts of 2-chloro-3-nitropyridine, 13.5 parts of 2-ethoxyethanamine, 13 parts of sodium hydrogen carbonate and 240 parts of ethanol was stirred for 6 hours at reflux temperature. After cooling, the mixture was filtered over diatomaceous earth and the filtrate was evaporated, yielding 25.5 parts (100%) of N-(2-ethoxyethyl)-3-nitro-2-pyridinamine as a residue (interm. 8).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[CH:3]1.[C:23](OC=C)(=[O:25])[CH3:24]>CC(CC(C)C)=O>[C:23]([O:1][C@@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)=[CH:3]1)(=[O:25])[CH3:24]
Reactant: C=COC(C)=O
Reactant: O=C1CC(O)C=C1Cc1cccc(OCc2ccccc2)c1
Solvent: CC(=O)CC(C)C
Product: CC(=O)O[C@H]1C=C(Cc2cccc(OCc3ccccc3)c2)C(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
4-Hydroxy-2-(3-Benzyloxybenzyl)cyclopent-2-enone (5.73 g, 19.48 mmol) was dissolved in isobutyl methyl ketone (60 mL), and vinyl acetate (11.2 g, 13.01 mmol) and Lipase derived from Alculigenese spp (0.6 g) was added to the solution, and the mixture was stirred at room temperature for 1 day. The reaction mixture was filtered to remove Lipase and the filtrate was evaporated. The resulting residue was purified by chromatography on a silica gel column using hexane-EtOAc as eluent to give the (R)-3-(3-benzyloxybenzyl)-4-oxocyclopent-2-enyl acetate as yellow oil: 2.51 g (yield: 38%, 96% ee by HPLC using a chiral column) and (S)-4-hydroxy-2-(3-(benzyloxy)benzyl)cyclopent-2-enone as yellow oil: 2.68 g (yield: 47%, >99% ee by HPLC using a chiral column)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[C:6]([I:8])[CH:7]=1.O.O.Cl[Sn]Cl.[BH4-].[Na+].[OH-].[Na+]>CCO>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([I:8])[CH:7]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cc(I)cc(I)c1
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(I)cc(I)c1
Temperature: 0 °C
Yield: 69.5 %

Procedure:
To a suspension of 3,5-diiodonitrobenzene (10 g, 26.7 mmol) in anhydrous EtOH (100 mL) was added SnCl2.2H2O (30 g, 133.6 mmol). The reaction mixture was brought to boil and a solution of NaBH4 (508 mg, 13.4 mmol) in EtOH (50 mL) was added slowly then stirred at reflux for 1 h. After the reaction was cooled down to 0° C., the mixture was neutralized with a solution of 3M NaOH (200 mL). The aniline derivative was extracted with chloroform, dried over Na2SO4 and evaporated under reduced pressure to afford 6.4 g of 3,5-diiodoaniline 11(70%) as a white solid. HR-ES(+): calculated for C6H5I2N [M] 345.8584, found 345.8583.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=O>C(O)C>[NH2:1][C:2]1[S:3][C:6]2[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]=2[N:4]=1
Reactant: CC1CCC(=O)C(Br)C1
Reactant: NC(N)=S
Solvent: CCO
Product: CC1CCc2nc(N)sc2C1
Temperature: 25 °C

Procedure:
Thiourea (22.3 g., 0.29 mole) was slurried in 275 ml. of ethanol. 2-Bromo-4-methylcyclohexanone was added and the mixture heated to reflux for 75 minutes. The reaction mixture was cooled to room temperature and the crude product recovered as the hydrobromide salt by filtration. The crude salt was dissolved in warm water, filtered and made basic with ammonium hydroxide to precipitate the free base as an oil, which crystallized on cooling. Purified 2-amino-4,5,6,7-tetrahydro-6-methylbenzthiazole (25.2 g., m.p. 98°-100° C.) was obtained by recrystallization from cyclohexane.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][S:6]([NH:9][C:10]1[CH:15]=[C:14]([CH:16]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[C:13]([Cl:35])=[CH:12][N:11]=1)(=[O:8])=[O:7])C.O.[OH-].[Li+].Cl.FC(F)(F)C(O)=O>O1CCCC1.O.C(Cl)Cl.CO>[Cl:35][C:13]1[C:14]([CH:16]([S:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[CH:15][C:10]([NH:9][S:6]([CH2:5][C:4]([OH:36])=[O:3])(=[O:8])=[O:7])=[N:11][CH:12]=1
Reactant: CCOC(=O)CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of the ethyl[[[5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]acetate (60 mg, 0.104 mmol) obtained in Example 283 in a mixture of tetrahydrofuran (5 ml) and water (1 ml) was added lithium hydroxide monohydrate (9.1 mg, 0.218 mmol). The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1N hydrochloric acid. The resulting mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the methanol:methylene chloride (=1:30) eluate containing 0.5% trifluoroacetic acid was concentrated under reduced pressure to give the title compound (54 mg, 0.098 mmol, 94%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].CN(C)C=O.Br[CH2:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH2:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nn(CC(=O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (0.7 g), potassium tert-butoxide (1.0 M tetrahydrofuran solution, 1.75 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-bromo-3,3-dimethylbutan-2-one (0.22 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless powder (0.58 g, 92%).