Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30].[C:34](=[O:37])([O-:36])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O.O>[C:8]([OH:9])(=[O:30])[C:34]([OH:36])=[O:37].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C(=O)CCCCCBr
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: O=C(O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 141 %

Procedure:
A mixture of 4.0 g (0.013 mole) of α,α-bis(4-fluorophenyl)-4-piperidinemethanol, 3.5 g (0.016 mole) of 6-bromo-N,N-dimethylhexanamide, 5.5 g (0.052 mole) of anhydrous sodium carbonate and 0.3 g (0.002 mole) of potassium iodide in 50 mL of N,N-dimethylformamide was stirred at ambient temperature for 16 h. The mixture was poured into 1 L of water and extracted twice with 250 mL of ethyl acetate. The combined ethyl acetate fractions were washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. The residue was converted to the oxalic acid salt, and recrystallized from 2-propanol to yield 4.9 g (71%) of the title compound as a white solid, mp 157°-160° C.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][N:8]([CH3:14])[C:9](=O)[N:10]([CH3:12])[CH3:11].C(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl-:4].[CH3:7][N:8]([CH3:14])[C:9]([Cl:4])=[N+:10]([CH3:12])[CH3:11]
Reactant: CN(C)C(=O)N(C)C
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)C(Cl)=[N+](C)C
Product: [Cl-]

Procedure:
A solution of 3.2 ml (0.037 mol) of oxalyl chloride in 30 ml of anhydrous carbon tetrachloride is added dropwise to a solution of 4.4 ml (0.037 mol) of tetramethylurea in 20 ml of anhydrous carbon tetrachloride with stirring. The reaction medium is maintained at reflux, with continued stirring, until the evolution of gases (CO and CO2) formed by the reaction has ceased. The CCl4 is than eliminated by distillation at atmospheric pressure. Tetramethylchloroformamidinium chloride is obtained in the form of a white solid (6.23 g). This solid is placed in solution at 0° C. in 40 ml of anhydrous acetonitrile.
Reaction SMILES: [CH2:1]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(C)C=CC=CC=1.N1C=CC=CC=1>O>[CH3:17][C:16](=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:14]=[CH:15][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=1
Reactant: Nc1ccccc1
Reactant: CCCCCCCCCc1ccc(C(C)=O)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCc1ccc(C(C)=Nc2ccccc2)cc1

Procedure:
A solution of p-nonyl acetophenone (90 g), aniline (75 g), Toluene (125 ml) and pyridine (20 ml) was refluxed with continuous removal of water. N-(alpha-methyl-p-nonyl benzylidene) aniline (XXX) was obtained by fractional distillation. XXX had a boiling point of 200°-208° at 0.075 millimeter.
Reaction SMILES: [CH2:1]([O:3]C(C1CC2C(=CC=CC=2)N1)=O)C.[CH2:15]([O:17][C:18]([CH:20]1[CH:28](OC)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[C:31](=[O:34])[CH:32]=[CH2:33])=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([CH:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:3][CH3:1])[CH:26]=2)[N:21]1[C:31](=[O:34])[CH:32]=[CH2:33])=[O:19])[CH3:16]
Reactant: C=CC(=O)N1c2ccccc2C(OC)C1C(=O)OCC
Reactant: CCOC(=O)C1Cc2ccccc2N1
Product: C=CC(=O)N1c2ccc(OC)cc2CC1C(=O)OCC

Procedure:
By substituting 2,3-dihydro-5-methoxy-1H-indole-2-carboxylic acid ethyl ester for 2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester in the procedure for Example 6, 2,3-dihydro-3-methoxy-1-(1-oxo-2-propenyl)-1H-indole-2-carboxylic acid ethyl ester was prepared.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C(N=C=NC(C)C)(C)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([O:9][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])=[O:8])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a mixture of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19.66 g, 112 mmol) and N-hydroxysuccinimide (13.29 g, 116 mmol) was added ethyl acetate (250 ml), and the mixture was cooled to 0-5° C. Diisopropylcarbodiimide (13.88 g, 110 mmol) was added and the reaction mixture was stirred at 0-5° C. for about 1 hour. The reaction mixture was warmed to room temperature. The solids (diisopropylurea by-product) were filtered and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to an oil. Isopropyl alcohol (200 ml) was added to the oil and the mixture was heated to about 50° C. to obtain a homogeneous solution. Upon cooling, crystalline solids formed. The solids were filtered and washed with isopropyl alcohol (3×20 ml) and dried to give the title compound as a white solid (23.2 g, 77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH2:15]([N:17](CC)[CH2:18][CH3:19])[CH3:16].C(NCC)C.Cl>CC(C)=O.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[N:17]([CH2:18][CH3:19])[CH2:15][CH3:16]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CC#N
Solvent: CC(C)=O
Solvent: CCNCC
Product: CCN(CC)S(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: -10 °C

Procedure:
7.6 g of 2-chloro-5-nitrophenylsulfonyl chloride was dissolved in 50 g of acetone, and the obtained solution was then cooled to -10° C. A solution obtained by dissolving 3.03 g of triethylamine and 2.2 g of diethylamine in 20 g of acetonitrile was added dropwisely to the obtained solution. During the addition, the mixture was agitated under cooling so that the temperature did not exceed 0° C. The temperature was gradually raised to room temperature, and the mixture was poured into a dilute solution of hydrochloric acid at pH of about 2. The produced crystals were filtered off and washed with water (yield: 7.8 g).
Reaction SMILES: [CH2:1]([Cl:4])[CH2:2]Cl.C1C=[CH:7][C:8]2N(O)N=[N:11][C:9]=2[CH:10]=1.CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:26]=[N:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30]([OH:32])=O>C(Cl)Cl>[Br:24][C:25]1[CH:26]=[N:27][C:28]([Cl:34])=[C:29]([CH:33]=1)[C:30]([NH:11][C:9]1[CH:10]=[CH:2][C:1]([Cl:4])=[CH:7][CH:8]=1)=[O:32]
Reactant: ClCCCl
Reactant: O=C(O)c1cc(Br)cnc1Cl
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cc1)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloroanaline (594 mg, 4.7 mmol, 1. eq.), EDC (1.62 g, 8.5 mmol, 2 eq.), HOBT (572 mg, 4.2 mmol, 1 eq.), and DIEA (1.1 ml, 6.3 mmol, 1.5 eq.) in CH2Cl2 (50 ml) was added 5-bromo-2-chloronicotinic acid from Step B (1.0 g, 4.2 mmol). The reaction was stirred at RT overnight. The solution was quenched with water and the organic layer was purified by chromatography (50% EtOAc in hexane) to afford a light-yellow compound. MS (ES+): 347.0, 349.0 (M+H)+; (ES−): 345.0, 347.0 (M−H)−.
Reaction SMILES: [CH3:1][CH2:2]CCCCCC/C=C\CCCC[CH2:15][CH2:16][CH2:17][C:18]([O:20]CC(O)CO)=[O:19].[CH3:26][CH2:27]CCCCCC/C=C\CCCCCCCC(OC[C@@H](O)[C@H]1OC[C@H](OC(CCCCCCC/C=C\CCCCCCCC)=O)[C@H]1OC(CCCCCCC/C=C\CCCCCCCC)=O)=O>>[CH2:1]=[CH2:2].[CH2:15]=[CH:16][CH2:17][C:18]([OH:20])=[O:19].[CH2:26]=[CH2:27]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](OC(=O)CCCCCCC/C=C\CCCCCCCC)[C@H]1OC(=O)CCCCCCC/C=C\CCCCCCCC
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)CO
Product: C=C
Product: C=CCC(=O)O

Procedure:
In the same manner as described in Preparation 1 except that Atmos 300 (oleic monoglyceride, HLB: 2.8, manufactured by Kao Atlas Co.) (3.6 parts by weight) is used instead of Span 85, there is obtained an ethylene-vinyl acetate copolymer emulsion having contents of ethylene: 16% by weight, vinyl acetate: 84% by weight and solid components: 54.2% by weight and containing the additives.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:36])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([C:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]=3)=[N:18][N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Br>CO.O.ClCCl>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:36])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH:24]=3)=[N:18][N:17]=[CH:16]4)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3=CCN(C(=O)OC(C)(C)C)CC3)nncc2c1
Agent: Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(C3=CCNCC3)nncc2c1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 4-(6-(5-(cyclopropylcarbamoyl)-2-methylphenyl)phthalazin-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate (100 mg, 206 μmol) (Method B) in 2 mL methanol was stirred at RT was treated with 1 mL HBr 48% in H2O. The mixture was stirred for 2 h from 0° C. to RT. The mixture was diluted with 20 mL dichloromethane, washed with 1N NaOH to pH11. The mixture was extracted with dichloromethane (3×20 mL). The combined organics were washed with 20 mL brine, dried over anhydrous Na2SO4, concentrated via vacuum and purified by silica gel chromatography eluting with 10% 2M ammonia methanol/dichloromethane to give the title compound as a pale yellow solid. Found MS (ES+): 385(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14](OC)=[O:15])[CH2:9]2)=[CH:5][CH:4]=1.[NH3:20]>>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([NH2:20])=[O:15])[CH2:9]2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccc(OC)cc2)C1
Reactant: N
Product: COc1ccc(CN2CC(C(N)=O)CC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A mixture of methyl 1-(4-methoxybenzyl)-5-oxopyrrolidine-3-carboxylate (65.8 g, 250 mmol) and aqueous ammonia (1.5 L) was stirred at room temperature overnight. The resulting reaction mixture was filtered. The filter cake was washed with H2O several times and dried in vacuo to afford 1-(4-methoxy-benzyl)-5-oxo-pyrrolidine-3-carboxylic acid amide as a white solid (60.0 g, yield: 96.5%).
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23](C4CCCCO4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCCCO2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3[nH]ncc23)cc1
Reaction time: 1 h
Yield: 61.1 %

Procedure:
Triethylsilane (150 μL, 0.94 mmol) was added to a solution of 4-(4-methanesulfonyl-phenoxy)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (150 mg, 0.4 mmol) in dichloromethane (3 mL). A solution of trifluoroacetic acid (1 mL) in dichloromethane (3 mL) was added dropwise and then the reaction mixture was stirred for 1 h. Toluene (2 mL) was added and the volatiles were evaporated. The residue was purified by column chromatography, eluting with 0-5% methanol/ethyl acetate to give 4-(4-methanesulfonyl-phenoxy)-1H-pyrazolo[3,4-d]pyrimidine (71 mg, 61%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:11]1([C:14]2[CH:15]=[C:16]([CH3:26])[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][CH:19]=2)[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH:11]4[CH2:12][CH2:13]4)=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(Br)cn1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Yield: 47 %

Procedure:
Using 5-bromo-2-picolinic acid (1.5 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.8 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.4 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:8])[N:7]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>ClCCl.N1C=CC=CC=1.C(OCC)(=O)C>[C:28]([NH:1][CH:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[N:3]1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1=C(C)N=C(N)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(NC(C)=O)N(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2-amino-4-methyl-6-(3-nitrophenyl)-1,5(6H)-pyrimidinedicarboxylic acid, diethyl ester (550 mg, 1.46 mmoles, see Example 2) in dichloromethane (5.0 ml) and pyridine (0.5 ml) was treated with acetic anhydride (0.3 ml) and the reaction was allowed to stir at room temperature for 1 hour. The colorless reaction mixture was diluted with ethyl acetate and was washed with 5% citric acid, sodium bicarbonate solution and brine. It was dried over anhydrous magnesium sulfate and evaporated to provide a colorless foam. Crystallization from ether-hexanes provided the title compound as a colorless solid, melting point 154.5°-156° C.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[CH2:7]([N:14]1[C@@H:19]2[C@H:20]([C:22]3[N:23]=[N:24][N:25]([CH2:27]SC)[N:26]=3)[CH2:21][C@@:15]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:16]([O:30][CH2:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[CH2:17][CH2:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:52](Cl)(Cl)Cl>>[CH2:7]([N:14]1[C@@H:19]2[C@H:20]([C:22]3[N:23]=[N:24][N:25]([CH2:27][S:3]([CH3:52])(=[O:5])=[O:2])[N:26]=3)[CH2:21][C@@:15]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:16]([O:30][CH2:31][C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[C:34]([C:42]([F:44])([F:45])[F:43])[CH:33]=1)[CH2:17][CH2:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S([O-])OO
Reactant: CSCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Reactant: ClC(Cl)Cl
Agent: [K+]
Product: CS(=O)(=O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 50 °C
Yield: 68 %

Procedure:
Oxone® (370 mg, 0.6 mmol) was added to a suspension of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(2-methylthiomethyl-2H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Compound 3 g in Table 3; 130 mg, 0.2 mmol) and wet alumina (200 mg) in chloroform (10 ml). The mixture was heated to 50° C. for 18 hours, then filtered through Celite™ and the filtrate concentrated in vacuo to yield the title compound (92 mg, 68%).
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=O)=[C:11]([N+:25]([O-:27])=[O:26])[C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[C:28](=[O:31])([O-])[O-].[K+].[K+].I[CH3:35].O>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[N:15]([CH3:14])[C:28]2=[O:31])=[C:11]([N+:25]([O-:27])=[O:26])[C:5]2[N:6]([CH3:35])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c([N+](=O)[O-])c2N1
Reactant: CI
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)COc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c([N+](=O)[O-])c21
Reaction time: 2 h

Procedure:
3-[7-Fluoro-5-nitro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-6-trifluoromethyl-2,4-(1H, 3H)-pyrimidinedione (1.0 g) was dissolved in DMF (20 ml) containing potassium carbonate (1.0 g) and iodomethane (0.5 ml). The mixture was stirred for 2 hr and then water (30 ml) and ethyl acetate (40 ml) were added. The organic phase was washed with water (15 ml×2) and brine (15 ml), then dried over sodium sulfate. Filtration and evaporation gave the title compound (0.9 g).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:29])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.O1CCCC1.[OH-].[Li+].Cl>CO>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:9]2[C:10]([O:17][CH:18]([F:19])[F:20])=[N:11][C:12]3[C:7]([C:8]=2[CH3:29])=[C:6]([O:5][CH2:4][C:3]([OH:30])=[O:2])[CH:15]=[CH:14][C:13]=3[F:16])=[CH:27][CH:26]=1
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cc2ccc(Cl)cc2)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12

Procedure:
A solution of [3-(4-chlorobenzyl)-2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.45 g), tetrahydrofuran (5.0 mL), methanol (5.0 mL) and 1.0 M aqueous lithium hydroxide solution (1.3 mL) was stirred at room temperature for 18 hours. The solution was acidified by the addition of 1.0 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Crystallisation of the residue from a mixture of water and propan-2-ol gave title compound as a white solid, 0.33 g.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:22])[CH:7]=[C:8]([Br:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1.ClC1C=CC(S(O[CH2:34][P:35](=[O:40])([O:38][CH3:39])[O:36][CH3:37])(=O)=O)=CC=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([Br:21])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH:18]([CH3:20])[CH3:19])[CH:12]=1)[O:22][CH2:34][P:35](=[O:40])([O:38][CH3:39])[O:36][CH3:37]
Reactant: CC(C)c1cc(Oc2c(Br)cc(O)cc2Br)ccc1O
Reactant: COP(=O)(COS(=O)(=O)c1ccc(Cl)cc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COP(=O)(COc1cc(Br)c(Oc2ccc(O)c(C(C)C)c2)c(Br)c1)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring mixture of DMF (20.0 mL) and NaH (0.074 g, 1.86 mmol) at 0° C. was added 3,5-dibromo-4-(3-isopropyl-4-hydroxy-phenoxy)phenol (Intermediate for the synthesis of compound 8-1, 0.75 g, 1.86 mmol) dissolved in DMF (2.0 mL). The reaction mixture was allowed to stir at rt for 1 hr and cooled to 0° C. Dimethyl 4-chloro-benzenesulfonyloxymethylphosphonate (0.11 g, 0.36 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction was quenched with ice H2O, the pH was adjusted to 1 with 2 M HCl, and the mixture was partitioned with ethyl acetate and H2O. The organic layer was concentrated and coevaporated with acetone (2×). The residue was treated with a hexane/ethyl acetate mixture and sonicated to afford dimethyl [3,5-dibromo-4-(4-hydroxy-3-iso-propyl-phenoxy)phenoxy]methylphosphonate as a white solid precipitate (0.070 g, 34%): 1H NMR (200 MHz, DMSO-d6): δ 9.00 (s, 1H), 7.47 (s, 2H), 6.65 (m, 2H), 6.23 (m, 1H), 4.60 (d, J=10.0 Hz, 2H), 3.75 (d, J=10.0 Hz, 6H), 3.12 (m, 1H), 1.09 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate; Rf=0.60
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[CH3:15])=[CH:5][N:4]([CH3:16])[C:3]=1[C:17]#[N:18].[C:19]([O:25][CH3:26])(=[O:24])[CH2:20][C:21]([CH3:23])=O.Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:26][O:25][C:19]([C:20]1[C:17]([NH2:18])=[C:3]2[N:4]([CH3:16])[CH:5]=[C:6]([C:7]3[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=3[CH3:15])[C:2]2=[N:1][C:21]=1[CH3:23])=[O:24]
Reactant: Cc1cc(C)c(-c2cn(C)c(C#N)c2N)c(C)c1
Reactant: COC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)cn(C)c2c1N

Procedure:
A mixture of 3-amino-1-methyl-4-(2,4,6-trimethylphenyl)-1H-pyrrole-2-carbonitrile (2 mmol), methyl acetoacetate (4 mmol) and SnCl4 (4 mmol) in 1,2-dichloroethane was heated at reflux for about six hours until all the starting material were consumed. The mixture was quenched with acetone, basified with saturated NaHCO3, then filtered through Celite?. The filtrate was concentrated to dryness. The residue was quenched with water and extracted with chloroform. The chloroform layer was washed with brine, dried and concentrated to dryness to give 7-amino-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid methyl ester. The product may be purified by trituration.
Reaction SMILES: [C:1]1([C:7]2([OH:19])[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:21][C:22](=[O:45])[C@H:23]([C@@H:42]([CH3:44])O)[NH:24]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[C:1]1([C:7]2([O:19][C@H:42]([CH3:44])[C@@H:23]([C:22]([OH:45])=[O:21])[NH2:24])[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: OC1(c2ccccc2)c2ccccc2-c2ccsc21
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OC1(c2ccccc2)c2ccccc2-c2ccsc21)[C@H](N)C(=O)O

Procedure:
from 8-phenyl-8H-indeno[2,1-b]thiophen-8-ol (Example 1pp) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18].C(N(CC)CC)C.C([O:29][C:30](=O)[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])C>C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:19])[N:8]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:30](=[O:29])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33]
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Reactant: Cc1nc2cccc3n(CCCCCN)c(=O)c1n23
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc2cccc3n(CCCCCNC(=O)C(F)(F)C(F)(F)F)c(=O)c1n23
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To a solution of 2.58 g (10.0 mmol) of 3-methyl-1-[5-(amino)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring at room temperature, 2.31 g (12.0 mmol) of pentafluoropropionic acid ethyl ester. The mixture was stirred for 4 hours at the same temperature. The solvent was distilled off. To the residue was added methylene chloride, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 2.04 g of the desired compound (50.4%, a pale yellow solid).