Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][C:10]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])([CH2:11]4)[CH2:9]2)[CH2:15]3)[N:5]=[CH:4][CH:3]=1.[I:28]N1C(=O)CCC1=O>CN(C)C=O>[I:28][C:3]1[CH:4]=[N:5][N:6]([CH2:7][C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][C:10]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])([CH2:11]4)[CH2:9]2)[CH2:15]3)[C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ccnn1CC12CC3CC(C1)CC(OCCOCCOCCO)(C3)C2
Solvent: CN(C)C=O
Product: Cc1c(I)cnn1CC12CC3CC(C1)CC(OCCOCCOCCO)(C3)C2
Reaction time: 2 h

Procedure:
To an ambient solution of EXAMPLE 83B (0.54 g) in N,N-dimethylformamide (5 mL) was added N-iodosuccinimide (0.35 g). The reaction mixture was stirred for 2 hours, and the crude reaction solution was purified by RP-HPLC on a Gilson system, eluting with a gradient of 20% to 100% acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to give the title compound.
Reaction SMILES: [C:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH:2]=1.[CH3:20][S:21]([CH2:24][C:25]([NH2:33])([CH3:32])[C:26]1[N:30]=[C:29]([CH3:31])[O:28][N:27]=1)(=[O:23])=[O:22]>>[C:1]1([C:5]2[C:6]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:7][C:8]([C:11]([NH:33][C:25]([C:26]3[N:30]=[C:29]([CH3:31])[O:28][N:27]=3)([CH3:32])[CH2:24][S:21]([CH3:20])(=[O:23])=[O:22])=[O:13])=[N:9][CH:10]=2)[CH2:4][CH2:3][CH:2]=1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2=CCC2)cn1
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OCC(F)(F)F)c(C3=CCC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(cyclobuten-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 127d) and 2-Methanesulfonyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (example 109d) as starting materials and isolated (25 mg, 14%); MS (ESI, m/z): 475.5 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[I-:28].[Na+]>[Cu]I>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([I:28])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: [I-]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Agent: [Cu]I
Agent: [Na+]
Product: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 53.6 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (980 mg) described in Preparation Example 112, sodium iodide (650 mg) and copper(I) iodide (205 mg) and by the reaction and treatment in the same manner as in Preparation Example 154, the title compound (580 mg) was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:10]([CH3:11])=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].[C:19](Cl)(=[O:21])[CH3:20]>C(OCC)(=O)C.O>[OH:8][CH2:7][C:6]1[CH:9]=[C:10]([CH3:11])[C:3]([CH2:2][NH:1][C:19](=[O:21])[CH3:20])=[C:4]([CH3:12])[CH:5]=1
Reactant: Cc1cc(CO)cc(C)c1CN
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NCc1c(C)cc(CO)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-aminomethyl-3,5-dimethylbenzyl alcohol (2.3 g) in ethyl acetate (70 ml) was added a solution of potassium carbonate (2.0 g) in water (35 ml). To this solution was added acetyl chloride (0.95 ml) under ice-cooling. This mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from methanol-ethyl acetate to give the title compound (2.0 g) as white crystals, m.p.=193.5-194.5° C.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]([CH3:36])[C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24]([C:27]1[S:28][CH:29]([CH2:32][C:33](O)=[O:34])[CH2:30][N:31]=1)=[CH:23]2)(=[O:16])=[O:15].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:5][O:4][N:3]([CH3:2])[C:33](=[O:34])[CH2:32][CH:29]1[S:28][C:27]([C:24]2[NH:25][C:26]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]([S:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH3:6])(=[O:15])=[O:16])[CH3:36])=[N:31][CH2:30]1
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)N(C)OC)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (48 mg) in N,N-dimethylformamide (10 mL) was added triethylamine (85 uL) under ice-cooling, and the mixture was stirred for 10 min under ice-cooling. (2-{7-[[(2-Methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (200 mg), 1H-1,2,3-benzotriazol-1-ol (90 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (130 mg) were added to the mixture, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0-95:5) to give the title compound (180 mg, yield: 85%) as a pale-yellow amorphous solid. MS:489(MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:11][N:12]1[C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]([CH3:20])=[N:13]1.O>CN(C)C(=O)C>[CH3:11][N:12]1[C:16]([C:17]([NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:18])=[CH:15][C:14]([CH3:20])=[N:13]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cccc([N+](=O)[O-])c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of 3-nitroaniline (1.0 g, 7.2 mmol) in N,N-dimethylacetamide (6 mL) was added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1260 mg, 8.0 mmol) in N,N-dimethylacetamide (2 mL), and the mixture was stirred at room temperature for 30 min. Water (200 mL) was added to the mixture under ice-cooling, and the mixture was filtrated. The obtained solid was washed with water and diethyl ether to give 1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1 mmol). To a solution of the obtained 1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1 mmol) in ethanol (50 mL) was added 10% palladium/carbon (190 mg). Hydrazine monohydrate (1090 mg, 22 mmol) was slowly added to the mixture at room temperature and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was filtrated, and the filtrate was evaporated under reduced pressure. To the residue were added ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (1650 mg, 99%) as a pale-yellow solid.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2.N1CCCCC1>C(O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[C:18]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13]
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2ccc(Cl)cc21
Yield: 87.6 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (4.5 g), 4.2 g of 5-chloro-2-oxindole, and 2.9 mL of piperidine in 50 mL of ethanol were heated to 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in acetone and the yellow precipitate was filtered, washed with cold ethanol, 2 N aqueous hydrochloric acid and water to pH 6 then dried in a vacuum oven overnight to give 7.2 g of the title compound (88%) as a yellow solid.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:20]([O:19][C:17](=[O:18])[NH:16][CH2:15][C@@H:11]1[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCC[C@@H](CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
S-amino enantiomer of N-({3-[(t-butoxy)carbonyl-amino]cyclohexyl}methyl) (phenylmethoxy)carboxamide (1.0 g, 2.76 mmol) was treated with TFA (5 mL) under N2. After 20 min of stirring at r.t. the reaction was complete. The crude was then concentrated to an oil which was purified on a Varian Bond-Elut SCX column (10 g). The column was eluted consecutively with CHCl3, MeOH, and ammonia (2.0M in MeOH). The pure product was recovered from the ammonia fractions. The solvent was removed in vacuo to afford 0.632 g (87%) as a colorless oil. MS (ES+) m/z 263.0 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:4].Br[CH2:14][CH2:15][CH2:16][CH3:17]>O>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4]
Reactant: CCCCBr
Reactant: CCOc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCOc1ccccc1OCC

Procedure:
The procedure was similar to that followed in the preparation of example 8 above, except that the reaction involved 150 ml of water, 15.8 ml of 50% sodium hydroxide solution, 25.4 ml (0.2 moles) of 2-ethoxyphenol, and 21.5 ml (0.2 moles) of 1-bromobutane. This compound was labeled as example 9.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[N:12]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+].C(O)(=O)C>CO>[CH3:23][O:22][C:20]([C:19]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[C:4]([C:3]=1[OH:2])=[CH:9][C:8]([O:10][CH3:11])=[CH:7][CH:6]=2)=[O:21]
Reactant: COC(=O)CN(c1ccccc1)c1ccc(OC)cc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1c(O)c2cc(OC)ccc2n1-c1ccccc1
Temperature: 20 °C
Yield: 82 %

Procedure:
A mixture of 1.7 kg (5.2 mole) of 5-methoxy-2-[(2-methoxy-2-oxoethyl)phenylamino]benzoic acid methyl ester, and 303 g (5.6 mole) of sodium methoxide in 10.0 l of anhydrous methanol was stirred at reflux for 90 minutes. The mixture was cooled to 20° C., filtered, and treated with 336 g (320 ml, 5.6 mole) of glacial acetic acid. The mixture was cooled in ice, and the precipitated crude product was filtered and washed with cold methanol followed by hexane. There was obtained 1267 g (82% yield) of the indole product of analytical purity, mp 114°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[CH3:21][S:22][C:23](SC)=[CH:24][N+:25]([O-:27])=[O:26]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][N:18]([C:23]([S:22][CH3:21])=[CH:24][N+:25]([O-:27])=[O:26])[CH2:19][CH2:20]1
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: COc1cc2ncnc(N3CCN(C(=C[N+](=O)[O-])SC)CC3)c2cc1OC
Yield: 31 %

Procedure:
To an ethanol solution (30 mL) of 6,7-dimethoxy-4-(1-piperazinyl)quinazoline described in South African Patent 67 06512 (1968) (Compound (i); 6.00 g, 21.9 mmol), commercially available 1,1-bis(methylthio)-2-nitroethylene (4.27 g, 25.8 mol) was added, followed by stirring under heating at 50 C for 9 hours and then heating under reflux for 2.5 hours. After the reaction solution was allowed to stand for cooling, the solvent was evaporated and then the resulting residue was purified by silica gel column chromatography to give the target compound (2.65 g, 6.78 mmol).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:9](=O)[C:8]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:7]=2[O:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2.[S-:20][C:21]#[N:22].[K+]>C(O)(=O)C>[F:15][C:13]1[CH:12]=[CH:11][C:8]2[C:9]3[NH:22][C:21]([SH:20])=[N:2][C:3]=3[C:4]3[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=3[O:6][C:7]=2[CH:14]=1
Reactant: N#C[S-]
Reactant: NC1C(=O)c2ccc(F)cc2Oc2ccccc21
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Product: Fc1ccc2c(c1)Oc1ccccc1-c1nc(S)[nH]c1-2
Reaction time: 0.25 h

Procedure:
11-Amino-7-fluorodibenz[b,f]oxepin-10(11H)-one hydrochloride (8 g) was suspended in acetic acid (120 ml); potassium thiocyanate (2.82 g) was added and the reaction mixture was heated to reflux. After 10 minutes complete solution was obtained and shortly thereafter a solid began to separate. Heating was continued for 15 minutes. After cooling, the solid product was collected by filtration, washed with water and dried to give 10-fluoro-1H-dibenzo[2,3:6,7]oxepino[4,5-d]-imidazole-2-thiol; m.p. 299°-300°. ##STR18##
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:12]=[N:13][N:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:15]=2)[N:5]=[C:4]([S:25][CH3:26])[N:3]=1.C(O[CH:32](N(C)C)[N:33]([CH3:35])[CH3:34])(C)(C)C>CN(C=O)C>[CH3:32][N:33]([CH3:35])/[CH:34]=[CH:1]/[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C:11]2[CH:12]=[N:13][N:14]([S:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:15]=2)[N:5]=[C:4]([S:25][CH3:26])[N:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CSc1nc(C)c(C#N)c(Nc2cnn(S(=O)(=O)c3ccccc3)c2)n1
Solvent: CN(C)C=O
Product: CSc1nc(/C=C/N(C)C)c(C#N)c(Nc2cnn(S(=O)(=O)c3ccccc3)c2)n1
Temperature: 100 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a solution of intermediate 29 (4.16 g, 10.8 mmol) in DMF (100 mL) was added tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (BBDM, 5.63 g, 32.3 mmol). The mixture was stirred for 16 h at 100° C. After cooling to room temperature, the mixture was poured into ice-water (800 mL), filtered and the solid was washed with water, petroleum and the mixture solvent (petroleum:ethyl acetate=3:1) successively, dried to obtain 4.2 g of product as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:4].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Cc1ccc(C(NC(=O)CN)c2ccccc2)cc1
Product: Cc1ccc(C(NC(=O)CNC(=O)c2ccc(Cl)cc2)c2ccccc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-(phenyl-p-tolyl-methyl)-acetamide (Example 3.3) and 4-chlorobenzoic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:35])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=3)[C:20]([O:31][CH2:32][CH2:33][OH:34])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC#N.C[N+]1([O-])CC[O:43]CC1.O>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O.CCOC(C)=O>[Cl:30][C:25]1[CH:24]=[C:23]([C:21]2[CH:22]=[C:17]([C:16](=[O:35])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:18]=[CH:19][C:20]=2[O:31][CH2:32][C:33]([OH:43])=[O:34])[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: C[N+]1([O-])CCOCC1
Reactant: O=C(NCCCCCCCCc1ccccc1)c1ccc(OCCO)c(-c2ccc(F)c(Cl)c2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: O=C(O)COc1ccc(C(=O)NCCCCCCCCc2ccccc2)cc1-c1ccc(F)c(Cl)c1
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a solution of N-(8-phenyloctyl)-4-(2-hydroxyethoxy)-5-(3-chloro-4-fluorophenyl)benzamide (200 mg, 0.415 mmol) in 5 mL CH2Cl2 was added NMMOH2O (96 mg, 0.712 mmol) and TPAP (12.5 mg, 0.0356 mmol). The reaction was stirred overnight and 50 mg, 0.14 mmol TPAP, 2 mL CH3CN, and 90 mg, 0.665 mmol NMMO.H2O were added and the reaction was stirred overnight. The reaction was worked up as in Step 3 of Example 135. The crude material was subjected to column chromatography (40% EtOAc:60% Hexanes) on HCOOH pretreated silica gel to yield 70 mg, 34% of the acid as a dark yellow oil. 1H NMR (DMSO-d6) 1.22-1.27 (m, 8H); 1.474-1.551 (m, 4H); 2.53 (t, J=7.47 Hz, t); 3.21 (q, J=6.59 Hz, 2H); 4.82 (s, 1H); 7.08-7.17 (m, 4H); 7.22-7.26 (m, 2H); 7.48 (t, J=8.79 Hz, 1H); 7.60-7.64 (m, 1H); 7.80-7.85 (m, 2H); 8.36 (t, J=5.60 Hz, 1H); IR 3400, 2930, 1730, 1600, 1550, 1470, 1210, 1075, and 700 cm−1; mass spectrum [(−)ESI], m/z 510/512 [M−H]−; Anal. Calcd. for C29H30BrClFNO4: C, 97.99; H, 6.10; N, 2.73; Found: C, 66.89; H, 6.17; N, 2.61.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)(=O)[CH3:11]>CO.C(O)=O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=3[CH3:9])[CH3:20])[N:14]=2)[CH3:11])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(O)ccc1N
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: O=CO
Solvent: CO
Product: CC(=Nc1ccc(O)cc1C)c1cccc(C(C)=Nc2ccc(O)cc2C)n1
Reaction time: 48 h

Procedure:
4-Amino-m-cresol (450 mg) and 300 mg 2,6-diacetylpyridine were dissolved in 20 ml methanol. Four drops of formic acid were added and the solution was stirred for 2 d. The yellow solid was washed with cold methanol. Yield: 600 mg. 1H-NMR (200 MHz, CDCl3): 8.35 (d, 2H), 7.85 (t, 1H), 6.53-6.74 (6 H), 4.50 (s, 2H), 2.32 (s, 6H), 2.09 ppm (s, 6H)
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([CH3:33])([CH3:32])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:30]#[N:31])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[CH:14]=2)=[O:9])C.O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:30]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH:14]=2)[C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:33])([CH3:32])[C:4]([OH:34])=[O:3])=[O:9])[N:11]=1)#[N:31]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3OC)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1ccc2c(O)c(C(=O)NCC(C)(C)C(=O)O)nc(C#N)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-{[1-Cyano-4-hydroxy-7-(2-methoxy-phenoxy)-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid ethyl ester (20 mg, 0.04 mmol) was dissolved in MeOH (3 mL) and 2 N NaOH (3 mL). After stirring for 4 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 12 mg. MS: (−) m/z 434.01 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26]([C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)=[O:27])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccco1
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccco4)c3C2=O)C(=O)N1
Yield: 88.5 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added furan-2-carbonyl chloride (0.52 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. To the reaction mixture was added additional furan-2-carbonyl chloride (0.26 g, 2 mmol). The mixture was heated to reflux for an additional 8 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.65 g (88%) of product as an off-white solid: mp 299-301° C.; 1H NMR (DMSO-d6) δ 11.19 (s, 1H), 10.37 (s, 1H), 8.68 (dd, J=1.4 and 8.4 Hz, 1H), 8.06 (s, 1H), 7.90 (t, J=8.1 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.39 (d, J=3.5 Hz, 1H), 6.79 (dd, J=1.5 and 3.2 Hz, 1H), 5.19 (dd, J=5.1 and 12.5 Hz, 1H), 2.98-2.84 (m, 1H), 2.67-2.49 (m, 2H), 2.13-2.08 (m, 1H); 3C NMR (DMSO-d6) δ 172.66, 169.62, 168.44, 166.59, 155.71, 146.80, 146.34, 136.55, 136.23, 136.12, 131.30, 124.86, 118.54, 116.64, 113.06, 48.98, 30.90, 22.01; Anal. Calcd. For C11H13N3O6: C, 58.86; H, 3.57; N, 11.44. Found: C, 58.69; H, 3.54; N, 11.41.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:63]([O:65][C:66]([C:68]1[C:73](Cl)=[C:72]([CH3:75])[N:71]2[N:76]=[CH:77][CH:78]=[C:70]2[N:69]=1)=[O:67])[CH3:64]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:63]([O:65][C:66]([C:68]1[C:73]([NH:10][C:3]2[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=2[F:1])=[C:72]([CH3:75])[N:71]2[N:76]=[CH:77][CH:78]=[C:70]2[N:69]=1)=[O:67])[CH3:64]
Reactant: CCOC(=O)c1nc2ccnn2c(C)c1Cl
Reactant: CSc1ccc(N)c(F)c1
Agent: [Pd+2]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc2ccnn2c(C)c1Nc1ccc(SC)cc1F
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
2-Fluoro-4-methylsulfanyl-phenylamine (1.01 equivalents), palladium(II) acetate (0.10 equivalents), rac-2,2-bis(diphenylphosphino)-1,1′-binaphthyl (0.15 equivalents), and cesium carbonate (1.50 equivalents) are added to a solution of 6-chloro-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylic acid ethyl ester (1.00 equivalent) in toluene in a sealed vial. After stirring 10 minutes, the mixture is heated to 80° C. After 24 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc. The resulting precipitate is filtered and washed with EtOAc. The filtrate is diluted with EtOAc and washed with water. The aqueous layer is re-extracted with EtOAc. The combined organic layers are washed with brine, dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([OH:20])[CH:11]=2)=[CH:4][N:3]=1.Cl[CH:22]([CH3:25])[C:23]#[CH:24]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:20][CH:23]([CH3:24])[C:22]#[CH:25])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)=[CH:4][N:3]=1
Reactant: C#CC(C)Cl
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(O)c1OC
Product: C#CC(C)Oc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Yield: 62 %

Procedure:
The title compound was prepared in 62% yield from 2,4-diamino-5-(3-hydroxy-4,5-dimethoxybenzyl)pyrimidine and 3-chloro-1-butyne by the procedure of Example 1A. Crystallization from methanol gave white solid; mp 153°-155°. Anal. Calcd for C17H20N4O3 : C, 62.18; H, 6.14; N, 17.06. Found: C, 61.93; H, 6.22; N, 16.98.