Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15]O)[CH:10]=[CH:9][N:8]=2)=[C:4]([I:20])[CH:3]=1.[C:21]1(=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[NH:22]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([O:6][C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH2:15][N:22]3[C:23](=[O:30])[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]3=[O:31])[CH:10]=[CH:9][N:8]=2)=[C:4]([I:20])[CH:3]=1
Reactant: OCCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOc1ccnc(Oc2cc(Cl)c(Cl)cc2I)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
A mixture of 2-(2-(4,5-dichloro-2-iodophenoxy)pyridin-4-yloxy)ethanol (130 mg, 0.31 mmol), isoindoline-1,3-dione (54 mg, 0.37 mmol), PPh3 (160 mg, 0.61 mmol) in THF (5 mL) at 0° C., DIAD (123 mg, 0.61 mmol) was added. The resulting mixture was allowed to warm to room temperature and stirred for 15 h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1 to 5:1) to afford the desired product (120 mg, 71% yield). ESI-MS m/z: 555.0[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([CH:25]2[C:34]3[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=3)[CH2:28][CH2:27][C:26]2=O)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:28]2[C:29]3[C:34](=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:25]([C:23](=[O:24])[C:22]3[CH:38]=[CH:39][C:19]([O:18][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:20][CH:21]=3)=[CH:26][CH2:27]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc2c(c1)CCC(=O)C2C(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2CC=C(C(=O)c3ccc(OCc4ccccc4)cc3)c3ccc(OC)cc32)cc1
Temperature: 45 °C

Procedure:
To a solution of about 50 grams (0.24 mole) of p-methoxyphenylmagnesium bromide in tetrahydrofuran (THF) were added at room temperature 30.2 grams (0.08 mole) of 1-(p-benzyloxybenzoyl)-6-methoxy-2-tetralone dissolved in THF. Upon completion of the addition, the entire mixture was warmed to 45° C. Analysis of a sample of the mixture by thin-layer chromatography (TLC) showed the absence of starting material. The mixture then was poured into aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extract was washed, dried, and evaporated. The resulting residue was dissolved in benzene, and a catalytic amount of p-toluenesulfonic acid was added. The mixture was stirred at room temperature until a TLC of the mixture indicated the absence of any carbinol intermediate. The mixture then was washed with water, dried, and concentrated. The residue was chromatographed over one kg. of alumina using 6 l. of benzene. The product was eluted with a mixture of 2 percent ethyl acetate in benzene. The product, 3-(4-methoxyphenyl-4-(4-benzyloxybenzoyl)-7-methoxy-1,2-dihydronaphthalene was obtained as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]([C:22](Cl)=[O:23])[CH2:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl.[C:36]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)#[N:37]>ClCCl>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]([C:22]([N:41]4[CH2:42][CH2:43][CH:38]([C:36]#[N:37])[CH2:39][CH2:40]4)=[O:23])[CH2:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1
Reactant: O=C(Cl)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)nc3)cc2C1
Reactant: N#CC1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1CCN(C(=O)N2CCOc3ccc(-c4ccc(-c5ncc[nH]5)nc4)cc3C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
Dichloromethane (2 mL) was added to 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carbonyl chloride was obtained in step 4 followed by diisopropylethylamine (0.12 mL, 0.65 mmol) and 4-cyanopiperidine hydrochloride (25 mg, 0.16 mmol). The mixture was stirred at room temperature for 30 min and then concentrated. Purification of the residue by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) provided the title compound (18 mg, 32% yield) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): 12.84 (br. S, 1H), 8.86 (d, 1H), 8.11 (m, 2H), 7.71 (d, 1H), 7.61 (dd, 1H), 7.25 (br. s, 1H), 7.10 (br. s, 1H), 7.06 (d, 1H), 4.49 (s, 2H), 4.23 (m, 2H), 3.61 (m, 2H), 3.30 (m, 2H), 3.00 (m, 3H), 1.87 (m, 2H), 1.73 (m, 2H); MS (EI) for C24H24N6O2: 429 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:22])[C@H:4]([CH:19]([CH3:21])[CH3:20])[NH:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1)=[O:7].[Li+].[OH-].Cl>O1CCOCC1>[CH3:18][N:8]([C:6]([NH:5][C@H:4]([C:3]([OH:22])=[O:2])[CH:19]([CH3:20])[CH3:21])=[O:7])[CH2:9][C:10]1[N:11]=[C:12]([CH:15]([CH3:17])[CH3:16])[S:13][CH:14]=1
Reactant: COC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
A solution of 1.42 g (4.3 mmol) N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine methyl ester in 17 ml of dioxane was treated with 17.3 ml of 0.50 M aqueous LiOH. The resulting solution was stirred at ambient temperature for 30 m in, treated with 8.7 ml of 1 M HCl, and concentrated in vacuo. The residue was taken up in dichloromethane, washed with water, dried over Na2SO4, and concentrated in vacuo to provide 1.1 g (81%) of the desired compound. Mass spectrum: (M+H)+ =314.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([N:8]([CH2:30][CH3:31])[C:9]1[N:29]=[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][C:21]=3[C:26](O)=[O:27])=[O:19])=[CH:16][N:11]2[N:10]=1)[CH3:7]>>[CH2:30]([N:8]([CH2:6][CH3:7])[C:9]1[N:29]=[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]([C:20]3[N:24]([CH3:25])[N:23]=[CH:22][C:21]=3[C:26]([CH:4]3[CH2:5][NH:1][CH2:2][CH2:3]3)=[O:27])=[O:19])=[CH:16][N:11]2[N:10]=1)[CH3:31]
Reactant: C1CCNC1
Reactant: CCN(CC)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1
Product: CCN(CC)c1nc2ccc(NC(=O)c3c(C(=O)C4CCNC4)cnn3C)cn2n1

Procedure:
Using pyrrolidine and 5-(2-diethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (60 mg, 75%). MS: m/z=411 (M+H+).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.Br[CH:24]([CH:31]=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].CN(C)C(=O)C>O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][C:24]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][N:13]=1)=[CH:8]2
Reactant: CCOC(=O)CC(Br)C=O
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)Cc1cnc(-c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.40 g), ethyl 3-bromo-4-oxobutyrate (0.48 g) and N,N-dimethylacetamide (25 mL) was stirred at 90° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.28 g, yield 55%) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 126-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:12](=O)[CH3:13].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:9][CH2:10][N:11]=[C:12]2[CH3:13]
Reactant: COc1ccccc1CCNC(C)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1cccc2c1CCN=C2C

Procedure:
In close analogy to the procedure described above, N-[2-(2-methoxy-phenyl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13]([CH:15]2[CH2:17][CH:16]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:14])[CH:3]=1.C[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27]1>CS(C)=O.CO>[C:30]([NH:26][CH:27]1[CH2:28][CH2:6][N:5]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13]([CH:15]3[CH2:17][CH:16]3[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[O:14])[CH:3]=2)[CH2:4][CH2:3]1)(=[O:31])[CH3:29]
Reactant: CN1CCCC1=O
Reactant: Cc1cc2nc(NC(=O)C3CC3c3ccc(F)cc3)cc(Cl)n2n1
Solvent: CS(C)=O
Solvent: CO
Product: CC(=O)NC1CCN(c2cc(NC(=O)C3CC3c3ccc(F)cc3)nc3cc(C)nn23)CC1
Temperature: 25 °C
Yield: 44 %

Procedure:
The title compound was prepared by combining N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(4-fluorophenyl)cyclopropanecarboxamide (13B, 0.15 g, 0.435 mmol) and the N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-2-(4-fluorophenyl)cyclopropanecarboxamide (0.15 g, 0.435 mmol) in NMP (Volume: 1.450 ml) and heating the mixture at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory 60-70% HPLC ([1:1 MeCN/MeOH]/H2O+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a tan solid (86 mg, 44%). 1HNMR (DMSO-d6) δ: 10.95 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.18-7.29 (m, 5H), 7.03-7.17 (m, 4H), 6.08 (s, 1H), 4.30 (d, J=13.1 Hz, 2H), 3.16 (t, J=12.1 Hz, 2H), 2.38-2.48 (m, 2H), 2.35 (s, 3H), 2.24-2.32 (m, 1H), 1.88 (d, J=12.9 Hz, 2H), 1.82 (s, 3H), 1.44-1.62 (m, 4H), 1.35-1.43 (m, 2H), 1.25-1.35 (m, 1H); ESI-MS: m/z 451.3 (M+H)+. It was noted that rotamers were present.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:31]1(B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34][CH2:33][CH:32]=1>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>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:31]4[CH2:35][CH2:34][CH2:33][CH:32]=4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
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: [Cs+]
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(C4=CCCC4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, cesium carbonate, 2-cyclopent-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and tetrakis(triphenylphosphine)Palladium (0). 1H NMR (400 MHz, DMSO-d6): δ 8.63 (t, J=5.91 Hz, 1H), 8.06 (d, J=8.91 Hz, 1H), 7.96 (dd, J=4.41, 8.91 Hz, 2H), 7.73 (d, J=9.02 Hz, 1H), 6.89 (s, 1H), 4.18 (s, 1H), 3.29 (s, 1H), 2.85-2.87 (m, 2H), 2.48-2.49 (m, 2H), 1.96-2.03 (m, 1H), 1.45-1.78 (m, 6H), 1.28-1.32 (m, 5H).
Reaction SMILES: COC([C:5]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=O.[Cl-].[Na+].CS(C)=O.Cl>O>[CH3:32][S:29]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:30])=[O:31]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)(C(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCC(CCCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O
Temperature: 185 °C
Yield: 95.7 %

Procedure:
A mixture of methyl 8-methoxycarbonyl-8 -methylsulfonyl-12-acetoxyheptadecanoate (36.7 g., 0.077 mole), sodium chloride (4.68 g., 0.08 mole), water (1 ml.) and dimethylsulfoxide (60 ml.) is heated in a bath maintained at 185° C. under nitrogen for 5 hours. The resulting reaction mixture is concentrated in vacuo at 100° C. providing an oily residue which is diluted with water. The aqueous mixture is acidified to Congo Red with 6N hydrochloric acid and extracted with ether. The organic extract is washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo leaving the title compound as a viscous oil (31 g., 95%), pmr (CDCl3) δ 2.0 (s, 3H), 2.82 (s, 3H), 3.63 (s, 3H) and 4.9 (b, H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:19](C1CCCC1(N)C(OCC)=O)=[O:20])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C([O:34]C(C1(N)CCCC1)=O)C>CO>[C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:19]([OH:20])=[O:34])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1(N)CCCC1
Reactant: CCOC(=O)C1(N)CCCC1C(=O)[C@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](C)C(=O)O

Procedure:
Ethyl N-acetyltyrosyl-alanyl-1-amino-1-cyclopentanecarboxylate, by the procedure of Example 1 from the preceding compound and ethyl-1-amino-1-cyclopentanecarboxylate, yield 88%, m.p. 168° to 171° C., [α]D20 -3.1° (c 0.2, MeOH).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([C:11]1[C:12](=[O:28])[CH2:13][CH:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH2:15][C:16]=1[OH:17])(=[O:10])[CH2:7][CH2:8][CH3:9]>C(Cl)(Cl)Cl>[C:6]([C:11]1[C:16](=[O:17])[CH2:15][CH:14]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:20][CH:19]=2)[CH2:13][C:12]=1[OH:28])(=[O:10])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(=O)C1=C(O)CC(c2cccc3ccccc23)CC1=O
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCCC(=O)C1=C(O)CC(c2ccc(S(=O)(=O)Cl)c3ccccc23)CC1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Chlorosulfonic acid (3.0 g) was added dropwise to a solution of 2-butyryl-3-hydroxy-5-(naphth-1-yl)cyclohex-2-en-1-one (1.3 g) in chloroform (15 ml) at 0° C. The mixture was stirred at 0° C. for 1 hr and at room temperature for 18 hrs. The mixture was poured onto ice-water (200 ml) which was subsequently extracted with dichloromethane. The dried (Na2SO4) organic extract was evaporated to give 2-butyryl-5-(4-chlorosulfonylnaphth-1-yl)-3-hydroxy cyclohex-2-en-1-one as a brown foam. Pmr spectrum (CDCl3 ; δ in ppm): 1.03 (3H,t); 1.43-1.89 (2H,m); 2.69-3.26 (6H,m); 4.00-4.49 (1H,m); 7.32-8.97 (6H,m); 18.35 (1H,s).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21](=[O:27])[CH2:20][CH2:19]3)[CH:13]=[N:14][CH:15]=1)(C)(C)C.Cl.O1CCOCC1>CO>[OH:6][CH2:7][CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21](=[O:27])[CH2:20][CH2:19]3)[CH:13]=[N:14][CH:15]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(NCCO[Si](C)(C)C(C)(C)C)c3)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN1C(=O)CCc2cc(-c3cncc(NCCO)c3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To solution of 6-{5-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-pyridin-3-yl}-1-methyl-3,4-dihydro-1H-quinolin-2-one (0.06 g, 0.146 mmol) in MeOH (2.5 mL) was added 4M HCl in dioxane (0.255 ml, 1.02 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, the residue dissolved in EtOAc (20 mL) and washed with aq. NaHCO3 (5 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 2% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.01 g, 22%) as an off white solid. MS: 298.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:27](I)([CH3:29])[CH3:28].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:27]([CH3:29])[CH3:28])=[CH:6][C:5]([N:9]2[C:10](=[O:19])[C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=3[C:13]2=[O:14])=[C:4]([F:20])[CH:3]=1
Reactant: CC(C)I
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 35.6 %

Procedure:
To a solution of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (2.95 g) in dimethylformamide (20 ml), there was added anhydrous potassium carbonate (0.8 g) while stirring at room temperature. After stirring for 10 minutes at about 40° C., isopropyl iodide (1.7 g) was added thereto, and the resultant mixture was stirred for 3 hours at 70°-80° C. After being allowed to cool to room temperature, the mixture was poured into water and extracted with toluene. The toluene layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography to obtain 1.2 g of N-(4-chloro-2-fluoro-5-isopropoxyphenyl)3,4,5,6-tetrahydrophthalimide (Compound No. 1). M.P., 81°-82° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[CH:11]=[C:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:16]=3)[CH3:14])[CH:9]=[N:8][C:6]=2[N:7]=1.Cl>[N+](C)([O-])=O>[NH2:1][C:2]1[N:3]=[C:4]([NH2:28])[C:5]2[CH:11]=[C:10]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=3)[CH3:14])[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CC(=Cc1cnc2nc(N)nc(N)c2c1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: CC(=Cc1cnc2nc(N)nc(N)c2c1)c1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A suspension containing 4.58 g of 2,4-diamino-6-[2-(4-tert-butoxycarbonylphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine in 200 mL of a saturated solution of hydrogen chloride gas in nitromethane was stirred at 0° C. for 1 hour, and then at room temperature for 3 hours. After dilution with ether, the reaction mixture was filtered and the collected solid was washed successively with water, methanol, and acetone and then dried under reduced pressure to give 3.90 g (100%) of 2,4-diamino-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine. NMR (DMSO-d6, 80 MHz) d 2.31(brs, 3H), 6.77 and 7.07 (brs, 1H), 7.74(d, 2H, J=8.5 Hz), 7.98(d, 2H, J=8.5 Hz), 8.26, (d, 1H, J=2.0 Hz), 8.74(d, 1H, J=2.0 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].[N:13](OC(C)(C)C)=O>C(O)(=O)C>[CH3:2][C:1]1[C:3]2[C:4](=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[NH:5][N:13]=1
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)(C)ON=O
Solvent: CC(=O)O
Product: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a mixture of 2-ethyl-5-nitroaniline (2 g, 12 mmol) in acetic acid (AcOH) (60 mL) at ambient temperature was added a solution of tert-butyl nitrite (t-BuONO) (1.8 mL, 12 mmol) in AcOH (8 mL). After stirring at ambient temperature for 1 h, AcOH was removed in vacuo. The resulting residue was dissolved in ethyl acetate (EtOAc), washed with Sat. NaHCO3, dried over Na2SO4, and concentrated to afford 3-methyl-6-nitroindazole (1.2 g).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[C:13]([C:18]2[O:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21][N:22]=2)[C:14]([NH2:17])=[N:15][CH:16]=1)([CH3:3])[CH3:2].ClC1C=C(C(OO)=[O:37])C=CC=1>ClCCl>[CH:1]([S:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[C:13]([C:18]2[O:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21][N:22]=2)[C:14]([NH2:17])=[N:15][CH:16]=1)=[O:37])([CH3:3])[CH3:2]
Reactant: CC(C)Sc1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)S(=O)c1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
5-(2-isopropylsulfanylphenyl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (50 mg, 0.1284 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0° C. in an ice-bath. 3-Chlorobenzenecarboperoxoic acid (26.59 mg, 0.1541 mmol) was added in one portion with rapid stirring. The mixture was stirred at 0° C. for 15 min, washed with saturated aqueous NaHCO3 solution (1×5 mL) and brine (1×5 mL), dried over MgSO4 and concentrated in vacuo to leave a solid which was purified by column chromatography on silica eluting with ether/ petroleum ether to yield the product as a yellow solid (16.1 mg, 31% yield); 1H NMR (400.0 MHz, CDCl3) d 1.2 (d, 3H), 1.35 (d, 3H), 3.5-3.6 (m, 1H), 7.5-7.75 (m, 2H), 7.5-7.65 (m, 7H), 8.25 (d, 2H) and 8.55 (s, 1H) ppm; MS (ES+) 406.1
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@@H:25]2[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N+:1]([C:4]1[C:5]([NH:23][CH2:24][C@@H:25]2[CH2:30][CH2:29][C@H:28]([O:31][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:27][CH2:26]2)=[N:6][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]([F:22])([F:21])[F:20])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@@H](O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
cis-4-{[5-Nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexanol (3.6 g, 8.16 mmol) was dissolved in dry DCM (150 mL) and cooled to 5° C. Methanesulfonyl chloride (0.94 ml, 12.2 mmol) and diisopropylethylamine (4.26 ml, 24.4 mmol) were added sequentially. After 2 h, the reaction was quenched with cold water (10 mL) and warmed to room temperature. The solution was partitioned between DCM (100 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield a yellow solid. The residue was then chromatographed (silica, 100:1 DCM/MeOH) and washed with cold methanol to yield a pale yellow solid as methanesulfonic acid cis-4-{[5-nitro-2-(2-trifluoromethoxy-benzylamino)-pyrimidin-4-ylamino]-methyl}-cyclohexyl ester (3.90 g, 7.50 mmol, 92%).