Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[C:27]([OH:38])=[C:28]([CH:31]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:33]=1)[CH:29]=[O:30].[Cl:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=1[F:46]>>[C:34]([C:32]1[CH:31]=[C:28]([CH:29]=[O:30])[C:27]([OH:38])=[C:26]([C:42]2[CH:43]=[CH:44][C:45]([F:46])=[C:40]([Cl:39])[CH:41]=2)[CH:33]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(F)c(Cl)c2)c1

Procedure:
5-(tert-Butyl)-3′-chloro-4′-fluoro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 3-chloro-4-fluorophenylboronic acid.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([S:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)(=[O:23])=[O:22])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:24]1([S:21]([N:17]2[CH2:16][C:15]3[CH:14]=[N:13][C:12]4[NH:8][N:9]=[CH:10][C:11]=4[C:20]=3[CH2:19][CH2:18]2)(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(S(=O)(=O)c2ccccc2)CC4)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)N1CCc2c(cnc3[nH]ncc23)C1
Temperature: 65 °C
Yield: 5.4 %

Procedure:
To 3-(4-methoxybenzyl)-7-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.109 g, 2.51 mmol) was added trifluoroacetic acid (2 mL). The reaction mixture was heated at 65° C. for 16 hours. On completion of the reaction, toluene (5 mL) was added. The reaction mixture was evaporated to dryness under reduced pressure to yield a dark brown solid. The crude product was purified using reverse phase HPLC chromatography to give the desired product, 7-(phenylsulfonyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine as a white solid (0.043 g, 54%). M.p.=270-271° C.; 400 MHz 1H NMR (DMSO-d6) δ: 13.59 (s, 1H), 8.33 (s, 1H), 8.1 (d, J=1.2 Hz, 1H), 7.88-7.84 (m, 2H), 7.73-7.61 (m, 3H), 4.35 (s, 2H), 3.43 (t, J=5.6 Hz, 2H), 3.14 (t, J=6.4 Hz, 2H); LCMS [M+H]: 315.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[CH2:6]1)=[O:4].Cl[C:27]1[S:28][C:29]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:30]=2[N:31]=1.[OH-].[Na+].Cl>C(O)CCC.Cl.O1CCOCC1.CO>[Cl:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([C:16]4[CH:17]=[CH:18][C:13]([C:11]([C@@H:7]5[CH2:8][CH2:9][CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]5)=[O:12])=[CH:14][CH:15]=4)=[CH:24][CH:23]=3)[S:28][C:29]=2[CH:35]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)C1CCCC(C(=O)c2ccc(-c3ccc(N)cc3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)[C@H]1CCC[C@@H](C(=O)c2ccc(-c3ccc(Nc4nc5ccc(Cl)cc5s4)cc3)cc2)C1
Temperature: 90 °C
Yield: 8.6 %

Procedure:
To a solution of 3-(4′-amino-biphenyl-4-carbonyl)-cyclohexanecarboxylic acid methyl ester (100 mg, 0.3 mmol) in butanol (5 μL), 2,6-dichloro-benzothiazole (60 mg, 0.3 mmol) and 5 drops of 4 M HCl in dioxane were added, and the reaction mixture was heated at 90° C. for 5 h. An additional sample of 2,6-dichlorobenzothiazole (60 mg, 0.3 mmol) and 5 drops of 4 M HCl in dioxane were then added, and the reaction mixture was heated overnight at 90° C. The solvent was removed by rotary evaporation, the residue was dissolved in DMF (2 mL), 1 N aqueous NaOH (0.3 mL, 0.3 mmol) was added, and the mixture was heated at 75° C. overnight. A solution of 1 N aqueous HCl (0.3 mL, 0.3 mmol) and methanol (5 mL) were added to the reaction mixture, and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford cis-3-[4′-(6-chloro-benzothiazol-2-ylamino)-biphenyl-4-carbonyl]-cyclohexanecarboxylic acid as a white solid (12.6 mg, yield 23.4%). 1H NMR (300 MHz, DMSO) δ 8.05 (d, 2 H), 7.75-8.00 (m, 7 H), 7.50 (d, 1 H), 7.35 (d, 1 H), 3.25 (m, 1 H), 2.50 (m, 1 H), 2.20-1.90 (m, 4 H), 1.70-1.50 (m, 4 H); LC-MS ret. time 3.99 min (method 2), m/z 491.11 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[Cl:30][C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:35][C:34]3[CH:37]=[CH:38][C:31]([Cl:30])=[CH:32][CH:33]=3)=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccc(Cl)cc2)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccc(Cl)cc2)c1

Procedure:
The reaction of hydroxylamine 55 (1.98 g, 5 mmol) with 4-chlorobenzaldehyde (62) (0.70 g, 5 mmol) afforded, after workup, a light yellow oil. The crude product was purified by flash chromatography with 1:1 ethyl acetate/petroleum ether as the eluant to obtain 1.97 g (3.74 mmol, 75%) of 73 as a light yellow gum: IR (CH2Cl2) 3440, 2980, 1700, 1625, 1590, 1550, 1475, 1300, 1215, 1110, 910, 840; 1H NMR 1.10 (d, J=6.2 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H), 2.26 (s, 6H), 3.31 (s, 3H), 3.56 (t, J=4.8 Hz, 2H), 4.18 (m, 2H), 4.93 (septet, J=6.2 Hz, 1H), 5.06 (s, 1H), 6.79 (s, 1H) 7.28-8.33 (m, 9H); 13C NMR (CDCl3) δ 19.77, 19.89, 22.48, 22.71, 40.52, 59.32, 63.35, 67.74, 71.21, 103.29, 104.13, 119.97, 122.02, 129.05, 129.52, 129.81, 130.85, 134.35, 136.94, 145.43, 146.25, 149.25, 150.39, 167.56, 168.01. Anal. Calcd for C28H31N2O6Cl; C, 63.81; H, 5.88. Found: C, 63.86; H, 5.84.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:5]([CH:18]=O)=[CH:4][CH:3]=1.Cl.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:26](=[NH:28])[NH2:27].O=[C:30]([CH3:37])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:18]2[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:30]([CH3:37])[NH:27][C:26]([C:22]3[S:21][CH:25]=[CH:24][N:23]=3)=[N:28]2)=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)c1nccs1
Reactant: O=Cc1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1-c1ccc(C(F)(F)F)cc1
Yield: 31.7 %

Procedure:
5-fluoro-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbaldehyde (2.11 g, 7.87 mmol) was reacted with thiazole-2-carboximidamide hydrochloride (1.29 g, 7.87 mmol) and ethyl 3-oxobutanoate (1.23 g, 9.44 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (1.22 g, 32%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][C:17](O)=[O:18])[C:13]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.CN(C)C=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:13]=3[N:14]2[CH2:15][CH2:16][C:17]1=[O:18]
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCC(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)c1cccc2nc3n(c12)CCC(=O)N3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
A mixture of 3-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]propanoic acid (Reference Example 30; 57.0 mg, 0.135 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.1 mg, 0.162 mmol), triethylamine (0.0226 mL, 0.162 mmol) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (44.8 mg, 0.111 mmol, 82%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][N:16]2[C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([NH2:25])[C:19]=3[CH:18]=[N:17]2)=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:25][C:20]2[C:19]3[CH:18]=[N:17][N:16]([CH2:15][C:14]4[CH:26]=[CH:27][C:11]([O:10][CH3:9])=[CH:12][CH:13]=4)[C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(Cn2ncc3c(N)cccc32)cc1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ncc3c(Nc4ccnc(Cl)n4)cccc32)cc1
Temperature: 90 °C
Reaction time: 65 h
Yield: 63.8 %

Procedure:
A suspension of 2,4-dichloropyrimidine (3.71 g, 24.87 mmol), 1-(4-methoxybenzyl)-1H-indazol-4-amine (6 g, 23.69 mmol) and N,N-diisopropylethylamine (4.54 mL, 26.06 mmol) in ethanol (60 mL) was stirred at 90° C. for 65 hours. The reaction mixture was concentrated to dryness, diluted with ethyl acetate (100 ml), washed with water (100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 5 to 70% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford N-(2-chloropyrimidin-4-yl)-1-(4-methoxybenzyl)-1H-indazol-4-amine (5.53 g, 64%) as a pink solid. NMR Spectrum: (DMSOd6) 3.70 (s, 3H), 5.57 (s, 2H), 6.86 (d, 2H), 6.93 (d, 1H), 7.22 (d, 2H), 7.37 (dd, 1H), 7.48 (d, 1H), 7.59 (d, 1H), 8.22 (d, 1H), 8.23 (s, 1H), 10.13 (s, 1H); Mass spectrum: MH+ 366
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:22]1[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]1>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:22]3[CH2:25][S:24](=[O:27])(=[O:26])[CH2:23]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=S1(=O)CC(Br)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(C3CS(=O)(=O)C3)c2)OC1(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
A 100-mL round bottomed flask was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.942 g, 4.85 mmol), N,N-dimethylformamide (20 mL) and cesium carbonate (3.16 g, 9.71 mmol). 3-Bromothietane 1,1-dioxide (0.925 g, 5.00 mmol) was added, and the reaction stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with water and brine and concentrated to afford an oil. This material was purified via column chromatography on silica gel (eluting with 1:5 ethyl acetate-hexanes) to afford 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thietane 1,1-dioxide (0.172 g, 12% yield) as a white solid. MS (ESI, pos. ion) m/z 299 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.N1C=CN=C1.[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:12][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=c1[nH]c2cc(Cl)c(O)cc2o1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1cc2oc(=O)[nH]c2cc1Cl)(C(C)C)C(C)C
Yield: 84.8 %

Procedure:
5-chloro-6-hydroxy-1,3-benzoxazol-2(3H)-one (0.93 g, 5 mmol) and imidazole (1.00 g, 15 mmol) were dissolved in dimethylformamide (10 mL) with stirring under inert atmosphere. Triisopropylsilylchloride (1.15 g, 6 mmol) was added and the resulting solution was stirred for 3 days. The reaction mixture was partitioned between water and heptane. The organic layer was washed with water and dried over magnesium sulphate, filtrated and concentrated, to give 1.45 g (85%) of the subtitled compound as a grey solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:10][C@H:9]1[CH3:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 1.02 g of (2R,4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-methylpyrrolidine (J. Med. Chem., 1988, 31, 1598-1611) in 10 ml of anhydrous dichloromethane, 1.7 ml of triethylamine and 1.16 g of p-toluenesulfonyl chloride were added, and then the mixture was stirred at room temperature overnight. The reaction solution was mixed with water, and followed by extraction with ethyl acetate twice. The organic layers were combined, washed in turn with water, 1N hydrochloric acid and a 1N aqueous sodium hydroxide solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.54 g of the objective compound as a colorless oily product.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=3)=[CH:35][N:34]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>C1COCC1>[OH:11][N:12]([CH:13]([CH2:23][S:24]([N:27]1[CH2:28][CH2:29][N:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=3)=[CH:35][N:34]=2)[CH2:31][CH2:32]1)(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]1[N:18]=[CH:19][CH:20]=[CH:21][N:22]=1)[CH:1]=[O:3]
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ccc(C#Cc3ccc(C(F)(F)F)cn3)cn2)CC1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CN(O)C(CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(C#Cc3ccc(C(F)(F)F)cn3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.9 %

Procedure:
To formic acid (0.36 mL, 9.5 mmol) at 0° C. was added acetic anhydride (90 μL, 0.95 mmol) and the mixture was stirred at RT for 10 minutes. The reaction was then recooled to 0° C., and added to a solution of 2-(4-(hydroxyamino)-5-{[4-(5-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridin-2-yl)piperazin-1-yl]sulfonyl}pentyl)pyrimidine (403 mg, 0.79 mmol) and formic acid (0.36 mL, 9.5 mmol) in THF (3 mL) at 0° C. The reaction was brought to RT and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×5 mL). The residue was then dissolved in MeOH (10 mL) and heated to 40° C. for one hour. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtOAc) to give the title compound as a pale yellow foam (66 mg, 0.11 mmol, 58%).
Reaction SMILES: [NH:1]1[C:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].O[CH2:14][C:15]1[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=1>>[O:21]=[C:18]1[NH:19][CH:20]=[C:15]([CH2:14][N:1]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4](=[O:11])[O:3][C:2]2=[O:12])[CH:16]=[CH:17]1
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Reactant: O=c1ccc(CO)c[nH]1
Product: O=c1ccc(Cn2c(=O)oc(=O)c3cccnc32)c[nH]1

Procedure:
May be prepared by a similar procedure as described for preparation 7B, starting from 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (can be prepared as described by Beckwith and Hickman in J. Chem. Soc. (C), 1968 pp 2756-2759) and 5-hydroxymethyl-1H-pyridin-2-one (prepared as described in WO 01/77078 A1).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C([NH:32][CH:33]2[C:46](=[O:47])[N:35]3[CH:36]([C:41]4[NH:45][N:44]=[N:43][N:42]=4)[C:37]([CH3:40])([CH3:39])[S:38][C@H:34]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[C:50]1([CH2:56][C:57](Cl)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O.C(OC(C)C)(C)C.CC(C)=O>[C:50]1([CH2:56][C:57]([NH:32][CH:33]2[C:46](=[O:47])[N:35]3[CH:36]([C:41]4[NH:42][N:43]=[N:44][N:45]=4)[C:37]([CH3:39])([CH3:40])[S:38][C@H:34]23)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C

Procedure:
A mixture of p-toluenesulfonic acid monohydrate (788 mg., 4.14 mmoles), acetone (35 ml.) and 6-triphenylmethylamino-2,2-dimethyl-3-(5-tetrazolyl)penam (2.0g.,) 4.14 mmoles) is stirred for twenty minutes at room temperature and is then diluted with water (100 ml.) and isopropylether (100 ml.). The biphasic mixture is stirred vigorously and adjusted to pH 7 with 2N sodium hydroxide. Phenylacetyl chloride (700 mg., 4.55 mmoles freshly distilled) is added and the reaction mixture maintained at pH between 5.5-6.5 by addition of 2N sodium hydroxide as necessary. Reaction is continued until the pH levels off at 6.5 The two phases are separated and the aqueous phase washed with ether (2 × 50 ml.). It is then layered with chloroform (100 ml.) and adjusted to pH 2 by addition of 6N HCl. The mixture is stirred, the phases separated and the aqueous phase extracted with chloroform (2 × 50 ml.). The chloroform phases are combined, dried (Na2SO4), and then concentrated under reduced pressure to about 50 ml. volume. A 1:1 solution of ether-hexane is added dropwise with vigorous stirring to the concentrate until precipitation of the product is complete. The white precipitate is filtered and air-dried. Yield = 850 mg. (57.4%) m.p. 168°-170°;
Reaction SMILES: [OH2:1].[ClH:2].Cl.[Cl:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)=[O:21])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.Cl.[OH-].[K+]>C(O)(=O)C>[ClH:4].[ClH:2].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29](=[O:1])[NH2:30])=[CH:27][CH:28]=3)=[O:21])[CH2:14][CH2:15]2)=[CH:31][CH:32]=1
Reactant: N#Cc1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Reactant: O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NC(=O)c1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 70.8 %

Procedure:
A solution of 1-{3-[4-(4-chlorobenzyl)piperazin-1-yl]-propyl}-3-(4-cyanophenyl)urea dihydrochloride monohydrate (10.0 g; 19.9 mmole), glacial acetic acid (120 ml), and concentrated hydrochloric acid (80 ml) was heated at 80° C. for 30 minutes. The mixture was then poured over ice, and basified with aqueous potassium hydroxide. The product was extracted with methylene chloride, dried (sodium sulfate), and the salt precipitated out ethereal hydrochloric acid. Several recrystallizations from ethanol provided the title compound (3.54 g; 38% yield) as colorless crystals, m.p. 224°-226° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:23])=[C:17]3[C:16]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)=[N:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[O:30]([C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:17]3[C:18](=[N:19][CH:20]=[N:21][C:22]=3[NH2:23])[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]=2)=[CH:29][CH:28]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.5 %

Procedure:
1-(1-benzyl-4-piperidinyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 1) (1.224 g, 2.57 mmol), 10% Palladium on carbon (1.22 g) and ammonium formate(0.81 g, 12.84 mmol) were mixed with 21 ml of methanol. After stirring at room temperature for 6 hours, the reaction mixture was filtered and washed with hot methanol. Solvent was removed and the residue was taking into dichloromethane and the organic layer was washed, dried, and evaporated to give 0.77 g of 3-(4-phenoxyphenyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (CDCl3) 2.05(d, J=12.17 Hz, 2H), 2.26(m, 2H), 2.87(m, 2H), 3.29(d, J=12.76 Hz), 4.89(m, 1H), 5.54(s, 2H), 7.09(m, 2H), 7.15(m, 3H), 7.39(m, 2H), 7.67(d, J=9.39 Hz, 2H), 8.37(s, 1H); LC/MS (MH+=387).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24].[CH:27](=O)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:27][CH3:28])[CH2:19][CH2:18]2)=[O:15])=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24]
Reactant: CC=O
Reactant: O=C(NC1CCNCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CCN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 199 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(piperidin-4-yl)thiophene-2-carboxamide (0.2 g, 0.46 mmol) and acetaldehyde (81.0 mg, 1.38 mmol). The title compound was obtained as a solid (8.0 mg, 4% yield). 1H NMR (400 MHz, d6-DMSO) δ:8.98 (2H, m), 8.73 (1H, m), 8.52 (1H, s), 4.28 (1H, m), 3.67 (2H, m), 3.17 (1H, m), 2.97 (2H, m), 2.16 (2H, m), 1.79 (2H, m), 1.58 (2H, m), 1.03 (3H, m). MS m/z: 461.08, 463.09 [M+H]+.
Reaction SMILES: [C:1]([CH:5]=[CH:6][CH:7]=[CH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:9]([CH:11]=[CH2:12])=[O:10].C(C1CCC(C=O)CC=1)(C)(C)C>>[C:1]([C:5]1[CH2:12][CH:11]([CH:9]=[O:10])[CH2:8][CH2:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC=O
Reactant: C=CC=CC(C)(C)C
Agent: CC(C)(C)C1=CCC(C=O)CC1
Product: CC(C)(C)C1=CCCC(C=O)C1
Yield: 30 %

Procedure:
Molar amounts of tert.-butylbutadiene and acrolein are refluxed for 6-8 hours. A mixture of about 70% of 4-tert.-butyl-cyclohex-3-ene-1-carboxaldehyde and about 30% of 3-tert.-butyl-cyclohex-3-ene-1-carboxaldehyde is obtained in a yield of about 80%. Boiling point: 112° C./28 mbar.