Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:28]([O-:30])=[O:29])=[CH:7][C:6]=2[NH:5][CH2:4]1.Cl.[CH3:32][N:33]([CH3:49])[CH2:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([C:46](O)=[O:47])=[CH:40]2.CCN=C=NCCCN(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])(=[O:17])=[O:18])=[CH:15][C:9]=3[C:8]([N+:28]([O-:30])=[O:29])=[CH:7][C:6]=2[N:5]([C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([O:36][CH2:35][CH2:34][N:33]([CH3:49])[CH3:32])=[CH:45][CH:44]=3)=[O:47])[CH2:4]1
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)NNS(=O)(=O)c1ccc2c3c(cc([N+](=O)[O-])c2c1)NCC3CCl
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3cc(S(=O)(=O)NNC(=O)OC(C)(C)C)ccc43)cc2c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 94 %

Procedure:
A mixture of 119 (59.4 mg, 0.13 mmol), 5-[2-(dimethylamino)ethoxy]indole-2-carboxylic acid hydrochloride (48 mg, 0.17 mmol), EDCI (100 mg, 0.52 mmol), and TsOH (4.5 mg, 0.03 mmol) in DMA (2 mL) was stirred at room temperature for 4.5 h and then cooled to 0° C. Ice-cold aqueous NaHCO3 was added and the precipitate was filtered off, washed with water, and dried to give tert-butyl 2-{[1-(chloromethyl)-3-({5-[2-(dimethylamino)ethoxy]indol-2-yl}carbonyl)-5-nitro-1,2-dihydro-3H-benzo[e]indol-7-yl]sulfonyl}hydrazinecarboxylate (120) (84 mg, 94%) as a yellow solid: mp 175-180° C. (dec.); 1H NMR [(CD3)2SO] δ 11.72 (d, J=1.8 Hz, 1H), 9.85 (br s, 1H), 9.30 (v br s, 1H), 9.29 (s, 1H), 8.83 (d, J=1.5 Hz, 1H), 8.44 (d, J=8.9 Hz, 1H), 7.98 (dd, J=8.9, 1.7 Hz, 1H, 7.42 (d, J=8.9 Hz, 1H), 7.21 (d, J=1.6 Hz, 1H), 7.18 (d, J=2.4H, 1H), 6.95 (dd, J=8.9, 2.4 Hz, 1H), 5.02-4.96 (1,1H), 4.72 (dd, J=10.9, 2.4 Hz, 1H), 4.70-4.64 (m, 1H), 4.17-4.09 (m, 2H), 4.07 (t, J=5.9 Hz, 2H), 2.66 (t, J=5.7 Hz, 2H), 2.25 (s, 6H), 1.10 (br s, 9H). HRMS (FAB) calcd. for C3H3635ClN6O8S (MH+) m/z 687.2004, found 687.2002.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([O:6][CH2:7][C:8]1[N:9]=[N:10][N:11]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH:12]=1)=[O:5].Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([O:6][CH2:7][C:8]1[N:9]=[N:10][N:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH:14]2[O:26][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)[CH:12]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(COC(=O)c3ccccc3Cl)nn2)C(OCc2ccc3ccccc3c2)C1
Agent: Cl
Solvent: CO
Product: O=C(OCc1cn(C2CCNCC2OCc2ccc3ccccc3c2)nn1)c1ccccc1Cl

Procedure:
In an analogous manner to that described in Example 136 (a), from tert-butyl (3RS,4RS)-4-[4-(2-chloro-benzoyloxymethyl)-[1,2,3]triazol-1-yl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by cleavage of the BOC group with hydrogen chloride in methanol there was obtained 1-[(3RS,4RS)-3-(naphthalen-2-yl-methoxy)-piperidin-4-yl]-1H-[1,2,3]triazol-4-ylmethyl 2-chloro-benzoate hydrochloride (1:1) in the form of colourless crystals; MS: 477 (M+H)+.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1.[CH3:15][C:16]([CH3:27])([CH2:25][F:26])[C:17](=[O:24])[CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:17]([CH2:18][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)([OH:24])[C:16]([CH3:27])([CH3:15])[CH2:25][F:26])=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CC(C)(CF)C(=O)Cn1cncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(CF)C(O)(C#Cc1ccc(Cl)cc1)Cn1cncn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
62 ml of butyl-lithium (15% strength in hexane, 0.1 mol) are added dropwise to 13.65 g (0.1 mol) of 4-chlorophenyl-acetylene in 50 ml of absolute tetrahydrofuran at 0° C., under nitrogen. The mixture is subsequently stirred at 0° C. for 15 minutes, and 18.5 g (0.1 mol) of 3,3-dimethyl-4-fluoro-1-(1,2,4-triazol-1-yl)-2-butanone in 30 ml of absolute tetrahydrofuran are then added dropwise. Thereafter, the reaction mixture is allowed to warm to room temperature and is subsequently stirred for 14 hours. It is concentrated by distilling off some of the solvent, the residue is taken up in ether and the mixture is washed neutral with water, dried over sodium sulphate and concentrated. The residue is recrystallized from diisopropyl ether. 19.9 g (61.9% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-5-fluoro-3-(1,2,4-triazol-1-ylmethyl)-1-pentin-3-ol of melting point 120° C. are obtained.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](SC)=[NH:37])=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1.C(N(C(C)C)CC)(C)C>CCO>[NH2:24][C:25]1[C:26]([C:33]([NH:35][C:36](=[NH:37])[NH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=3)[CH:15]=2)=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CCCCN)ccc2c1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(CCCCNC(=N)NC(=O)c3nc(Cl)c(N)nc3N)ccc2c1
Temperature: 70 °C
Yield: 50.6 %

Procedure:
To a solution of amine 77 (337 mg, 1.02 mmole) and methyl 3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 596 mg, 1.53 mmole) in EtOH (20 mL) was added diisopropylethylamine (1.06 mL, 6.13 mmole) at room temperature. The reaction mixture was heated at 70° C. in a sealed tube for 6 h, then cooled to room temperature, and concentrated to dryness. The residue was purified by column chromatography (silica gel, 80:18:2 CHCl3/CH3OH/NH4OH) to afford carboxamide 78 (280 mg, 50%) as a light yellow solid: 1H NMR (300 MHz, CD3OD) δ 7.67 (d, J=9.2 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.57 (br s, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.14 (br s, 1H), 7.03 (dd, J=9.2, 1.7 Hz, 1H), 3.30 (m, 2H), 2.81 (t, J=7.0 Hz, 2H), 1.95-1.62 (m, 4H), 1.03 (s, 9H), 0.24 (s, 6H).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([O:7][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCCCC1
Reaction time: 2 h

Procedure:
To a stirred solution of cyclohexanol (Aldrich, 10.2 g, 100 mmol) in methylene chloride (250 mL) at 0° C., Methane sulfonyl chloride (8.52 mL, 110 mmol) and triethyl amine (17.5 mL, 125 mmol) were added slowly and the mixture was stirred for 2 hrs. The reaction was quenched with water and the mixture was washed with 0.5 N HCl and brine solution. The organic layer was dried with sodium sulfate. Removal of solvent gave a yellow oil. 18.05 g.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3]([O:5]CC)=O.[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>O.CO>[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:3](=[O:5])[CH2:2][C:1]([OH:9])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1ccccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)CC(=O)Nc1ccccc1Br
Temperature: 180 °C
Yield: 57.3 %

Procedure:
Diethyl malonate (101 mL, 0.989 mol) and 2-bromoaniline (50.g, 0.291 mol) were combined and heated at 180° C. for six hours. A Dean-Stark trap was used to collect the volatiles. The reaction was allowed to cool to ambient temperature overnight; a precipitate formed. The precipitate was isolated by filtration and combined with methanol (160 mL), water (800 mL), and solid sodium carbonate (105 g). The mixture was heated at reflux for two hours, allowed to cool to ambient temperature, and then cooled to 0° C. The mixture was adjusted to pH 2 with the addition of 3 N hydrochloric acid; a white precipitate formed. The precipitate was isolated by filtration, washed with water, and dried overnight on the filter funnel to provide 43 g of N-(2-bromophenyl)malonamic acid as a white solid.
Reaction SMILES: [NH2:1][C:2](=O)[CH2:3][N:4]1[C:9](=[N:10]S(C2C=CC(C)=CC=2)(=O)=O)[CH:8]=[CH:7][C:6]([O:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:24]([F:39])[CH:23]=2)=[CH:5]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1>[NH2:1][C:2]1[N:10]=[C:9]2[CH:8]=[CH:7][C:6]([O:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[C:24]([F:39])[CH:23]=3)=[CH:5][N:4]2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)cn2CC(N)=O)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Nc1cn2cc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To a solution of benzyl (4-{[1-(2-amino-2-oxoethyl)-6-{[(4-methylphenyl)sulfonyl]imino}-1,6-dihydropyridin-3-yl]oxy}-2-fluorophenyl)carbamate (28.0 g) in tetrahydrofuran (280 mL) was added trifluoroacetic acid anhydride (196 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran was added to the residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine in this order, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, ethanol (140 mL) and 4N aqueous sodium hydroxide solution (40 mL) were added to the residue, and the mixture was stirred at room temperature for 4 hr. The solvent was concentrated under reduced pressure to 1/3, water was added to the residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1→9/1) to give the title compound (12.1 g, 51%).
Reaction SMILES: [I-].[K+].CS(O[CH2:8][CH2:9][O:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:23]([F:35])[CH:22]=2)[NH:13][N:12]=1)(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:35][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([O:10][CH2:9][CH2:8][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[C:19]=23)[CH:26]=[CH:25][C:24]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCOS(C)(=O)=O)c34)cc2F)cn1
Agent: [I-]
Agent: [K+]
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCCC5)c34)cc2F)cn1
Yield: 54 %

Procedure:
The procedure described in Example 23 was repeated (except that potassium iodide was not used) using 2-{[4-({3-fluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and pyrrolidine to give the title compound in 54% yield; NMR Spectrum: 1.67 (s, 4H), 2.45 (s, 3H), 2.54 (hidden by DMSO, 4H), 2.89 (t, 2H), 4.45 (t, 2H), 7.23 (m, 3H), 7.53 (dd, 1H), 8.01 (dd, 1H), 8.24 (d, 1H), 8.36 (s, 1H), 8.70 (br s, 1H); Mass Spectrum: 450 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:29]2[O:28][CH2:27][C:21]3([CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:30][CH3:31])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:29]2[O:28][CH2:27][C:21]3([CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:30][CH3:31])=[CH:16][CH:15]=1)=[O:11]
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(CCOCC1)CO2
Reactant: Cc1c(Cl)cncc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(CCOCC1)CO2

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (59 mg, 0.36 mmol) with compound 520 (85 mg, 0.28 mmol) in THF (1.5 mL) in the presence of LiHMDS (0.85 mL, 0.85 mmol) afforded compound 127 as a white solid material after purification by column chromatography (60-70% EtOAc in light petroleum). LC-MS: RT=3.70 min.; m/z 438.21, 440.21 (M+H)+, 436.30, 438.27 (M−H)−. 1H NMR (DMSO-d6): δ 8.65 (2H, s), 7.42 (1H, d, J 8.9), 6.87 (1H, d, J 9.0), 4.63 (2H, s), 4.25 (2H, s), 4.07 (2H, s), 3.84 (3H, s), 3.64 (4H, t, J 5.3), 1.60 (4H, t, J 5.3).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:14][C:15]1[CH:25]=[C:18]2[C:19](=[O:24])[NH:20][CH2:21][CH2:22][CH2:23][N:17]2[N:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:27][CH:28]1[CH2:30][CH2:29]1>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:25]=[C:18]2[C:19](=[O:24])[N:20]([CH2:27][CH:28]3[CH2:30][CH2:29]3)[CH2:21][CH2:22][CH2:23][N:17]2[N:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NCCCn2nc(OCc3ccccc3)cc21
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2cc(OCc3ccccc3)nn2CCCN1CC1CC1
Temperature: 150 °C
Reaction time: 18 h
Yield: 26.9 %

Procedure:
To a solution of Cs2CO3 (0.8 g, 2.43 mmol) in DMF (10 mL) were added 2-(benzyloxy)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one (0.3 g, 1.16 mmol) and (bromomethyl)cyclopropane (0.3 g, 2.34 mmol) at 0° C. The mixture was stirred at 150° C. for 18 hours. The mixture was diluted with ice-water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in petroleum ether 0/10 to 1/10) to yield 2-(benzyloxy)-5-(cyclopropylmethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-4-one (97 mg, 27% yield). C18H21N3O2. 1H NMR (400 MHz, CDCl3) δ ppm 0.27-0.39 (m, 2H), 0.51-0.66 (m, 2H), 1.01-1.14 (m, 1H), 2.28 (quin, J=6.7 Hz, 2H), 3.43 (d, J=7.3 Hz, 2H), 3.48 (t, J=6.4 Hz, 2H), 4.28 (t, J=7.0 Hz, 2H), 5.18 (s, 2H), 6.18 (s, 1H), 7.28-7.40 (m, 3H), 7.41-7.47 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.[NH2:11][C:12]([NH2:14])=[S:13].II>>[NH2:14][C:12]1[S:13][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[N:11]=1
Reactant: NC(N)=S
Reactant: CC(=O)c1ccc(O)cc1
Agent: II
Product: Nc1nc(-c2ccc(O)cc2)cs1

Procedure:
According to Group 4-scheme 2, 4'-hydroxyacetophenone (Aldrich Chemical Co., Milwaukee, Wis., USA) was reacted with thiourea and iodine according to the method of R. M. Dodson and L. C. King, J. Amer. Chem. Soc. 1945, 67, 2242 to give 4-(2-amino-4-thiazolyl)phenol (5). Reaction of the latter compound with 1,1-dimethylethyl 2-bromoacetate in the presence of potassium carbonate gave 1,1-dimethylethyl 2-{4-(2-amino-4-thiazolyl)phenoxy}acetate (6). Subsequent hydrolysis of the later compound gave the thiazolylphenoxyacetic acid derivative of formula 2 wherein R1C is amino.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[CH2:9]1)=O)(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[CH2:9]1.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CC(Cn2cccn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnn(CC2CNC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 41.5 mg (0.17 mmol) 3-pyrazol-1-ylmethyl-azetidine-1-carboxylic acid tert-butyl ester was added 2 mL of 25% TFA in DCM and the reaction was stirred at room temperature for 1 hour. The solvent was evaporated to give the desired product as a TFA salt, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][CH2:7][CH:8]([OH:13])[CH2:9][N:10]=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][CH2:7][CH:8]([OH:13])[CH2:9][NH2:10]
Reactant: [N-]=[N+]=NCC(O)COCc1cccc(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)COCc1cccc(Cl)c1
Yield: 60.7 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 6.22 g of 3-(3-chlorobenzyloxy)-2-hydroxypropylazide (prepared as described in Preparation 92), 1.97 g of lithium aluminum hydride and 120 ml of anhydrous tetrahydrofuran were used, to give 3.37 g of the title compound having an Rf value of 0.03 (on silica gel thin layer chromatography, using a mixture of ethyl acetate as the developing solvent).
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][CH2:5][OH:6].CC(C)=[O:13].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O.C(Cl)Cl>[Br:1][C:2]([F:10])([F:9])[C:3]([Cl:8])([F:7])[CH2:4][C:5]([OH:13])=[O:6]
Reactant: OCCC(F)(Cl)C(F)(F)Br
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(O)CC(F)(Cl)C(F)(F)Br
Temperature: 0 °C
Yield: 85 %

Procedure:
A solution of 4-bromo-3-chloro-3,4,4-trifluorobutanol (IX) (2.41 g, 10 mmol) in acetone (35 mL) was treated with Jones reagent (7.5 mL) in 10 min with stirring and cooling (ice-water bath). The mixture was then stirred at room temperature for 30 min and 0.5 mL of i-propanol was then added. The precipitated salts were removed by filtration, washed with acetone. The residue obtained after concentration of the filtrate was dissolved in methylene chloride (100 mL), washed with 1N HCl (50 mL), brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 2.17 g (85%) of 4-bromo-3-chloro-3,4,4-trifluorobutanoic acid (VIII) as a clear oil.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]=1[C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[CH3:2].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]=1[C:14]1[N:15]=[CH:16][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:18]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: CCc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 30 %

Procedure:
As described for Example 30 e), 5-ethyl-4-(1H-imidazol-4-yl)-3-phenyl-isoxazole (100 mg, 0.43 mmol) was converted using 1-fluoro-4-nitro-benzene instead of 4-fluoroacetophenone to the title compound (45 mg, 30%) which was obtained as a white solid. MS: m/e=347.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])/[CH:4]=[C:5](/[O-:7])\[CH3:6].[Na+].[I-].[K+].Br[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:5]([CH:4]([CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:3]([O:2][CH3:1])=[O:8])(=[O:7])[CH3:6]
Reactant: BrCCCC1CCCCC1
Reactant: COC(=O)/C=C(\C)[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Product: COC(=O)C(CCCC1CCCCC1)C(C)=O

Procedure:
Analogously to Example 28A, 10 g (72.4 mmol) of sodium (2E)-4-methoxy-4-oxo-2-buten-2-olate and 0.4 g (2.41 mmol) of potassium iodide are reacted with 14.9 g (72.4 mmol) of (3-bromopropyl)cyclohexane to give methyl 2-acetyl-5-cyclohexylpentanoate.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][O:23][C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)=[O:25]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: COC(=O)c1ccc(CCl)cc1
Product: COC(=O)c1ccc(CN2C(=O)C(CCO)Oc3ccccc32)cc1
Yield: 65 %

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by methods F and G, alkylating with 4-(methoxycarbonyl)benzyl chloride, to afford the alcohol as a white solid in 65% yield, mp=94°-95° C.; 1H NMR (CDCl3) δ8.00 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 6.95-7.04 (m, 2H), 6.89 (dt, J=2.1, 8.0 Hz, 1H), 6.77 (dd, J=7.8, 1.5 Hz, 1H), 5.20 (s, 2H), 4.86 (dd, J=5.4, 7.7 Hz, 1H), 3.82-3.96 (m, 5H with 3H singlet at δ3.89), 2.16-2.37 (m, 3H, one of which is exchangeable). 13C NMR (CDCl3) δ166.8, 166.5, 144.1, 141.1, 130.1 (CH), 129.4, 128.4, 126.3 (CH), 124.2 (OH), 122.8 (OH), 117.3 (OH), 115.2 (OH), 75.1 (OH), 58.7 (OH2), 52.0 (CH3), 45.1 (CH2), 33.1 (CH2). IR 3450-3500 (br), 1719, 1660 cm-1. MS 342 (MH+), 324 (M-OH)+, 310 (M-OMe)+. Anal. Calc'd. for C19H19NO5 : C, 66.85; H, 5.61; N, 4.10. Found: C, 66.48; H, 5.47; N, 3.97.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Br:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].[CH2:24](Br)[CH:25]=[CH2:26].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([O:21][CH2:26][CH:25]=[CH2:24])[C:18]([Br:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1)[CH3:2]
Reactant: C=CCBr
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(-n2c(OCC)nc(C(F)(F)F)cc2=O)c(F)cc1Br

Procedure:
using 2-ethoxy-1-(4-bromo-2-fluoro-5-hydroxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone and allyl bromide with sodium hydride in dimethylformamide there is obtained 2-ethoxy-1-[4-bromo-2-fluoro-5-(2-propenyloxy)-phenyl]-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 68°-70° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: NCCCN1CCOCC1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCCCN3CCOCC3)nc21
Temperature: 125 °C
Reaction time: 0.03 h

Procedure:
A mixture of 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37, 1.00 g (6.90 mmol) of N-(3-aminopropyl)morpholine and 0.5 mL of dimethylformamide was heated with stirring in a 125° C. oil bath. After 2 minutes, solution was complete. After 1.5 hours, the excess amine and dimethylformamide were evaporated at reduced pressure and the residue was triturated with 5 mL of water. The gum was dissolved in 25 mL of ethyl acetate, and the solution was washed with 2×5 mL of water, dried (potassium carbonate), and concentrated. Upon dissolution in 5 mL of ether, crystals of pure product separated; wt 0.101 g; mp 140°-142° C.