Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCCC1>[O:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]1[O:26][CH2:25][CH2:24][CH2:23][CH2:22][O:19][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: BrCCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a stirring solution of 2.0 g (7.0 mmol) of oleic acid and 1.6 g (7.0 mmol) of 2-(4-bromobutoxy)tetrahydro-2H-pyran in 20 mL of tetrahydrofuran is added 2.3 g (7.1 mmol) of cesium carbonate and the reaction mixture is stirred overnight at room temperature. The reaction mixture is poured into water and extracted with three 100 mL portions of ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording 2.9 g (100%) of (Z)-9-octadecenoic acid 4-[(tetrahydro-2H-pyran-2-yl)oxy]butyl ester. Next, 500 mg of Dowex 50W 8X resin is added to a stirring solution of 2.9 g (7.0 mmol) of (Z)-9-octadecenoic acid 4-[(tetrahydro-2H-pyran-2-yl)oxy]butyl ester in 100 mL of 1:1 tetrahydrofuran/methanol and the reaction mixture is stirred overnight at room temperature. The reaction mixture is filtered and concentrated in vacuo affording 2.4 g (100%) of alcohol. Next, 11 mL of 2.0M Jones reagent is added at 0° C. to a stirring solution of 2.4 g (7.0 mmol) of alcohol in 75 mL of acetone and the reaction mixture is stirred for 2 hours. The reaction mixture is poured into water and extracted with three 50 mL portions of ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording 2.1 g (81%) of title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>ClCCl.CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH2:41][O:42][CH3:43])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COCCN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
To a solution of 133e (180 mg, 0.287 mmol) in dichloromethane (5 mL) and methanol (5 mL) was added NaBH4 (21.7 mg, 0.574 mmol). After stirring at room temperature for 1 h, it was quenched with aqueous NH4Cl (5 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×20 mL) The combined organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure, and purified by reverse-phase prep-HPLC to afford 133 (50 mg, 27%) as a white solid. MS-ESI: [M+H]+ 629.3. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J=5.5 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 8.22 (s, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.78 (dd, J=1.5, 13.5 Hz, 1H), 7.51 (d, J=5.5 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 5.89 (s, 1H), 4.90-4.88 (m, 1H), 4.42 (s, 2H), 3.92 (t, J=5.5 Hz, 2H), 3.61 (s, 2H), 3.59 (s, 3H), 3.50 (t, J=5.0 Hz, 2H), 3.25 (s, 3H), 2.90 (t, J=5.5 Hz, 2H), 2.67 (t, J=5.0 Hz, 2H), 1.40 (s, 9H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]P(=O)(OCC)OCC.[Li]CCCC.[CH:25]([C:27]1[N:28]=[C:29]2[C:34]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:33][CH:32]=[N:31][N:30]2[C:41]=1[C:42]1[CH:54]=[CH:53][C:45]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[CH:44][CH:43]=1)=O.[NH4+].[Cl-]>C1COCC1.O>[O:38]1[CH2:37][CH2:36][N:35]([C:34]2[C:29]3[N:30]([C:41]([C:42]4[CH:54]=[CH:53][C:45]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])=[CH:44][CH:43]=4)=[C:27](/[CH:25]=[CH:11]/[C:2]4[CH:3]=[CH:4][C:5]5[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=5[N:1]=4)[N:28]=3)[N:31]=[CH:32][CH:33]=2)[CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: CCOP(=O)(Cc1ccc2ccccc2n1)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3ccc4c(n3)CCCC4)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of compound 58a (125 mg, 0.441 mmol) in 2.5 mL of THF at RT was added n-BuLi (275 μL, 0.441 mmol, 1.6M in hexane) dropwise. After stirring at rt for 15 min, the mixture was added slowly to a suspension of compound 5f (150 mg, 0.367 mmol) in 2.5 mL of THF. The resulting mixture was stirred at rt for 30 min, then 2 mL of saturated NH4Cl was added. The mixture was diluted with 10 mL of water, then extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (15 mL) and dried with Na2SO4, filtered and concentrated. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (0:1-1:4 EtOAc/DCM) to afford compound 60a as a pale yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.16 (d, J=8.1 Hz, 2H), 7.98 (d, J=5.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 2H), 7.73 (d, J=15.7 Hz, 1H), 7.50-7.58 (m, 1H), 7.29-7.35 (m, 1H), 7.21-7.26 (m, 1H), 6.11 (d, J=5.6 Hz, 1H), 4.02-4.09 (m, 4H), 3.93-4.02 (m, 4H), 2.93 (t, J=6.3 Hz, 2H), 2.77 (t, J=6.1 Hz, 2H), 1.86-1.95 (m, 2H), 1.77-1.86 (m, 2H), 1.63 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C32H35N5O3, 538.1 (M+H). found 538.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20](=[O:26])[C:21]1[O:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH:14]([CH:20]([OH:26])[C:21]2[O:25][CH:24]=[CH:23][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=Cc1ccco1
Reactant: CCOC(=O)Cc1nsc(NC(=O)OC(C)(C)C)n1
Product: CCOC(=O)C(c1nsc(NC(=O)OC(C)(C)C)n1)C(O)c1ccco1

Procedure:
1.0 g (3.5 mMol) of product from Example 28 were reacted with 0.87 ml (~10 mMol) of furfural for 5 days in the manner described in Example 29 and worked up by aqueous extraction.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]([S:20]([C:23]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=1[NH2:25])(=[O:22])=[O:21])[CH3:19]>>[CH2:18]([S:20]([C:23]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:24]=1[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)(=[O:22])=[O:21])[CH3:19]
Reactant: CCS(=O)(=O)c1ccc(O)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: CCS(=O)(=O)c1ccc(O)cc1Nc1cc(C(F)(F)F)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 2-ethylsulfonyl-5-hydroxyaniline (46 mg, 0.231 mmol) similar to Example 180. The reaction mixture was evaporated under vacuum to give a residue. The residue was precipitated using acetone to give the product as a yellow solid (30 mg, 46%). 1H NMR (DMSO-d6): 9.45 (s, 1H), 8.71 (m, 3H), 7.84 (brs, 1H), 7.0 (brd, 1H), 6.08 (brd, 1H), 3.0 (q, 2H), 1.0 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7](=[O:13])O[C:9]2=[O:12])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:18]([NH:20][CH:21]1[CH2:23][CH2:22]1)=[O:19]>C1(C)C=CC=CC=1.C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7](=[O:13])[N:14]([C:15]3[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:18]([NH:20][CH:21]3[CH2:22][CH2:23]3)=[O:19])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2C(=O)O1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1N1C(=O)Cc2ccc(Br)cc2C1=O
Temperature: 150 °C
Yield: 60.5 %

Procedure:
A suspension of 7-bromo-1H-isochromene-1,3(4H)-dione (1.09 g) and 3-amino-N-cyclopropyl-4-methylbenzamide (0.91 g) in a mixture of toluene (8 ml) and acetic acid (2.5 ml) was heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 60 minutes. This was process was repeated and the batches combined, diluted with ethyl acetate and washed with 1N HCl, saturated NaHCO3 solution, water, brine, dried (magnesium sulfate) to yield 3-(7-bromo-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide as a brown solid (1.13 g); NMR Spectrum: (DMSOd6) 0.60 (m, 2H), 0.71 (m, 2H), 2.12 (s, 3H), 2.89 (m, 1H), 4.34 (d, 1H), 4.42 (d, 1H), 7.48 (d, 1H), 7.53 (d, 1H), 7.70 (s, 1H), 7.85 (d, 1H), 7.99 (d, 1H), 8.20 (s, 1H), 8.45 (d, 1H); Mass Spectrum: M+Na+ 435.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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.CN(C=O)C>[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cccc(B(O)O)c1C
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
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: [K+]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: O
Product: Cc1cccc(-c2cncc(NC(=O)c3ccccc3)c2)c1C
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 3.93 g (13.9 mmol) of N-(5-bromopyridin-3-yl)benzamide, 2.50 g (16.7 mmol) of (2,3-dimethylphenyl)boronic acid and 3.84 g (27.8 mmol) of potassium carbonate were dissolved in 50 ml of 1,2-dimethoxyethane, 17 ml of water and 100 ml of DMF. The mixture was flushed with argon, 81 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was triturated with methyl tert-butyl ether, the solid was filtered off and the filtrate was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 2:1→1:1). The separated solid and the appropriate fraction from the chromatography were combined. Yield: 4.2 g (96% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1.Cl[CH2:30][CH:31]1[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:30][CH:31]2[CH2:35][O:34][C:33]([CH3:37])([CH3:36])[O:32]2)[CH:22]=1
Reactant: CC1(C)OCC(CCl)O1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(O)c2)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCC3COC(C)(C)O3)c2)c1N
Temperature: 150 °C
Reaction time: 2 h
Yield: 18.3 %

Procedure:
To a stirred solution of 3-[5-amino-4-(3-hydroxy-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (75 mg, 0.2 mmol) and 4-chloromethyl-2,2-dimethyl-[1,3]dioxolane (36 mg, 0.24 mmol) were dissolved in DMF (4 ml) was added K2CO3 and the mixture stirred at 150° C. for 2 h in microwave oven. The solvent was removed, residue was dissolved in EtOAc, washed by water, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (EtOAc:Hex=3:1) and the product was obtained as a colorless oil (18 mg, 18%). HPLC (4 minute gradient) tR 2.57 min; MS m/z 491.11 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]#[N:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[F:12][C:13]1[CH:14]=[C:15]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.ClCCl>[F:12][C:13]1[CH:14]=[C:15]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([NH:23][C:2]2[N:7]=[N:6][C:5]([C:8]#[N:9])=[C:4]([CH3:10])[C:3]=2[CH3:11])[CH2:21][CH2:22]1
Reactant: NC1CCN(Cc2cc(F)cc(F)c2)CC1
Reactant: Cc1c(Cl)nnc(C#N)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: Cc1c(C#N)nnc(NC2CCN(Cc3cc(F)cc(F)c3)CC2)c1C
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
A mixture of 6-chloro-4,5-dimethyl-pyridazine-3-carbonitrile (D11) (0.120 g, 0.72 mmol), 1-(3,5-difluoro-benzyl)-piperidin-4-ylamine (D5) (0.194 g, 0.86 mmol) and diisopropylethylamine (0.188 ml, 1.08 mmol) in acetonitrile was stirred at 180° C. for 20 min., under microwave irradiation (Biotage MW-oven), and then again at 180° C. for additional 30 min. Dichloromethane, water and a saturated solution of sodium carbonate were then added. The organic phase was separated, filtered over cotton and evaporated in vacuo. The residue was purified by column chromatography (silica gel; 0-1% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and the solvent evaporated in vacuo to yield E19 (0.108 g, 42%) as a solid. C19H21F2N5 requires 357. Found 358 (MH+).
Reaction SMILES: OCCC#CC1N(CC2C3C(=CC=CC=3)C=CC=2)C=C2C=1CN(C)CN2CC(C)C.[OH:31][CH2:32][CH2:33][C:34]#[C:35][C:36]1[N:37]([CH2:52][C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[CH:56]=[CH:55][CH:54]=2)[CH:38]=[C:39]2[C:44]=1[C:43](=[O:45])[N:42]([CH3:46])[C:41](=[O:47])[N:40]2[CH2:48][CH:49]([CH3:51])[CH3:50]>>[OH:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]1[N:37]([CH2:52][C:53]2[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[CH:56]=[CH:55][CH:54]=2)[CH:38]=[C:39]2[C:44]=1[C:43](=[O:45])[N:42]([CH3:46])[C:41](=[O:47])[N:40]2[CH2:48][CH:49]([CH3:51])[CH3:50]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCO)n(Cc3cccc4ccccc34)cc21
Agent: CC(C)CN1CN(C)Cc2c1cn(Cc1cccc3ccccc13)c2C#CCCO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(CCCCO)n(Cc3cccc4ccccc34)cc21

Procedure:
The title compound was prepared from the compound of Example 15, 5-(4-hydroxybut-1-ynyl)-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo [3,4-d]pyrimidine-2,4(3 H,6 H)-dione, in a manner analogous to the method of Example 14 above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:12]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]2)[CH:10]=[O:11])=[CH:4][CH:3]=1.CC(=CC)C.[OH:28]P([O-])(O)=O.[K+].Cl([O-])=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(O)(C)C.O>[C:18]([O:17][C:16]([NH:15][C:12]1([CH:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:10]([OH:28])=[O:11])[CH2:14][CH2:13]1)=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1(C(C=O)Cc2ccc(Cl)cc2)CC1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C(Cc2ccc(Cl)cc2)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 1-(1-(4-chlorophenyl)-3-oxopropan-2-yl)cyclopropylcarbamate (3.06 mmol), 2-methyl-2-butene (7.6 mL, 2.0M THF solution, 15.3 mmol) and KH2PO4 (0.416 g, 3.06 mmol) were dissolved in t-BuOH (100 mL)-water (30 mL). Sodium chlorite (0.830 g, 9.17 mmol) was added portionwise at 0° C. The mixture was stirred at room temperature for 2 hours and then acidified with 10% citric acid. The reaction was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to give 2-(1-(tert-butoxycarbonylamino)cyclopropyl)-3-(4-chlorophenyl)propanoic acid as a white solid. LCMS: 339.9 [M+H+] (APCI+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13].[OH-].[Na+].Cl>C(O)C.O>[O:14]=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=[CH:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1cccc(C(=O)O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(C=CC(=O)c2ccccc2)c1
Yield: 84.5 %

Procedure:
A mixture of 3-formylbenzoic acid (2 g, 13.32 mmol), acetophenone (1.6 g, 13.32 mmol), and sodium hydroxide (1.06 g, 26.64 mmol) is stirred 18 hours in ethanol-water (175 mL, 1:1) and then acidified with concentrated hydrochloric acid. The resulting solid is collected by filtration and dried to provide 2.84 g of the title compound; mp 198°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([C:13]1[N:17]=[C:16]([CH2:18]Cl)[O:15][N:14]=1)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([C:13]1[N:17]=[C:16]([CH2:18][O:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[O:15][N:14]=1)[CH:11]=[CH2:12]
Reactant: C=CCc1noc(CCl)n1
Reactant: Oc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCc1noc(COc2ccc(F)cc2Cl)n1
Yield: 80.7 %

Procedure:
0.71 g of 2-chloro-4-fluorophenol, 0.77 g of 3-allyl-5-chloromethyl-1,2,4-oxadiazole and 0.83 of potassium carbonate were added to 20 ml of acetone. After completion of the reaction, the resulting precipitates were filtered out from the mixture and then acetone was removed by distillation, and the residue was purified by column chromatography (benzene:hexane=1:1) to obtain 1.05 g of the desired product(yield: 80.8%).
Reaction SMILES: [Cl:1][CH2:2][N:3]([CH2:15][CH2:16][CH:17]=[O:18])[C:4]([NH:6][C:7]1[S:8][C:9]([CH2:12][CH:13]=[CH2:14])=[N:10][N:11]=1)=[O:5].Cl>O>[CH2:12]([C:9]1[S:8][C:7]([N:6]2[CH:17]([OH:18])[CH2:16][CH2:15][N:3]([CH2:2][Cl:1])[C:4]2=[O:5])=[N:11][N:10]=1)[CH:13]=[CH2:14]
Reactant: C=CCc1nnc(NC(=O)N(CCl)CCC=O)s1
Agent: Cl
Solvent: O
Product: C=CCc1nnc(N2C(=O)N(CCl)CCC2O)s1

Procedure:
The dimethyl acetal of 3-[1-chloromethyl-3-(5-allyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde (15 grams), water (400 ml) and hydrochloric acid (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. The reaction mixture is then filtered while hot and the filtrate is cooled to form a precipitate. The precipitate is recovered by filtration, is dried and is recrystallized to yield the desired product tetrahydro-1-(5-allyl-1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-hydroxy-2(1H)-pyrimidinone.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]1.[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:5]1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O[C@@H]1CCC[C@H](OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1CCC[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under an atmosphere of argon, 12 g of sodium hydride (55-65%) are initially charged in 200 ml of abs. DMF, and the mixture is stirred at RT for 10 min. With ice-cooling, 54 g of benzyl (1S,3R)-3-hydroxycyclohex-1-yl ether in 70 ml of DMF are added dropwise. The mixture is stirred at RT for 90 min. With ice-cooling, 50 g of allyl bromide are slowly added dropwise. After the addition has ended, the mixture is stirred at 45° C. for 1 h. According to TLC, the reaction is complete. The reaction solution is quenched with 15 ml of iPrOH, diluted with water and sat. NaCl solution and extracted with MTBE. The combined organic phases are washed with water and NaCI solution, dried over MgSO4 and concentrated. This gives 60 g of benzyl (1S,3R)-3-allyloxycyclohex-1-yl ether as a light-beige oil. C16H22O2 (246.35), MS (ESI): 247 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[N+:8]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cccc([N+](=O)[O-])c1

Procedure:
Ethyl bromoacetate is reacted with meta-nitrophenol under standard conditions to afford ethyl 2-(3-nitrophenoxy)acetate, which is elaborated to ethyl 2-(3-hydrazinophenoxy)acetate using the reduction/oxidation sequence described for Example Y.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:7]([Br:19])=[N:6]1.[OH-].[Li+]>CO>[Br:19][C:7]1[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9](=[O:10])[N:5]([CH2:4][C:3]([OH:20])=[O:2])[N:6]=1
Reactant: COC(=O)Cn1nc(Br)n(Cc2ccccc2F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1nc(Br)n(Cc2ccccc2F)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
The compound from Example 138A (360 mg) is dissolved in 10 ml methanol and treated with 4.2 ml of a 1 M aqueous lithium hydroxide solution. The mixture is stirred overnight at RT and then freed of methanol on the rotary evaporator. The residue is diluted with 200 ml water and slowly acidified to pH 2 with 1 N hydrochloric acid. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases dried over sodium sulphate and the solvent removed on the rotary evaporator. The residue is dissolved in a little DMSO and purified by preparative HPLC (Method 20). 246 mg (0.75 mmol) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]12[CH2:10][CH2:9][CH:5]([CH:6]([OH:8])[CH2:7]1)[C:4]([CH3:12])([CH3:11])[NH:3]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>C(O)(=O)C>[C:13]([O:8][CH:6]1[CH2:7][C:2]2([CH3:1])[CH2:10][CH2:9][CH:5]1[C:4]([CH3:12])([CH3:11])[NH:3]2)(=[O:15])[CH3:14]
Reactant: CC12CCC(C(O)C1)C(C)(C)N2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC1CC2(C)CCC1C(C)(C)N2
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To a solution of 1.8 g (0.016 moles) of 1,3,3-trimethyl-2-azabicyclo[2.2.2]octane-5ol in 30 ml of glacial acetic acid in a 100 ml flask equipped with a magnetic stirrer, thermometer, condenser, and drying tube was added 1.0 ml (0.106 moles) of acetic anhydride. The solution was boiled under reflux for 20 hours. The reaction mixture was then cooled and evaporated under reduced pressure. The residue was taken up in hexane, and allowed to stand at room temperature overnight. The solution was then filtered and the filtrate evaporated under reduced pressure and dried under vacuum at 35° C, yielding 1.23 g of the desired material as a colorless oil.