Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12]Br.[Na]>O1CCOCC1.CO>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: Fc1ccccc1CBr
Reactant: OC1CCOC1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1COCCO1
Product: Fc1ccccc1COC1CCOC1
Temperature: 50 °C
Yield: 80 %

Procedure:
8.8 g (0.1 mole) of 3-hydroxy-tetrahydrofurane were added dropwise, whilst stirring, to a mixture of 2.8 g (0.12 mole) of sodium hydride (3.5 g of 80% strength sodium hydride in paraffin oil) in 100 ml of absolute dioxan at room temperature. The mixture was then heated for 30 minutes under reflux. After cooling to 50° C., 19 g (0.1 mol) of 2-fluorobenzyl bromide were added dropwise to the sodium salt thus obtained. The mixture was then heated for 3 hours under reflux and was allowed to cool to room temperature, 10 ml of methanol were added to destroy the excess sodium hydride, and the mixture was concentrated by distilling off the solvent in vacuo. The residue was taken up in 100 ml of water and extracted with methylene chloride. The organic phase was dried over sodium sulphate and concentrated. The residue was distilled in vacuo. 15.7 g (80% of theory) of 3-(2-fluorobenzyloxy)-tetrahydrofurane of boiling point 89° C./0.1 mm Hg were obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[F:43].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=2[F:43])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Fc1cccc(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cccc(F)c2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 1-(bromomethyl)-2,3-difluorobenzene (0.70 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.76 g, 46%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[C:10]([CH3:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[CH2:24]=O.Cl>C(OCC)C.O.O1CCOCC1>[C:1]1([C:7]2[C:11]([C:12](=[O:15])[CH:13]([CH3:24])[CH2:14][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:10]([CH3:16])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: CCC(=O)c1c(-c2ccccc2)noc1C
Reactant: C=O
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1C(=O)C(C)CN1CCCCC1

Procedure:
Added to 3 ml of dioxane were 2.0 g (9.3 mmol) of 3-phenyl-4-propionyl-5-methylisoxazole prepared above in the procedure (2), 1.4 g (11.6 mmol) of piperidine hydrochloride, 0.4 g (13.3 mmol) of paraformaldehyde and 3 droplets of 12N-hydrochloric acid. The resultant mixture was heated under reflux for 30 minutes. After completion of the reaction, water and ethyl ether were added, followed by separation of a water layer. An aqueous solution of sodium carbonate was added to the water layer to alkalinize the same, followed by extraction with ethyl ether. The organic layer was dried and the solvent was distilled off, whereby a Mannich base, namely, 3-phenyl-5-methyl-4-(2-methyl-3-piperidinopropionyl)isoxazole was obtained as oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](Cl)=[N:11]OS(C)(=O)=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1.[S-:24][C:25]#[N:26].[Na+].[Br:28][C:29]1[CH:30]=[C:31]([O:36][C:37]2[C:38]([CH3:43])=[N:39][CH:40]=[CH:41][CH:42]=2)[C:32]([NH2:35])=[N:33][CH:34]=1>C(#N)C>[Br:28][C:29]1[CH:30]=[C:31]([O:36][C:37]2[C:38]([CH3:43])=[N:39][CH:40]=[CH:41][CH:42]=2)[C:32]([NH:35][C:25]2[S:24][N:11]=[C:10]([CH:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)[N:26]=2)=[N:33][CH:34]=1
Reactant: N#C[S-]
Reactant: Cc1ncccc1Oc1cc(Br)cnc1N
Reactant: CC(=O)N1CCC(C(Cl)=NOS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3Oc3cccnc3C)n2)CC1
Temperature: 40 °C
Yield: 100.4 %

Procedure:
1-acetyl-N-(methylsulfonyloxy)piperidine-4-carbimidoyl chloride (2.27 g, 8.03 mmol), pyridine (1.95 mL, 24.1 mmol) and sodium thiocyanate (0.651 g, 8.03 mmol) were dissolved in acetonitrile (45 mL). The solution was heated to 40° C. for 40 minutes. 5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-amine (1.50 g, 5.35 mmol) was added and the reaction was heated at 60° C. overnight. The solution was cooled to 0° C., filtered and the solid was dried to give 1-(4-(5-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (2.63 g, 5.37 mmol, 100% yield) as a white solid. 1H NMR (CDCl3) δ 1.78-1.97 (m, 2H), 2.01-2.20 (m, 2H), 2.12 (s, 3H), 2.51 (s, 3H), 2.86 (t, 1H), 3.05-3.11 (m, 1H), 3.24 (t, 1H), 3.90 (d, 1H), 4.57 (d, 1H), 6.97 (d, 1H), 7.24-7.37 (m, 2H), 8.23 (d, 1H), 8.50 (d, 1H), 9.10 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]1=[O:9].[CH3:11][Mg]Br.[Cl-].[NH4+]>CCOCC>[CH3:11][C:3]1([OH:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH2:6][C:2]1([CH3:10])[CH3:1]
Reactant: C[Mg]Br
Reactant: CC1(C)CCC(C)(C)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)C1(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2,2,5,5-tetramethylcyclopentanone (30 g, 0.215 mole) in ether (50 ml) was treated, under nitrogen, with a 3M solution of methyl magnesium bromide in ether (100 ml). The reaction mixture was stirred overnight at room temperature and saturated aqueous ammonium chloride (65 ml) then added dropwise. The mixture was stirred for 10 minutes, the ether solution decanted and the solid residue triturated with ether. The ether extracts were dried (Na2SO4) and evaporated under reduced pressure to give crude 1,2,2,5,5-pentamethylcyclopentanol (30 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]([O:16]CC)=[O:15])=[CH:4][C:3]=1[O:19][CH3:20].O.[Li+].[OH-]>C1COCC1.CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[O:19][CH3:20]
Reactant: CCOC(=O)C1=C(c2ccc(Br)c(OC)c2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(C2=C(C(=O)O)CCCC2)ccc1Br
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a solution of the product from Step 2, ethyl 2-(4-bromo-3-methoxyphenyl)cyclohex-1-ene-1-carboxylate (2.0 g, 5.9 mmol) in THF (120 mL), EtOH (50 mL), and water (12 mL) was added LiOH (0.565 g, 23.6 mmol) and the reaction was stirred at 70° C. for 24 h. After cooling to r.t., the EtOH and THF were removed in vacuo and the aqueous layer was washed with Et2O. The pH was then adjusted to 1.4 with concentrated HCl and extracted with DCM two times. The organic layer was then dried over Na2SO4 and the solvent was removed in vacuo to yield 2-(4-bromo-3-methoxyphenyl)cyclohex-1-ene-1-carboxylic acid, which was dissolved in PhMe (9.6 mL) and treated with TEA (0.94 mL, 6.75 mmol) and diphenylphosphoryl azide (1.04 mL, 4.82 mmol). After 1 h at r.t., the mixture was filtered through a pad of silica washing with PhMe. Diphenylmethane (10 mL) was then added and the PhMe was removed in vacuo. The mixture was then heated to 250° C. for 2 h, cooled to r.t., the solids were removed by filtration, and washed with hexanes to give the title product as a tan solid. LRMS (M+H)+=307.9.
Reaction SMILES: [C:1]12([C:11]([OH:13])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14]1([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C.[Cl:47]CCl>>[ClH:47].[ClH:47].[C:14]1([CH2:20][N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][NH:29][C:11]([C:1]34[CH2:8][CH:7]5[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]5)[CH2:2]3)[CH2:10]4)=[O:13])[CH2:25][CH2:26]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: NCCN1CCN(Cc2ccccc2)CC1
Reactant: ClCCl
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(NCCN1CCN(Cc2ccccc2)CC1)C12CC3CC(CC(C3)C1)C2
Yield: 10 %

Procedure:
To a solution of adamantane-1-carboxylic acid (11.85 g, 0.065 mol) and 2-[4-(phenylmethyl)-1-piperazinyl]ethylamine (12.0 g, 0.054 mol) in dichloromethane (200 mL) at 4° C. was added, with stirring, a solution of diethylcyanophosphonate (11.8 mL, 0.065 mol) in dichloromethane (50 mL), followed by a solution of triethylamine (9.2 mL, 0.065 mol) in dichloromethane (50 mL). The resulting mixture was stirred overnight, during which time it came up to room temperature. The reaction mixture was then washed with 10% aqueous potassium carbonate (200 mL), dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The desired product (TLC on silica gel using 10% methanol/ethyl acetate, Rf=0.33) was isolated by crystallization from hexane and recrystallized from hexane. It was then converted to its dihydrochloride salt with isopropanolic HCl (12.71 g, 52%), mp=259°-260° C.
Reaction SMILES: Cl.[NH2:2][O:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6].[CH:14]1[C:23]2[N:24]3[C:28]([C:29](=O)[C:21]4[C:22]=2[C:17]([CH:18]=[CH:19][N:20]=4)=[CH:16][CH:15]=1)=[CH:27][CH:26]=[CH:25]3>O.C(O)C.N1C=CC=CC=1>[C:5]([CH:4]([O:3][N:2]=[C:29]1[C:21]2[C:22]3[C:17]([CH:18]=[CH:19][N:20]=2)=[CH:16][CH:15]=[CH:14][C:23]=3[N:24]2[C:28]1=[CH:27][CH:26]=[CH:25]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:7])=[O:6]
Reactant: O=c1c2nccc3cccc(c32)n2cccc12
Reactant: NOC(C(=O)O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C(ON=c1c2nccc3cccc(c32)n2cccc12)c1ccccc1
Yield: 70.4 %

Procedure:
A solution of α-aminooxyphenylacetic acid hydrochloride (15.0 g.) in water (6.6 cc.) is added to a stirred boiling solution of 7H-indolizino[5,6,7-ij]isoquinoline-7-one (15.0 g.) in ethanol (450 cc.) and pyridine (583 g.). Boiling is maintained for 2 hours 30 minutes. After cooling, the yellow crystals obtained are filtered off and then washed with 90% ethanol, then with absolute ethanol and finally with diethyl ether. After drying, 7-(α-carboxybenzyloxyimino)-7H-indolizino[5,6,7-ij]isoquinoline (17.7 g.), melting at 200° C. with decomposition, is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10](COCC3C=CC=CC=3)[CH:9]=[C:8]([CH2:20][NH:21][CH2:22][C@H:23]([OH:27])[CH2:24][S:25][CH3:26])[C:4]=2[N:5]=[CH:6][N:7]=1.O.NN>N.CO.[Pd]>[NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH2:20][NH:21][CH2:22][C@H:23]([OH:27])[CH2:24][S:25][CH3:26])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CSC[C@@H](O)CNCc1cn(COCc2ccccc2)c2c(N)ncnc12
Agent: [Pd]
Agent: N
Agent: NN
Solvent: O
Solvent: CO
Product: CSC[C@@H](O)CNCc1c[nH]c2c(N)ncnc12
Reaction time: 0.67 h

Procedure:
The product from Example 2.5 (0.08 g, 0.206 mmol) was dissolved in 7M NH3-MeOH solution (8 ml) and Pd black (80 mg) added followed by hydrazine hydrate (1.2 ml). The mixture was stirred for 40 mins, filtered and the solvent evaporated. The residue was chromatographed on silica gel (CH2Cl2-7M NH3 in MeOH, 85:15) to give(S)-1-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-3-(methylthio)propan-2-ol (0.042 g, 76%) as a colourless solid. [α]D20 −12.4 (c, 0.355, MeOH). 1H NMR (CD3OD), δ 8.16 (s, 1H), 7.48 (s, 1H), 4.00 (d, J=13.5 Hz, 1H), 3.92-3.84 (m, 2H), 2.85 (dd, J=12.2, 3.5 Hz, 1H), 2.65 (dd, J=12.2, 8.5 Hz, 1H), 2.55 (d, J=6.5 Hz, 2H), 2.10 (s, 3H). 13C NMR (CD3OD, referenced to the centre line of CD3OD at 49.0 ppm), δ 152.1, 150.9, 146.6, 129.1, 115.4, 114.2, 70.2, 54.6, 43.5, 40.4, 16.2. +ESMS Found 268.1241 (M+H)+ C11H18N5OS requires 268.1232.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](O)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([Cl:20])[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(Cl)cc2)nc2c1CCC2
Product: Clc1ccc(-c2nc(Cl)c3c(n2)CCC3)cc1
Reaction time: 3 h

Procedure:
8.0 g of 2-(4-chlorophenyl)-4-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine are heated to 100° C in 10 ml of phosphorus oxychloride. After 3 hours, the cooled solution was cautiously poured onto ice water. The crystalline product was filtered off with suction, washed well with water and dried in vacuo at room temperature.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][NH:8][C:9](=[O:11])[CH:10]=1.[H-].[Na+].Br[CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31]>CN(C=O)C>[F:1][C:2]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][N:8]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[C:9](=[O:11])[CH:10]=1
Reactant: CCOC(=O)c1c[nH]c(=O)cc1Nc1ccc(I)cc1F
Reactant: COCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCOCCOC)c(=O)cc1Nc1ccc(I)cc1F

Procedure:
Ethyl 4-(2-fluoro-4-iodoanilino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate was reacted with NaH and 1-bromo-2-(2-methoxyethoxy)ethane in DMF under the same conditions as for example 22, step A to give a crude solid which was purified by column chromatography on silica gel (1% MeOH/CH2Cl2 as eluant). Ethyl 4-(2-fluoro-4-iodoanilino)-1-[2-(2-methoxyethoxy)ethyl]-6-oxo-1,6-dihydro-3-pyridinecarboxylate was isolated as a pale yellow oil (41%). 1H NMR [(CD3)2SO, 400 MHz] δ 9.30 (s, 1H), 8.43 (s, 1H), 7.77 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (ddd, J=8.3, 1.9, 0.8 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H), 5.44 (d, J=1.3 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 4.06 (t, J=5.1 Hz, 2H), 3.61 (t, J=5.2 Hz, 2H), 3.54-3.50 (m, 2H), 3.43-3.39 (m, 2H), 3.22 (s, 3H), 1.32 (t, J=7.1 Hz, 3H). HRMS (EI+) calcd C19H22FIN2O5 (M+) 504.0558, found 504.0552.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:8]=2[CH:7]=[CH:6][C:5]=1[CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:2][CH3:3].CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31].Cl>C(Cl)Cl>[CH3:29][S:30]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]1[CH:6]=[CH:7][C:8]2[C:9]([C:13]([F:15])([F:14])[F:16])=[N:10][O:11][C:12]=2[C:4]=1[CH2:1][CH2:2][CH3:3])(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CCCc1c(CCCCO)ccc2c(C(F)(F)F)noc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(CCCCOS(C)(=O)=O)ccc2c(C(F)(F)F)noc12
Reaction time: 2 h

Procedure:
To a solution of 4-[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]butan-1-ol, from this Example step 4, in CH2Cl2 (25 mL) was added Et3N (0.42 mL, 2.99 mmol) and methanesulfonyl chloride (0.17 mL, 2.2 mmol) at 0° C. The mixture was stirred from 0° C. to room temperature for 2 hours. 0.5N HCl was added and the mixture extracted 3 times with CH2Cl2. Combined organic extracts were washed with water and brine then dried over Na2SO4. The solvent was evaporated in vacuo to give the title compound.
Reaction SMILES: [C:1]([NH:7][C:8]1[C:9]2[N:10]([C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=2)[CH:11]=[CH:12][CH:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([Li])(C)(C)C.[CH:24](=[O:33])[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCCCC.C(OCC)C>[CH3:17][C:15]1[N:16]=[C:9]2[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[C:13]([CH:24]([OH:33])[CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:12]=[CH:11][N:10]2[C:14]=1[CH3:18]
Reactant: O=CC=Cc1ccccc1
Reactant: Cc1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: Cc1nc2c(NC(=O)C(C)(C)C)c(C(O)C=Cc3ccccc3)ccn2c1C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 47.6 %

Procedure:
A vigorously stirred solution of 41 g of 8-pivaloylamino-2,3-dimethylimidazo[1,2-a]pyridine is treated dropwise at −78° C. under argon protective gas with 320 ml of a commercially available, 1.5 molar solution of t-butyllithium in n-pentane such that the temperature does not exceed −70° C. After stirring at −78° C. for a further 15 min, a solution of 61 g of cinnamaldehyde in 50 ml of dry diethyl ether is added dropwise (internal temperature <−68° C.). The mixture is then allowed to warm to room temperature, and is poured cautiously onto ice water and extracted three times with a total of 500 ml of ethyl acetate, the reddish-colored, organic phase is washed with distilled water and dried over sodium sulfate, and the solvent is stripped off in vacuo. The residual, yellowish suspension is treated with diethyl ether. The crystals obtained are filtered off with suction. 30 g of 2,3-dimethyl-7-(3-phenyl-1-hydroxy-2-propenyl)-8-pivaloylaminoimidazo[1,2-a]pyridine of melting point 194-5° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C([Li])(CC)C.CN([CH:27]=[O:28])C>C1COCC1>[CH:27]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[C:4]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:28]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(F)(F)F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c(C=O)cccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a solution of tert-butyl 2-(trifluoromethyl)phenylcarbamate (1.0 g, 3.83 mmol) and N,N,N′N′-tetramethylethylenediamine (1.27 mL, 8.43 mmol) in 20 mL of anhydrous THF at −78° C. was added sec-butyllithium (8.43 mL of a 1.0 M solution in hexanes, 8.43 mmol) dropwise over 15 min. The reaction was stirred at −78° C. for 1 h and then there was added DMF (0.33 mL, 4.21 mmol). The reaction was stirred at −78° C. for 1 h and then was quenched with sat'd aq NH4Cl (10 mL) and allowed to warm to ambient temperature. The reaction mixture was diluted with water and extracted with EtOAc. The organics were washed with 1N HCl and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 6:1 hexane/EtOAc) to afford 0.4 g (36%) of the title compound. 1H NMR (CDCl3): δ 10.06 (s, 1H), 8.07 (d, 1H, J=7.7 Hz), 7.83 (d, 1H, J=7.8 Hz), 7.43 (t, 1H, J=7.8 Hz), 6.83 (broad s, 1H), 1.47 (s, 9H). LRMS (ESI): 290.15 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:33]/[C:34](=[N:37]/[H])/[NH:35]O.[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:35]=[C:34]([CH2:33][C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=3[Cl:25])[N:37]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: [H]/N=C(/Cc1cccc(Cl)c1Cl)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(Cc3cccc(Cl)c3Cl)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 54.8 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol) and (1Z)-2-(2,3-dichlorophenyl)-N-hydroxyethanimidamide (36 mg, 0.165 mmol; Entry 3, Table 7) and 21% ethanolic sodium ethoxide (0.083 ml, 0.22 mmol) were heated together in EtOH (0.75 ml) in the microwave reactor at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl, the organic phase separated, evaporated and the product purified by MDAP to give the title compound as a solid (42.1 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].[CH3:24][C:25]1[C:26]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:8]=1[C:9]([N:38]1[CH2:39][CH2:40][N:35]([C:26]2[C:25]([CH3:24])=[CH:30][C:29]([C:31]([F:34])([F:32])[F:33])=[CH:28][N:27]=2)[CH2:36][CH2:37]1)=[O:10]
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1N1CCCS1(=O)=O
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2N2CCCS2(=O)=O)CC1
Yield: 52.8 %

Procedure:
Using 2,4-bis(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (200 mg) described in Preparation Example 34 and 1-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine (136 mg) described in Preparation Example 84 and by the reaction and treatment in the same manner as in Example 87, the title compound (172 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]([C:21]4[CH:35]=[CH:34][C:24]([CH2:25][N:26](C)[C:27](=O)C(F)(F)F)=[CH:23][CH:22]=4)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CO.O1CCCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]([C:21]4[CH:22]=[CH:23][C:24]([CH2:25][NH:26][CH3:27])=[CH:34][CH:35]=4)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(Cc1ccc(C(=O)Cn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1)C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CNCc1ccc(C(=O)Cn2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 19.8 %

Procedure:
A mixture of the compound (0.49 g) obtained in Example 12, potassium carbonate (0.39 g), water (4 ml), methanol (8 ml) and tetrahydrofuran (8 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (79 mg) as a colorless powder.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.C(O)C.[C:14]([OH:18])(=[O:17])[CH:15]=O>O>[C:3]1([CH3:2])[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][N:10]=[CH:15][C:14]([OH:18])=[O:17])[CH:4]=1
Reactant: O=CC(=O)O
Reactant: Cc1cccc(NN)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cccc(NN=CC(=O)O)c1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 68.5 %

Procedure:
3-Methylphenylhydrazine hydrochloride (15.9 g, 100 mmol) was dissolved in water (450 mL) and ethanol (600 mL) with heating at 60° C. A solution of glyoxylic acid (9.21 g, 100 mmol) in water (100 mL) was added to the warm solution using water (3×15 mL) to rinse. The reaction mixture was stirred at 60° C. for 45 minutes and then cooled slightly and concentrated to remove ethanol. The aqueous mixture was neutralized with NaOH and then water was added (800 mL). The precipitate was filtered, washed with water (3×100 mL), washed with hexanes (100 mL) and dried to give the subtitle compound as a brown solid (12.2 g, 69%).