Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl.[NH2:17]O.O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C1CC1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: Brc1ccc(-c2cc(C3CC3)on2)cc1
Yield: 40.5 %

Procedure:
To a solution of 1-(4-bromophenyl)-3-cyclopropyl-1,3-propanedione (2.60 g, 9.73 mmol) in anhydrous MeOH (80 ml) was added hydroxylamine hydrochloride (2.71 g, 39.00 mmol). The mixture was heated to reflux for 14 h. Upon cooling, the solution was poured into water, and extracted with CH2Cl2 (3×200 ml). The combined organic phases were dried with MgSO4 and concentrated in vacuo. The regioisomers were separated by flash chromatography (CH2Cl2/hexanes, 10:90 to 40:60) to yield the title compound as a white solid (1.04 g, 40%).
Reaction SMILES: C[O:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br.N>C(Cl)Cl.CO>[OH:2][C:3]1[C:16]2[O:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:17])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(=O)c3ccccc3oc12
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=c1c2ccccc2oc2c(O)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a solution of 4-methoxy-xanthen-9-one (12 g, 53 mmol) in methylene chloride (100 mL) at 0° C. was added a 1M solution of boron tribromide in methylene chloride (160 mL, 160 mmol) and the mixture was stirred at rt for 2 h. The reaction was slowly poured into a solution of ammonia in methanol (2M). The reaction was concentrated under reduced pressure and the resulting residue was partitioned between 1N HCl and methylene chloride. The organic phase was separated, dried over MgSO4, filtered, and evaporated to afford 7.5 g of Compound 3a, without further purification. MS m/z (M-H)− 243.1.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[CH2:38]([N:42]([CH3:47])[C:43](=O)[CH2:44]Cl)[CH2:39][CH2:40][CH3:41]>>[CH2:38]([N:42]([CH3:47])[CH2:43][CH2:44][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCCCN(C)C(=O)CCl
Product: CCCCN(C)CCOc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 53.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and N-butyl-2-chloro-N-methylacetamide (9.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.1 mg) was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>COCCOC>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: COCCOC
Product: CC(=O)Nc1ccc(S(=O)(=O)NC(C)(C)C)cc1
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a suspension of 4-acetylaminobenzenesulfonyl chloride (10 g, 43 mmol) in DME (103 mL) is added, at 0° C., tert-butylamine (9 mL, 86 mmol) in DME (103 mL). Next, the reaction mixture is stirred for 4 h at reflux. The solvent is removed and CHCl3 is added. The resulting suspension is filtered and the solid is washed with CHCl3, H2O and Et2O. The solid obtained is dried in vacuo to give 8.0 g of the product as a white solid (yield: 68%).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:5][C:4](=[O:14])[CH:3]=1.[C:15](O)(=[O:18])[CH:16]=[CH2:17]>C(Cl)(Cl)Cl>[CH2:8]([CH:6]1[CH2:7][C:2]2[NH:1][C:15](=[O:18])[CH2:16][CH2:17][C:3]=2[C:4](=[O:14])[CH2:5]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC1CC(=O)C=C(N)C1
Reactant: C=CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCC1CC(=O)C2=C(C1)NC(=O)CC2
Temperature: 140 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
The obtained 3-amino-5-n-hexyl-2-cyclohexene-1-one (16.8 g) and acrylic acid (12.4 g) were mixed, and the mixture was stirred at 140° C. for 2 hours. After completion of the reaction, chloroform was added, and the mixture was washed with sodium bicarbonate water, water and aqueous NaCl solution in this order, followed by drying over sodium sulfate. A crude product was obtained when the solvent was evaporated. The crude was purified by silica gel column chromatography (eluent=chloroform:methanol (50:1)). as a result, 11.2 g of 7-n-hexyl-1,2,3,4,5,6,7,8-octahydroquinoline-2,5-dione was obtained as colorless needles having a melting point of 142°-144° C. (52.0%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>C(#N)C>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([NH:5][C:6]2[CH:19]=[CH:18][C:9]3[O:10][C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:8]=3[CH:7]=2)=[O:4])[CH2:23][CH2:22]1
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN1CCN(CC(=O)Nc2ccc3oc4c(c3c2)CCCCC4)CC1
Yield: 25.4 %

Procedure:
Following the procedure of Example 40, 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), N-methylpiperazine (0.062 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) provided 2-(4-methylpiperazin-1-yl)-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.039 g) as its trifluroacetic acid salt after reverse-phase HPLC purification. MS (ESI) m/z 342 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[Na].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.[I-].[K+]>CN(C)C=O>[NH2:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[N:8][N:7]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[CH:6]=2
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc3cc(C)c(N)c(C(=O)O)c3n2)cc1
Reaction time: 18 h

Procedure:
To a suspension of 6-amino-5-methyl-1H-indazole-7-carboxylic acid (0.956 g, 5 mmol) in dimethylformamide (4 ml) was added sodium hydrogenocarbonate (0.462 g, 5.5 mmol) and the resulting mixture was stirred at 40° C. for 15 minutes before 4-methoxybenzyl chloride (0.861 g, 5.5 mmol) was introduced. A catalytic amount of potassium iodide was added and the mixture was stirred for 18 hours at that temperature. After cooling down, the crude mixture was placed on top of a silica gel column and the product was purified by flash chromatography using a gradient starting from 50% ethyl acetate-50% cyclohexane to 100% ethyl acetate, then 1% acetic acid in ethyl acetate. The fractions containing the desired compound were evaporated and the residue was triturated with diethyl ether and filtered to yield light orange crystals.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([B:24]2[O:32][C:29]([CH3:31])([CH3:30])[C:26]([CH3:28])([CH3:27])[O:25]2)=[CH:20][CH:19]=1>C(#N)C>[CH3:1][C:2]1[O:8][CH:7]=[CH:6][C:4](=[O:5])[C:3]=1[O:9][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([B:24]2[O:25][C:26]([CH3:28])([CH3:27])[C:29]([CH3:31])([CH3:30])[O:32]2)=[CH:22][CH:23]=1
Reactant: Cc1occc(=O)c1O
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1occc(=O)c1OCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
Maltol (0.50 g, 3.96 mmol) was dissolved in 25 mL of acetonitrile followed by the addition of 1.6 g (11.88 mmol) of K2CO3. The reaction was heated to reflux for 10 min before adding 4-bromomethylphenyl boronic acid pinacol ester (1.3 g, 4.4 mmol). The reaction was left stirring under refluxing conditions for 12 h then cooled to room temperature and filtered rinsing with DCM. The resulting filtrate was concentrated and purified via silica gel chromatography eluting with 0-2% MeOH in DCM. B20 (1.03 g, 3.0 mmol) was collected and dried yielding a pale yellow solid in 76% yield. 1H NMR (400 MHz, CDCl3) δ=7.77 (d, J=7.6 Hz, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.37 (d, J=7.6 Hz, 2H), 6.35 (d, J=5.6 Hz, 1H), 5.19 (s, 2H), 2.06 (s, 3H), 1.34 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=175.3, 160.0, 153.6, 143.9, 140.0, 135.1, 128.5, 117.4, 84.1, 73.6, 25.1, 15.2. ESI-MS(+): m/z 343.18 [M+H]+. Anal. calcd. for C19H23BO5: C, 66.69; H, 6.77. Found: C, 66.34; H, 6.67.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([C:34]([F:37])([F:36])[F:35])=[N:15][N:16]([C:17]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:18]=4[C:19]([NH:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)=[O:20])[C:10]=3[C:9]2=[O:38])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:17]([N:16]2[C:10]3[C:9](=[O:38])[N:8]([C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)[CH2:13][CH2:12][C:11]=3[C:14]([C:34]([F:36])([F:35])[F:37])=[N:15]2)=[C:18]([CH:28]=1)[C:19]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:20]
Reactant: [H][H]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c(C(=O)Nc2cccnc2)c1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccccc2)CC3)c(C(=O)Nc2cccnc2)c1
Yield: 94.2 %

Procedure:
2-[6-(4-Iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-N-pyridin-3-yl-benzamide (15 mg, 0.023 mmol) was combined with 5% palladium on carbon and stirred in ethanol under 1 atmosphere of hydrogen for 12 h. The reaction mixture was filtered through diatomaceous earth and the solvent evaporated to give the title compound (11 mg, 95%) as a colorless solid. MS (ES+) 508.0 (M+H)+(100%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[C:10]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([NH:14][C:15]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-[5-(oxane-4-carbonylamino)-6-(2-phenylethynyl)pyridin-2-yl]-carbamate C5b (29 mg, 0.07 mmol) and DCM:TFA (9:1, 3 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19](O)=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:13]([O:12][C:10]([N:17]1[CH2:24][CH2:23][CH2:22][CH:18]1[C:19](=[O:20])[NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NCc1ccc(Br)cc1
Reaction time: 0.75 h
Yield: 94.4 %

Procedure:
To a mixture of 4-Bromo-benzylamine (2.00 g), Boc-L-proline (2.01 g), and 4-methylmorpholine (3.26 mL) in DMF (40 mL) was added HATU (3.48 g). Reaction mixture was stirred for 45 minutes, then concentrated, diluted with dichloromethane and washed with 10:1 H2O/saturated sodium bicarbonate solution. The aqueous layer was back-extracted with dichloromethane and the combined organic layers were dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 50 to 100% ethyl acetate/hexanes) to give 2-(4-Bromo-benzylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.38 g): LCMS-ESI+: calc'd for C17H24BrN2NaO3: 405.29 (M+Na+). Found: 405.0 (M+Na+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:7][CH2:6][C:5]=2[N:4]=1.[F:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][CH:25]=1)[O:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[N:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COc1ccc(CN2CCc3nc(CO)ccc3C2=O)cc1
Reactant: Oc1cccc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3nc(COc4cccc(F)c4)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
2-(Hydroxymethyl)-6-(4-methoxybenzyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (270 mg, 0.9 mmol) from above and 3 equiv of 3-fluorophenol was dissolved in THF (10 mL). To this mixture was added polystyrene bound-PPh3 (3 equiv) and diisopropylazodicarboxylate (3 equiv) in THF (2 mL) dropwise. The mixture was allowed to warm to RT and stirred for 6 h. The residue was loaded directly onto a silica and eluted with EtOAc/hexanes to give the compound (310 mg, 88%). LC-MS (M+H)=393.2.
Reaction SMILES: [I:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14](OCC)=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[NH3:21]>>[I:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:21])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Reactant: N
Product: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2
Temperature: 130 °C
Yield: 36 %

Procedure:
A suspension of ethyl 9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (300 mg, 0.78 mmol) in 7 M ammonia solution (in methanol, 3 ml) was heated in a microwave apparatus to 130° C. for 70 minutes. After cooling the volatiles were removed in vacuo and the residue was purified by FCC (silica, 20-100% ethyl acetate in heptane) to give 99 mg (36%) of the title compound as an off-white solid. 1H NMR (DMSO, 500 MHz) δ 3.17 (2H, t, J=5.8 Hz), 4.47 (2H, t, J=5.9 Hz), 6.71 (1H, s), 7.03 (1H, d, J=8.5 Hz), 7.36 (1H, s), 7.66 (1H, dd, J=8.5, 2.2 Hz), 7.81 (1H, s), 8.29 (1H, d, J=2.2 Hz); M+1=356
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[N:15]2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[N+:19]([C:17]1[CH:16]=[N:15][N:14]([CH:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)[CH:18]=1)([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc([N+](=O)[O-])cn2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnn(C2CCNC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.5 %

Procedure:
A solution of HCl (4N in dioxane, 50 mL, 150 mmol, 3.4 eq.) was added to a solution of tert-butyl-3-(4-nitro-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (prepared as described in Tetrahedron Lett. (2008), 49(18), 2996-2998, 13 g, 46 mmol, 1 eq.) in dry dioxane (75 mL) at 000° C. The reaction mixture was then stirred at RT for 5 h. It was concentrated under reduced pressure to give the title compound as an off-white solid (9.5 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ 9.73 (brs, 1H), 9.46 (brs, 1H), 9.07 (s, 1H), 8.37 (s, 1H), 5.24 (m, 1H), 3.50-3.72 (m, 3H), 2.28-2.49 (m, 3H).
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[N:9]1([CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])[CH:13]=[CH:12][N:11]=[CH:10]1.C(N(CC)CC)C>ClCCl>[CH2:1]([S:5]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]([NH:17][CH2:16][CH2:15][CH2:14][N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)([CH3:20])[CH3:19])=[CH:22][CH:23]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCS(=O)(=O)Oc1ccc(C(C)(C)NCCCn2ccnc2)cc1

Procedure:
In a similar manner to Example 71, a solution of butanesulphonyl chloride (0.45 g) in dichloromethane (5 ml) was added in portions over 5 minutes to a solution of 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenol (0.75 g) and triethylamine (0.29 g) in dicloloromethane (5 ml) at 0° C. with stirring, to give 4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl 1-butanesulphonate as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([CH2:10][OH:11])=[CH:4][N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:12](=[O:14])[CH3:13])[C:5]([CH2:10][OH:11])=[CH:4][N:3]=1
Reactant: Cc1cc(CO)c(CO)cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1cc(C)ncc1CO

Procedure:
2-Methyl-4,5-di(hydroxymethyl)pyridine (0.1 mole) is stirred in pyridine (50 ml.) with acetic anhydride (0.1 mole) at room temperature overnight. The pyridine is evaporated and the residue is dissolved in 10 ml. water and extracted with 2 × 30 ml. of chloroform. After drying over magnesium sulfate, the chloroform is evaporated and the residue is chromatographed on a silica gel column using benzene-ethanol as eluate. By this procedure is obtained:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][CH:7]1[C:12]2[C:13](=[O:21])[N:14](Cl)[CH:15]=[C:16]([S:18][CH3:19])[O:17][C:11]=2[NH:10][CH2:9][NH:8]1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][CH:7]1[C:12]2[C:13](=[O:21])[N:14]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH3:31])[CH:15]=[C:16]([S:18][CH3:19])[O:17][C:11]=2[NH:10][CH2:9][NH:8]1
Reactant: Cc1ccccc1B(O)O
Reactant: CSC1=CN(Cl)C(=O)C2=C(NCNC2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)O1
Product: CSC1=CN(c2ccccc2C)C(=O)C2=C(NCNC2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)O1
Yield: 80.8 %

Procedure:
In a similar manner to Reference Example 11, 4-[3,5-bis(trifluoromethyl)benzyl]-6-chloro-8-(methylthio)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine (Compound of Reference Example 10; 2.36 g) was reacted with 2-methylphenylboronic acid (816 mg) to obtain 4-[3,5-bis(trifluoromethyl)benzyl]-6-(2-methylphenyl)-8-(methylthio)-5-oxo-2,3,4,5-tetrahydropyrimido[5,4-f][1,4]oxazepine (2.13 g, 81%).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][C:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:3]=1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.[C:26](=[O:28])=[O:27].Cl>>[CH:20]1([C:3]2[CH:4]=[C:5]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:6]=[C:7]([CH:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)[C:2]=2[C:26]([OH:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Brc1c(C2CCCCC2)cc(C2CCCCC2)cc1C1CCCCC1
Reactant: O=C=O
Agent: Cl
Product: O=C(O)c1c(C2CCCCC2)cc(C2CCCCC2)cc1C1CCCCC1
Yield: 80 %

Procedure:
A Grignard reagent was prepared from 28.4 g of 2-bromo-1,3,5-tricyclohexylbenzene (prepared in Synthesis Example 1-4) and poured to 300 g of dry ice, whereupon dry ice sublimated. Hydrochloric acid was added to the reaction mixture for quenching, followed by extraction with 200 g of isopropyl ether. The organic layer was taken out, washed with water, and combined with 150 g of 10 wt % sodium hydroxide aqueous solution. The aqueous layer was taken out, combined with 100 g of 35 wt % hydrochloric acid, and extracted with 200 g of diisopropyl ether. The organic layer was washed with water again, and concentrated under reduced pressure. The concentrate was crystallized from 150 g of hexane. The crystal precipitate was filtered and dried, obtaining the target compound, 2,4,6-tricyclohexylbenzoic acid. Amount 39.7 g, yield 80%.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]([P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[CH:10]=[C:11]([CH3:13])[CH3:12]>CCOCC>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][P:14]([O:15][CH3:16])(=[O:19])[O:17][CH3:18]
Reactant: Oc1cccc(O)c1
Reactant: COP(=O)(CC=C(C)C)OC
Solvent: CCOCC
Product: COP(=O)(CCC(C)(C)c1ccc(O)cc1O)OC

Procedure:
55.0 Parts of resorcinol, 17.8 parts of dimethyl prenylphosphonate and 5.0 parts of Fulmont 237® were stirred at 125° C. for 18 hours. The cooled reaction mixture was then diluted with ether, filtered free of catalyst, and poured into 500 parts of water. The oil which separated out was then washed by decantation with water and extracted with ether. Following further washes with sodium bicarbonate solution and water, the ether solution after concentration yielded dimethyl 3-(2',4'-dihydroxyphenyl)-3-methyl-butane-phosphonate, m.p. 142°-3° C., with the following percentage composition by weight.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=[O:7])=[CH:4][CH:3]=1.O.[NH2:14][NH2:15]>CCOCC>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:14][NH2:15])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: NN
Solvent: O
Solvent: CCOCC
Product: NNC(=O)c1ccc(F)cc1

Procedure:
The p-fluorobenzoic acid hydrazide is prepared as follows. Ethyl p-fluorobenzoate (8.4 g) is refluxed with hydrazine hydrate (3.75 g) for 3 hours. The mixture is then cooled, ether is added and the precipitate of p-fluorobenzoic acid hydrazide (3.2 g) is removed by filtration, washed with ether and desiccated, m.p. 149°-151° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3C[CH2:12]3)[CH:10]=[C:6]2[CH:5]=[C:4]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[N:3]=1.[C:27]([N:30]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>CN1C(=O)CCC1>[C:27]([N:30]1[CH2:36][CH2:35][CH2:34][N:33]([C:6]2[N:7]3[N:8]=[C:9]([CH2:11][CH3:12])[CH:10]=[C:2]3[N:3]=[C:4]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[CH:5]=2)[CH2:32][CH2:31]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCCNCC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc3cc(C4CC4)nn3c(Cl)n2)cc1
Solvent: CN1CCCC1=O
Product: CCc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCCN(C(C)=O)CC3)n2n1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
In a 2 mL microwave vial was placed N-(7-chloro-2-cyclopropylpyrazolo[1,5-c]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2H, 75 mg, 0.21 mmol) and N-acetylhomopiperazine (59 mg, 0.42 mmol). To the sealed vial was then added NMP (2 ml) and the mixture was then heated in the microwave at 120° C. for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between brine and EtOAc. The aqueous layer was extracted once more with EtOAc, and the combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by recrystallization from ether and EtOAc to give the titled compound (50 mg, 51% yield) as an off-white solid. ESI-MS: m/z 465 (M+H)+.