Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:17]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:1][C:2]2[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=2[CH3:16])[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 23 °C
Reaction time: 20 h
Yield: 99 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (6.00 g, 25.7 mmol) in CH2Cl2 (120 mL) and AcOH (6 mL) was added N-Boc piperidinone (6.70 g, 33.4 mmol) and sodium triacetoxyborohydride (13.6 g, 64.3 mmol). The reaction mixture was stirred at 23° C. for 20 hours. Then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×50 mL) and the combined organic layer were concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2 heptane/EtOAc=4/1) to give the titled compound (10.6 g, 98% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.37 (s, 1H), 6.88 (s, 1H), 4.05 (m, 2H), 3.90 (s, 3H), 3.01 (m, 3H), 2.32 (s, 3H), 1.71 (m, 2H), 1.48-1.61 (m, 2H), 1.45 (s, 9H); MS (ES) [M−H] 415.1.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl.[Al+3].[Cl-].[Cl-].[Cl-]>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:1](=[O:4])[CH2:2][CH3:3])=[CH:10][CH:9]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A procedure similar to step 2 of Example 47 was used. Propionyl chloride prepared in the step 1 and methylphenyl ether were used as starting materials, allowed to react in dichloromethane with AlCl3 as catalyst, stirred at −5° C. to −10° C. for 30 minutes and then at room temperature for 1 hour, a crude product was obtained, purified under a reduced pressure by silica gel column chromatography eluted with petroleum ether and ethyl acetate at a ratio of 25:1 (V:V) to obtain a product of colorless liquid in a yield of 71.8%, 1H-NMR (CDCl3, 400 MHz) δ: 1.22 (3H, t, J=7.00 Hz, CH2CH3), 2.96 (2H, q, J=7.00 Hz, CH2CH3), 3.87 (3H, s, OCH3), 6.93 (2H, d, J=8.72 Hz, ArH), 7.95 (2H, d, J=8.72 Hz, ArH); ESI-MS: 187.2 (M+Na, 20), 165.2 (M+1, 100).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[C:23](OCC)(=O)[CH3:24]>[Pd]>[CH2:23]([O:19][C:17](=[O:18])[C@@H:16]([O:20][CH2:21][CH3:22])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1)[CH3:24]
Reactant: CCOC(C)=O
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: [Pd]
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Yield: 76 %

Procedure:
3-(4-Benzyloxyphenyl)-2-(S)-ethoxypropanoic acid (7.13 g; 21.7 mmole) was hydrogenated at atmospheric pressure for 2 hours in ethyl acetate (70 ml) using Pd/C as catalyst. Purification by chromatography on silica gel using toluene:ethyl acetate as eluant gave 3.83 g (yield in 3 step 76%) of (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1>O1CCCC1.CO.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1cncnc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N)cc1-c1cncnc1
Yield: 99.7 %

Procedure:
A suspension of 5-(2-methyl-5-nitrophenyl)pyrimidine (0.431 g) in tetrahydrofuran (4 ml) and methanol (4 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 129 mg) under hydrogen atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 5-(5-amino-2-methylphenyl)pyrimidine (370 mg, 99.7%).
Reaction SMILES: [CH:1]1([C:6]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:18]([O-])([OH:20])=[O:19]>>[CH:1]1([C:6]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])O
Reactant: O=C(C1CCCC1)C1(c2ccc(Cl)cc2)CC1
Product: O=C(C1CCCC1)C1(c2ccc(Cl)c([N+](=O)[O-])c2)CC1

Procedure:
Prepared analogously to Example 1a from 4-[1-(cyclopentylcarbonyl)cyclopropyl]-chlorobenzene and fuming nitric acid.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][OH:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].O=[C:27]1[CH:31]=[N:30][S:29][NH:28]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:25][C:27]1[CH:31]=[N:30][S:29][N:28]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=c1cns[nH]1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cnsn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
Diisopropyl azodicarboxylate (1.1 ml, 5.5 mmol) was added dropwise to a solution of 2-(t-butoxycarbonylamino)ethanol (850 μl, 5.5 mmol), 3-oxo-2,3-dihydro-1,2,5-thiadiazole (Method 75; 510 mg, 5 mmol) and triphenylphosphine (1.44 g, 5.5 mmol) in THF (20 ml) and the mixture was stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel eluting with iso-hexane: EtOAc (100:0 increasing in polarity to 4:1) to give the title compound (1.17 g, 95%) as a white solid. NMR 1.38 (s, 9H), 3.31 (m, 2H), 4.16 (t, 2H), 6.96 (m, 1H), 8.35 (s, 1H); m/z 246.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].Cl[C:24]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:25]=1[C:26](OC)=[O:27].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:34]([C:31]1[CH:30]=[C:25]2[C:24](=[CH:33][CH:32]=1)[N:6]1[N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)[C:3]([C:20]([NH2:22])=[O:21])=[C:2]1[NH:1][C:26]2=[O:27])([O-:36])=[O:35]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1[nH]c(=O)c1cc([N+](=O)[O-])ccc12
Temperature: 80 °C
Yield: 25.7 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (220 mg, 0.75 mmol), methyl 2-chloro-5-nitrobenzoate (160 mg, 0.75 mmol) and K2CO3 (155 mg, 1.13 mmol) in DMF (10 mL) was heated to 80° C. for 16 hr under N2. The reaction was poured into water (30 ml), and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated under reduced pressure to a residue, which was purified by a silica gel column eluting with 10% to 50% EA in PE to afford 85 mg (27.3%) of 7-nitro-5-oxo-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide as a yellow solid. MS (ESI, m/e) [M+1]+ 442.1.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:42][NH:43][C@@H:44]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:45][N:46]1[CH2:49][CH:48]([OH:50])[CH2:47]1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([N:43]([C@@H:44]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:45][N:46]2[CH2:47][CH:48]([OH:50])[CH2:49]2)[CH3:42])=[O:17])=[CH:18][CH:19]=1
Reactant: CCCC[C@@H](CN1CC(O)C1)NC
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@@H](CN1CC(O)C1)N(C)C(=O)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 29.6 %

Procedure:
DIPEA (0.275 mL, 1.58 mmol) was added to a stirred suspension of 4-chlorobenzoic acid (0.082 g, 0.53 mmol) and TBTU (0.169 g, 0.53 mmol) in DCM (1 mL) at rt. The suspension was stirred for 5 min. A solution of (S)-1-(2-(methylamino)hexyl)azetidin-3-ol (Compound G2.2) (0.11 g, 0.53 mmol) in DCM (1 mL) was added and the reaction was stirred at rt overnight. The reaction mixture was washed with an 8% aq. sol. of NaHCO3 (2 mL). The organic layer was dried through a phase separator and the solvent was removed in vacuo. Purification by preparative HPLC afforded the title compound (51 mg, 30%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.75-0.80, 0.82-0.87, 0.91-0.99, 1.02-1.46, 2.31-2.39, 2.44-2.62, 2.65-2.73, 3.16-3.53, 3.99-4.17, 4.36-4.48, 5.23, 7.30-7.33, 7.35-7.39, 7.45-7.49. Total number of protons in spectrum: 25. HRMS (M+H)+: calculated 325.1683. found 325.169
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][CH:23]=[C:24]([CH:26]=O)[N:25]=2)=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[O:22][CH:23]=[C:24]([CH2:26][N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[N:25]=2)=[CH:19][CH:20]=1
Reactant: O=Cc1coc(-c2ccc(F)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2coc(-c3ccc(F)cc3)n2)CC1
Yield: 42 %

Procedure:
This compound was synthesized from tert-butyl piperazine-1-carboxylate and 2-(4-fluorophenyl)oxazole-4-carbaldehyde as described for example 82 step 3 (240 mg, yield 42%). 1H NMR (400 MHz, CDCl3) δ 8.07-8.03 (dd, J=9.1 Hz, 5.3 Hz, 2H), 7.59 (s, 1H), 7.16-7.12 (t, J=8.8 Hz, 2H), 3.54 (s, 2H), 3.49-3.47 (m, 4H), 2.52-2.49 (m, 4H), 1.46 (s, 9H). MS (ESI) m/z: Calculated for C19H24FN3O3: 361.18. found: 362.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[N:11]=[C:10]2[O:23][CH3:24])=[C:4]([F:25])[CH:3]=1.[CH2:26](Br)[CH:27]=[CH2:28].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:28]([O:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:25])=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:21])([F:22])[C:17]([F:20])([F:18])[F:19])[N:11]=[C:10]2[O:23][CH3:24])[CH:6]=1)[CH:27]=[CH2:26]
Reactant: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOc1cc(-n2c(OC)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone and allyl bromide with sodium carbonate in acetone there is obtained 1-(5-allyloxy-4-chloro-2-fluorophenyl)-2-methoxy-4-pentafluoroethyl-6(1H)-pyrimidinone, m.p. 82°-83° C.;
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4]1.[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:3]3[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4]3)(=[O:31])=[O:32])=[CH:29][C:16]=2[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.5 %

Procedure:
NaH (0.49 mg, 60%, 12.4 mmol) was a solution of 1H-Pyrrole-3-carbaldehyde (0.21 mg, 2.47 mmol) in THF (30 mL) at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour at room temperature and cooled down to 0° C. again. 2-tert-Butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.1 g, 20.97 mmol) was added slowly, allowed the reaction to warm to room temperature and stirred for 1 hour. The reaction mixture was quenched with NaHCO3 (5 mL), diluted with EtOAc (100 mL), washed with brine (2×15 mL) and dried over Na2SO4. The crude product was purified by MPLC on silica gel using Hexane/EtOAc (1:1) to give 0.44 g (34%) of a white solid as the title compound. 1H NMR (400 MHz, CHLOROFORM-D) δ 1.45-1.55 (m, 4 H), 1.56 (s, 9 H), 2.16-2.31 (m, 1 H), 3.25-3.35 (m, 2 H), 3.94-4.02 (m, 2 H), 4.22 (d, J=7.42 Hz, 2 H), 6.67 (dd, J=3.42, 1.66 Hz, 1 H), 7.18-7.22 (m, 1 H), 7.44 (d, J=8.79 Hz, 1 H), 7.76-7.82 (m, 2 H) 8.36 (d, J=1.76 Hz, 1 H) 9.79 (s, 1 H); MS (ESI) (M+H)+=430.00.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:12]1([O:18][CH2:19][CH:20]=[CH2:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:18]([CH2:19][CH:20]=[CH:21][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CCOc1ccccc1
Reactant: COC(=O)c1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1C=CCOc1ccccc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 14.6 %

Procedure:
To a solution of methyl 2-bromobenzoate (0.206 g, 0.96 mmol) in acetonitrile (3 ml) were added allyl phenyl ether (0.65 ml, 1.09 mmol), tri-o-tolylphosphine (0.014 g, 0.045 mmol), palladium acetate (0.006 g, 0.027 mmol) and triethylamine (0.16 ml, 1.15 mmol), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was filtered through celite, and ethyl acetate was added to the filtrate. The mixture was washed with water, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give methyl 2-(3-phenoxypropenyl)benzoate (0.037 g, 0.14 mmol, yield 15%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:14][C:15]([OH:17])=[O:16].Cl>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
4-nitro-phenol (5.0 g, 36 mmol) was added to a stirred suspension of sodium hydride (3.13 g; 55% in mineral oil; 71.9 mmol) in dry tetrahydrofuran (100 mL) and stirred for 30 min at ambient temperature. Bromoacetic acid (6.0 g, 43.2 mmol) was added and the mixture then heated at reflux overnight. The reaction mixture was cooled to ambient temperature, neutralised with dilute hydrochloric acid and extracted with ethyl acetate. The separated organic layer was extracted with sodium bicarbonate solution and the aqueous solution was acidified with concentrated HCl to pH ˜3 to afford a white precipitate, which was filtered and dried under vacuum to give (4-nitro-phenoxy)-acetic acid (3.5 g, 45%).
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].OS(O)(=O)=O.[Br:12][C:13]1[S:17][C:16]([C:18]([OH:20])=[O:19])=[CH:15][CH:14]=1.[C:21](O)([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[C:21]([O:19][C:18]([C:16]1[S:17][C:13]([Br:12])=[CH:14][CH:15]=1)=[O:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1ccc(Br)s1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Br)s1
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a mixture of anhydrous MgSO4 (11.60 g, 96.4 mmol) in 100 mL CH2Cl2 was added concentrated H2SO4 (1.45 mL, 24.1 mmol) and the mixture was stirred for 15 minutes followed by addition of 5-bromo-thiophene-2-carboxylic acid (5.0 g, 24.1 mmol). After stirring for 1 minute, tert-butanol (11.6 g, 20 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was quenched with saturated NaHCO3. The layers were separated, the aqueous layer was extracted with CH2Cl2, and the combined organic layers were dried over MgSO4. The organic solution was concentrated to give a clear oil which was purified via medium pressure chromatography (3% EtOAc in hexanes) to afford the title compound (4.97 g). 1H NMR (400 MHz, CDCl3) δ 7.45 (d, 1H), 7.02 (d, 1H), 1.54 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C(N(C(C)C)C(C)C)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:8]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)[NH:25][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of C-(3-chloropyrazin-2-yl)-C-(2-phenylquinolin-7-yl)-methylamine (231.4 mg, 0.6672 mmol), DMAP (4 mg, 0.033 mmol), and (iPr)2EtN (174 μL, 129 mg, 1 mmol) in dry CH2Cl2 (5 mL), cooled to 0° C., pivaloyl chloride (90 μL, 89 mg, 0.734 mmol) was added under N2 atmosphere, the cooling bath was removed, and the reaction mixture was allowed to stir at ambient temperature for 16 h. The reaction was quenched with H2O and extracted with CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with (1×30 mL each) 0.25M citric acid (pH 2-3), H2O, NaHCO3 sat. aq. sol., and brine, dried over anhydrous MgSO4, and filtered. Sample was purified by filtration through a plug of silica gel, eluting with EtOAc:CH2Cl2 10:1→5:1 (300 mL). Filtrate was concentrated in vacuo, yielding the title compound, as a yellow solid, containing approximately 10% of bis-acetylated material; 1H NMR (CDCl3, 400 MHz) δ 1.23 (s, 9H), 6.75 (d, J=7.6 Hz, 1H), 7.43-7.48 (m, 1H), 7.49-7.55 (m, 2H), 7.60 (d, br, J=7.6 Hz, —NH), 7.72-7.77 (m, 1H), 7.81-7.89 (m, 2H), 7.90 (s, 1H), 8.07-8.14 (m, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.38 (d, J=2.8 Hz, 1H), 8.59 (d, J=2.0 Hz, 1H); MS (ES+): m/z 430.9/432.9 (100/37) [MH+]; HPLC: tR=3.5 min (OpenLynx, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=O)=[CH:4][C:3]=1[O:13][CH3:14].P(Cl)(Cl)([Cl:17])=O>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:17])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2cc[nH]c(=O)c2cc1Br
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ccnc(Cl)c2cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step 2 (7-bromo-6-methoxyisoquinolin-1(2H)-one) (4.7 g, 18.5 mmol) in phosphorus oxychloride (30 mL) was heated to reflux. After 2 h, the mixture was cooled to RT; the volatiles were evaporated, and the residue was partitioned between 3M NaOH and DCM. The organic phase was dried over Na2SO4; solvent was evaporated; and the solid was triturated with Et2O (20 mL) and filtered to give a solid (3.75 g). LRMS ESI+ (M+H)+274.0.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H].[N-]=C=O>O1CCOCC1.C(N(CC)CC)C>[CH:1]1([NH:7][CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C=NC1CCCCC1
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=CNC1CCCCC1
Temperature: -15 °C
Yield: 83.5 %

Procedure:
A solution of cyclohexyl isocyanate (1.25 g.; 0.01 mole) in 100 ml. anhydrous 1,4-dioxane containing two drops of anhydrous triethylamine was mixed with 0.5 gram 10% Pd-on-carbon and shaken at a pressure of 50 p.s.i. of hydrogen on a Parr low pressure hydrogenator. The uptake of hydrogen was complete in two hours. Work up, as in Example 1, gave 1.15 g. of colorless oil containing a trace of isocyanate. The product was purified by slurrying the oil with Skellysolve B, chilling at -15° C. and decanting the supernatant from the crystalline formamide. After drying under high vacuum, the weight of title product was 1.06 g. (83.5% yield). The ir, nmr and glc were identical to an authentic sample.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH2:15][Si](C)(C)C)=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][C:15]3[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=3)=[O:12])[CH:9]=2)[CH2:4][CH2:3]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2c(c1)[C@@H](O)CC2
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C(OCc1ccccc1)c1ccc2c(c1)[C@@H](OCc1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
To a solution of the alcohol from Step 2 (140 mg, 0.503 mmol) was added NaH (28.2 mg, 1.18 mmol) in one portion at RT. After stirring for 30 min, BnCl (116 μL, 1.01 mmol) was added dropwise and the resulting mixture was stirred overnight. The excess NaH was quenched with water and the mixture was transferred to a seperatory funnel where the aqueous layer was washed 3× with DCM. The organic layers were combined, dried with MgSO4, filtered and concentrated to yield an oil. The title compound was purified on a Biotage MPLC (grad: 100% Hex to 60% EtOAc in Hex).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ccc(F)cc4)CC3)nc2c1
Yield: 90 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 3.17 (s, 4H), 3.78-3.89 (m, 6H), 4.11-4.15 (m, 4H), 6.88-7.02 (m, 4H), 7.14-7.36 (m, 3H), 7.58-7.62 (m, 1H).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:10]=[CH:11][NH:12][CH:13]=1.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>ClCCl>[Br:8][C:9]1[N:10]=[CH:11][N:12]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:13]=1
Reactant: Brc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Brc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
0.3787 g of triethylamine is added dropwise over 15 minutes to a solution of 0.500 g of 4-bromoimidazole, 1.043 g of trityl chloride and 25 ml of dichloromethane. The reaction mixture is stirred at room temperature for 11 hours and then poured onto 50 ml of aqueous saturated sodium hydrogencarbonate solution. The mixture is extracted twice with 75 ml of dichloromethane. The combined organic phases are washed with 50 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (1:3 EtOAc-heptane); Rt=5.02.