Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Br:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[N:22]([C:25]1[N:30]=[C:29]([C:31](OC)=[O:32])[CH:28]=[C:27]([CH3:35])[N:26]=1)[CH2:23][CH3:24].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:16]=[CH:15][C:14]=1[N:22]([CH2:23][CH3:24])[C:25]1[N:30]=[C:29]([C:31]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[O:32])[CH:28]=[C:27]([CH3:35])[N:26]=1
Reactant: CCN(c1nc(C)cc(C(=O)OC)n1)c1ccc(C(C)C)cc1Br
Reactant: Brc1nccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(c1nc(C)cc(C(=O)c2nccs2)n1)c1ccc(C(C)C)cc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of n-butyl lithium in hexanes (2.4 M, 1.34 mL, 3.24 mmol) in anhydrous THF (5 mL) at −78° C. under a nitrogen atmosphere was added 2-bromothiazole (0.49 g, 0.27 mL, 3.0 mmol) dropwise. After the addition was complete, the reaction mixture was stirred at −78° C. for 30 min. A solution of methyl 2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate (Example 18) (1.0 g, 2.5 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was then warmed to −60° C. and stirred for 4 h. A saturated aqueous solution of NaHCO3 was added and the reaction mixture was warmed to ambient temperature. Three extractions with ethyl acetate, followed by two washings of the combined organic layers with water, drying over MgSO4, filtration and concentration in vacuo gave a dark brown oil. Column chromatography (ethyl acetate: hexanes::1:1) afforded the title product, a brown solid (950 mg, 85% yield, Rf 0.43): mp 97-98.5° C.; NMR (CDCl3, 300 MHz):8.0 (s, 1H), 7.60 (s, 1H), 7.4-7.2 (m, 4H, J=6), 3.05-2.9 (m, 1H), 2.8-2.7 (m, 1H), 2.6 (br s, 3H), 1.4-1.2 (m, 9H); CI-HRMS Calcd: 445.0698 (M+H), Found: 445.0699; Anal.(C20H21BrN4S): C, 54.05; H, 4.73; N, 12.61; Br, 18.02; S, 7.21; Found: C, 53.86; H, 4.66; N, 12.53; Br, 18.20; S, 7.46.
Reaction SMILES: [NH2:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=O.[NH2:13][C:14](N)=[O:15]>O>[Br:12][C:7]1[CH:6]=[C:3]2[C:2](=[C:9]([O:10][CH3:11])[CH:8]=1)[NH:1][C:14](=[O:15])[N:13]=[CH:4]2
Reactant: NC(N)=O
Reactant: COc1cc(Br)cc(C=O)c1N
Solvent: O
Product: COc1cc(Br)cc2cnc(=O)[nH]c12
Temperature: 180 °C
Reaction time: 1 h

Procedure:
2-amino-5-bromo-3-methoxybenzaldehyde (2.5 g, 10.87 mmol) is homogeneously mixed with urea and the mixture is heated to 180° C. The melt formed is kept at this temperature for 1 h. Then the reaction mixture is mixed with water, the precipitate formed is filtered off, dried and 6-bromo-8-methoxy-1H-quinazolin-2-one (HPLC-MS: tRet.=1.53 min MS(M+H)+=255/257; method FSUN) is obtained.
Reaction SMILES: [N+](=[C:3]([C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5])=[N-].[CH2:22]([N:29]1[C@@H:34]2[CH2:35][CH2:36][C@@:30]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:31]([OH:37])[CH2:32][CH2:33]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:22]([N:29]1[C@@H:34]2[CH2:35][CH2:36][C@@:30]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:31]([O:37][C@H:3]([C:4]([O:6][CH3:7])=[O:5])[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=1)[CH2:32][CH2:33]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)C(=[N+]=[N-])c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: COC(=O)[C@@H](O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
Slow addition of methyl 2-diazo-2-(3,5-bis(trifluoromethyl)phenyl)acetate (504 mg, 1.61 mmol) as a solution in benzene (3 ml) to (1R*,2R*,5R*)-8-benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 430 mg, 1.47 mmol) in benzene (3 ml) was carried out in the presence of catalytic rhodium acetate (5 mg) at reflux under N2. The reaction mixture was concentrated in vacuo to give a green oil then purified by flash column chromatography [15% ethyl acetate in iso-hexane] to give the title compound as a yellow oil (mainly 1 isomer)(735 mg, 87%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[N:31][OH:32])[CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCCC(=O)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCC(=NO)c1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Yield: 82 %

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-(4-butyrylphenyl)isoquinoline (0.27 g) obtained in the previous Example was dissolved in ethanol (40 ml), to which was then added a solution of hydroxylamine hydrochloride (0.14 g) and sodium acetate (0.22 g) dissolved in water (10 ml), and the mixture was heated under reflux. The solvent was evaporated, and the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/methanol system), to give 0.23 g of the free compound of the title compound as a pale brown amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[CH:26]=2)=[CH:4][C:5]([F:23])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[O:10])[CH:7]=1.[C:32](=[O:39])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[NH2:33].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[O:10])[C:5]([F:23])=[CH:4][C:3]=1[O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([NH:33][C:32](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH:26]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: O=C(Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F)N1CCN(C2CCOCC2)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(Oc2cc(F)c(NC(=O)N3CCN(C4CCOCC4)C3=O)cc2Cl)ccn1
Temperature: 100 °C
Yield: 112.6 %

Procedure:
A mixture of Example C8 (1 g, 2.131 mmol), t-butyl carbamate (0.749 g, 6.39 mmol), Cs2CO3 (2.083 g, 6.39 mmol) and Xantphos (0.555 g, 0.959 mmol) in dioxane (15 mL) was sparged with Ar, treated with Pd2(dba)3 (0.293 g, 0.320 mmol), sparged again with Ar and heated at 100° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, passed through a pad of silica gel and concentrated to dryness to afford crude tert-butyl (4-(2-chloro-5-fluoro-4-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamido)phenoxy)pyridin-2-yl)carbamate (1.32 g, 113%) which was used without further purification. MS (ESI) m/z: (M+H+): 550.1.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17][O:18][C:19]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH3:30])=[CH:26][CH:27]=5)[N:22]=[CH:21][CH:20]=4)=[N:15][N:16]=3)[N:13]=2)=[CH:4][CH:3]=1.[NH2:31][CH:32]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]1.CS(C)=O>O>[CH3:30][O:29][C:25]1[CH:24]=[C:23]2[C:28]([C:19]([O:18][CH2:17][C:14]3[N:12]4[N:13]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([NH:31][CH:32]6[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]6)=[N:7][CH:6]=5)[CH:9]=[CH:10][C:11]4=[N:16][N:15]=3)=[CH:20][CH:21]=[N:22]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(F)nc5)nn34)ccnc2c1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(NC6CCN(C(=O)OC(C)(C)C)C6)nc5)nn34)ccnc2c1
Reaction time: 1 h

Procedure:
A 0.5-2 mL microwave vial was charged with 4-((6-(6-fluoropyridin-3-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.100 g, 0.249 mmol), tert-butyl 3-aminopyrrolidine-1-carboxylate (0.116 g, 0.622 mmol), and DMSO (4.00 ml, 56.4 mmol), sealed and placed in a Personal Chemistry microwave for 1 hour at 100° C. and then 30 minutes at 120° C. Water was added slowly to the reaction mixture until a precipitate formed. The solid was collected and purified by MPLC using a 40 g RediSep column, eluting with a gradient of 3-6% MeOH/DCM over 40 minutes. The solid was triturated with MeCN and filtered; the mother liquor was concentrated to give tert-butyl 3-(5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyridin-2-ylamino)pyrrolidine-1-carboxylate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34].[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(C(F)(F)F)=O>[CH3:31][C:32]([CH3:37])([CH3:36])[C:33]([NH:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:34]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccccc1N1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
1-Boc-4-(2-Aminomethyl-phenyl)-piperazine (0.75 g, 2.6 mmol) was dissolved in methylene chloride (20 mL). DIPEA (2.3 mL, 13 mmol) was added, and the mixture was cooled to about 0° C. The solution was treated with trimethylacetyl chloride (0.28 g, 0.28 mL, 2.3 mmol) and stirred for about 1 hour at 0° C. The solution was warmed to r.t. and stirred overnight. The mixture was diluted with ethyl acetate (400 mL), washed with water (60 mL), saturated aqueous sodium bicarbonate (60 mL) and brine (60 mL) and then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and purified via silica gel chromatography (80% ethyl acetate in hexanes) to afford a clear oil, which was subsequently stirred in neat TFA (5 mL) for about 1 hours. The solvent was evaporated under reduced pressure and the residue taken up in water (30 mL). Sodium hydroxide (1 g, 25 mmol) and ethyl acetate (30 mL) were added, and the mixture was stirred for about 45 minutes. The organic phase was collected and the aqueous phase was extracted with ethyl acetate (60 mL). The combined organic fractions were washed with water (45 mL) and brine (30 mL) and then dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded the title compound (0.54 g, 75%) as a clear oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[C:13](=[O:28])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C:15](=[O:16])[CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CCO.ClCCl>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:15]([OH:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:19][CH:18]=3)[C:13](=[O:28])[CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1c1ccc(OC(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: O=C1C2CN(Cc3ccccc3)CC2C(O)N1c1ccc(OC(F)(F)F)cc1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a cooled (−35˜−40° C.) solution of 5-Benzyl-2-(4-trifluoromethoxy-phenyl)-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione (0.6 g, 0.5 mmol) and CeCl3.7H2O (0.56 g, 0.5 mmol) in 250 mL EtOH/dichloromethane (1.5:1) were sequentially added NaBH4 (0.057 g, 10 mmol). The temperature was kept at −35˜−40° C. for 2 h, poured into cold water (100 mL) and extracted with dichloromethane (2×80 mL). After washing the organic phase with brine (100 mL) and drying over anhydrous Na2SO4, the solvent was removed and the crude product was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (5:1 to 2:1) to yield the title compound (0.17 g, 29%). 1H NMR (300 MHz, CDCl3): δ 7.78 (d, 2H, J=9.0 Hz), 7.38-7.22 (m, 7H), 5.52 (d, 1H, J=6.9 Hz), 3.69 (q, 2H, J=12.6 Hz), 3.20-3.18 (m, 3H), 3.07 (bs, 1H), 2.52 (t, 1H, J=10.1 Hz), 2.31-2.28 (m, 1H); LC-MS: [M+1]+ 393.0.
Reaction SMILES: C([NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>O>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@@H:19]([C:30]([OH:32])=[O:31])[NH2:18])=[CH:22][CH:23]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Solvent: C1CCNCC1
Solvent: O
Product: CC(=O)c1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
Fmoc-4-acetyl-L-phenylalanine was purchased from RSP Amino Acid Analogues, Inc.(Worcester, Mass.). This compound (1.0 g, 2.3 mmol) was stirred with 4 mL of piperidine (20% in DMF) for 2 hours at room temperature. The solvent was evaporated to obtain white powder. The solid was then resuspended in 10 mL of cold water (0.1% TPA), and the supernatant was collected by filtration. Preparative reverse-phase HPLC (Microsorb C18, Rainin Instrument Co., Inc., Woburn, Mass.) was used to separate the desired product from the reaction mixture (5-30% CH3CN in H2O with 0.1% TFA over 30 min). The eluant (tR=12 min) was lyophilized to a obtain white solid (0.45 g, 88%). 1HNMR (D2O): δ 7.85-7.28 (m, 4H), 4.23 (dd, 1H, 5.4 Hz), 3.2 (m, 2H), 2.7 (s, 3H). LRMS, calcd for C11H13NO3 (M++1): 208.09. Found (ESI): 208.47.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:35]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.O>CN(C=O)C>[CH:35]1([NH:41][C:3]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[NH:12][C:13]4[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[CH:9][CH:10]=2)=[O:4])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)c1ccc(-c2nc3ccc(C(=O)O)cc3[nH]2)cc1
Reactant: NC1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(C(=O)NC4CCCCC4)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-methoxycarbonyl-phenyl)-3H-benzoimidazole-5-carboxylic acid (5.0 g) in DMF (250 mL) and CDI (7.1 g) was stirred at RT for 3.0 hours and then treated with cyclohexyl amine (2.0 g) and refluxed for 96 hours. The reaction mixture was cooled and then poured into water (2.0 L) and stirred at RT for 16 hours. The product was filtered, washed with water and ether and then recrystallized from THF, methanol and ether. Yield 0.4 g. TLC one spot (9:1)-CH2Cl2—CH3OH.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6]([OH:8])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:6]([N:51]1[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]1)=[O:8]
Reactant: CN1CCNCC1
Reactant: COc1ccc(COc2ccc(C(=O)O)cc2OC)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(C(=O)N3CCN(C)CC3)cc2OC)cc1
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 3-methoxy-4-p-methoxybenzyloxybenzoic acid (2.88 g: 10 mMol.), 1-hydroxybenzotriazole (1.49 g: 1.1 Eq.), and dicyclohexylcarbodiimide (2.27 g: 1.1 Eq.) in tetrahydrofuran (100 ml) is kept at room temperature for 3 hours. To this solution is added N-methylpiperazine (2.22 ml: 2 Eq.), and the mixture is kept at room temperature overnight to give 1-(3-methoxy-4-p-methoxybenzyloxybenzoyl)-4-methylpiperazine (3.45 g). Yield: 93%.
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(O)(=O)C.[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O)([O-:17])=[O:16].Cl>CO.O.CO.O.CCO.CC([O-])=O.CC([O-])=O.[Cu+2].O>[OH:5][CH2:4][C:3]1[C:2]2[NH:1][C:20]([C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[N+:15]([O-:17])=[O:16])=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: Nc1cccc(CO)c1N
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: CO
Product: O=[N+]([O-])c1ccccc1-c1nc2cccc(CO)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
2,3-Diaminobenzyl alcohol 2 (3.45 g, 25 mmol) was dissolved in a MeOH/H2O mixture (200 mL, v/v=1:1). Acetic acid (3 mL), 2-nitro-benzaldehyde (5.3 g, 35 mmol) in MeOH (50 mL) and Cu(OAc)2.H2O (7.0 g, 35 mmol) in water (100 mL), were added sequentially to the stirring solution. It was then heated to reflux under vigorous stirring for 3 hr, after which a pale yellow precipitate was formed. The mixture was filtered hot and then washed with water to afford a gray-yellow solid. The precipitate was redissolved in EtOH (150 mL) and concentrated HCl (24 mL), and then a solution of Na2S.9H2O (12.8 g, 50 mmol) in water (100 mL) was added. The mixture was heated at reflux for 1 hour resulting in a black slurry. It was then allowed to cool to room temperature, and filtered through a pad of celite to remove the resulting CuS. The filtrate was neutralized with ammonium hydroxide to pH=8-9 and then concentrated by rotary evaporation to yield a green-yellow precipitate. After filtration and vacuum evaporation, 4-hydroxymethyl-2-(2-nitrophenyl)-benzimidazole (5.55 g, 82%) was obtained as a green-yellow solid. Rf=0.28 (hexane/ethyl acetate=1:2); 1H NMR (200 MHz, DMSO) δ 4.84 (broad s, 2H), 5.22 (broad s, 1H), 7.28 (m, 2H), 7.49 (d, J=6.8 Hz, 1H), 7.71-8.06 (m, 4H), 12.93 (broad s, 1H); HRMS: Calcd. for C14H11N3O3 269.0800, found 269.0845.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19](=[O:36])[CH2:20][NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[NH:21][CH2:20][C:19]([NH:18][CH:16]1[CH2:17][N:14]([CH:2]2[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]2)[CH2:15]1)=[O:36]
Reactant: CCOC(=O)CC1CCC(=O)CC1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)CC1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of ethyl 2-(4-oxocyclohexyl)acetate with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:2].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][C:5]=1[OH:9])([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 24.8 %

Procedure:
3-ethylphenol (5.00 g, 41 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (3.83 g, 45 mmol). The addition of sulfuric acid (50 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.7 g, 25%). 1H NMR (CD3COCD3): δ 8.02 (d,1H), 6.99 (s,1H), 6.85 (d, 1H), 2.69 (q, 2H), 1.30 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH:23]=C)[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]=[O+][O-]>CO>[C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH:23]=[O:25])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: C=CC[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Solvent: CO
Product: C[C@H](c1ccccc1)N1C[C@@](CC=O)(C(=O)OC(C)(C)C)CC1=O
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
A solution of (3S)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.29 g, 10.0 mmol) in methanol (100 mL) was bubbled with ozone at −74° C. When the reaction solution turned blue, ozone bubbling was stopped and then the solution was bubbled with nitrogen at the same temperature. Sodium borohydride (568 mg) was added at the same temperature, and the mixture was stirred for 1.5 hours while heating to −40° C. The reaction solution was poured into a 10% citric acid solution (50 mL), and then the mixture was stirred sufficiently. The methanol component was evaporated, and then the aqueous layer was extracted with ethyl acetate (200 mL, 100 mL). The organic layer was washed with brine (50 mL×2), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure into a slurry. Hexane was added to the resulting residue, and the slurry was stirred. The solid was collected by filtration and dried to give 1.70 g of the title compound as a white solid. The filtrate was concentrated, hexane was added to the resulting residue, and the slurry was stirred. The solid was collected by filtration to give 0.66 g of the title compound as a white solid. The same operation was repeated to give 0.35 g of the title compound as a white solid (total yield: 2.71 g, 82%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1F)[C:24]([O:26][CH3:27])=[O:25]>>[F:20][C:21]1[CH:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[CH:28]=[CH:29][C:30]=1[N:10]1[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]1
Reactant: COC(=O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 44.8 %

Procedure:
Potassium carbonate (5.56 g, 40.3 mmol) and tert-butyl piperazine-1-carboxylate (6.92 g, 37.2 mmol) were combined; methyl 3,4-difluorobenzoate (5.33 g, 31.0 mmol) was added, and the reaction mixture was stirred at 90° C. for 1 d. The mixture was triturated with ethyl acetate (3×5 mL) and the combined organic extracts were filtered, concentrated down to about 5-10 mL, and subjected to flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 1:0 to 4:1) to afford the title compound as a white solid (4.702 g, 13.90 mmol, 44.9% yield). ESI-MS: m/z 339 (M+H)+.