Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:31])[C:6]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]2[O:12]S(C(F)(F)F)(=O)=O.C(O[C@@H](C1C(C)=CC2C(=CC=C(C)C=2)C=1OS(C(F)(F)F)(=O)=O)C(OCC)=O)(C)(C)C.BrC1C=CC=CC=1CC(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:31])[C:6]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]2[OH:12]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(Br)cccc2c1OS(=O)(=O)C(F)(F)F
Agent: CC(=O)Cc1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C)ccc2c1OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(Br)cccc2c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (S)-ethyl 2-(5-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (0.90 g, 1.7 mmol; prepared in a similar fashion to (S)-ethyl 2-tert-butoxy-2-(3,6-dimethyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate beginning with 1-(2-bromophenyl)propan-2-one) in THF (7 mL) cooled to 0° C. was treated with tetrabutylammonium fluoride (1M in THF, 1.7 mL, 1.7 mmol) dropwise. After 1 hour, saturated NaHCO3 and EtOAc were added and the aqueous layer extracted with EtOAc. The combined organics were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. Purification via Yamazen column chromatography (0-15% EtOAc/hex) afforded (S)-ethyl 2-(5-bromo-1-hydroxy-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate. LCMS-ESI− (m/z): [M−H]− calcd for C19H22O4Br: 395.07. found: 395.04.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[NH:5][CH:4]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[C:3]=1[C:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][C:43]1[O:47][C:46]([C:48]([O:50][CH3:51])=[O:49])=[CH:45][CH:44]=1>CN(C)C=O.CO>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH:4]2[N:5]([CH2:42][C:43]3[O:47][C:46]([C:48]([O:50][CH3:51])=[O:49])=[CH:45][CH:44]=3)[C:6](=[O:18])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=3)[C:2]([CH3:1])=[C:3]2[C:27]([C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:28])=[CH:20][CH:21]=1)#[N:24]
Reactant: CC1=C(C(=O)c2cccnc2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)c3cccnc3)C2c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred suspension of (4-{6-methyl-2-oxo-5-(pyridin-3-ylcarbonyl)-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzonitrile (Example 21A) (100 mg, 0.22 mmol) and potassium carbonate (60 mg, 0.43 mmol) in dimethylformamide (3 ml) is added methyl 5-(chloromethyl)-2-furoate (57 mg, 0.32 mmol). The suspension is stirred at room temperature for 72 hours. The mixture is diluted with methanol (5 ml) and purified directly by preparative HPLC (RP18 column; eluent: acetonitrile/water 10:90→90:10).
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH:11]([O:22][CH3:23])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=O)=O.Cl>>[NH:6]1[CH:10]=[C:9]([CH:11]([O:22][CH3:23])[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[N:8]=[CH:7]1
Reactant: COC(c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1)c1ccnc2ccccc12
Agent: Cl
Product: COC(c1c[nH]cn1)c1ccnc2ccccc12
Yield: 100 %

Procedure:
To 2-(tert-Butyldimethylsilyl)-4-(methoxyquinolin-4-yl-methyl)-imidazole-1-sulfonic acid dimethylamide. (0.32 g, 0.672 mmol), 7 ml of 1.5N HCl was added and the solution refluxed for two hours. The reaction mixture was concentrated, partitioned between water(10 ml) and EtOAc (2×10 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and column purified (CH2Cl2:MeOH:metanol-NH3 (1.0M); (4.5:0.25:0.25) to yield 0.160 g (100%) of the product as a syrup.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[C:22]3[C:17](=[CH:18][C:19]([OH:43])=[C:20]([O:41][CH3:42])[CH:21]=3)[C:16]2=[O:44])=[CH:11][CH:10]=1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[C:22]3[C:17](=[CH:18][C:19]([OH:43])=[C:20]([O:41][CH3:42])[CH:21]=3)[C:16]2=[O:44])=[CH:11][CH:10]=1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1-c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
The compound obtained in Example 5 (10.0 g) is dissolved in chloroform (20 ml), and thereto are added a 4M solution of hydrogen chloride in ethyl acetate (60 ml). The mixture is stirred at room temperature overnight. The resulting suspension is neutralized with 2M aqueous sodium hydroxide solution (120 ml) under ice-cooling, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is dissolved in a small amount of ethyl acetate, and crystallized from diethyl ether to give 2-(4-aminophenyl)-7-hydroxy-6-methoxy-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (5.47 g).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:3]=1.[C:19]1([C:25]2[C:29](B(O)O)=[CH:28][N:27]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:19]1([C:25]2[C:29]([C:2]3[C:7](=[O:8])[CH:6]=[CH:5][N:4]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=4)[N:3]=3)=[CH:28][N:27]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccccc1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A mixture of 3-bromo-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (319 mg, 1.0 mmol), (3-phenyl-1-trityl-1H-pyrazol-4-yl)boronic acid (645 mg, 1.5 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), Na2CO3 (318 mg, 3.0 mmol), DME (7.5 mL), and H2O (1.5 mL) was refluxed overnight under Ar atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/AcOEt (1/1) and crystallized from MeOH to give the title compound (418 mg, 67% yield) as a white solid: mp 216-218° C.; 1H NMR (300 MHz, CDCl3): δ ppm 6.58 (1H, d, J=7.9 Hz), 7.08 (1H, dd, J=2.3, 7.9 Hz), 7.23-7.39 (20H, m), 7.47-7.54 (3H, m), 8.17 (1H, d, J=7.9 Hz), 8.67 (1H, s). LC-MS (ESI) m/z 625 [M+H]+. Anal. Calcd for C39H27F3N4O: C, 74.99; H, 4.36; N, 8.97. Found: C, 74.84; H, 4.39; N, 9.01.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1
Reactant: COC(=O)C(C)CNCc1ccccc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)CN(Cc1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a mixture of 2.73 g (0.010 mole) of (rac)-3-benzylamino-2-methyl-propanoic acid methyl ester, 1.84 g (0.010 mole) of 2,4-dichloro-5-nitro-pyrimidine, 50 mL of ethyl acetate and 25 mL of water was added 3.0 g (0.030 mole) of potassium bicarbonate. The mixture was stirred for 3 hours, then diluted with 50 mL of ethyl acetate and 50 mL of water. The layers were separated, and the aqueous layer extracted twice with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (100:0-97:3) to give 2.55 g of (rac)-3-[benzyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-2-methyl-propanoic acid methyl ester (IV-42) as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]([OH:19])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O/[N:21]=[C:22](/[C:24]1[C:25](=[O:31])[NH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)\[NH2:23].C(N=C=NC(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C2C(C3ON=C(N)N=3)CN(C2)C1>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:19][N:23]=[C:22]([C:24]4[C:25](=[O:31])[NH:26][C:27]([CH3:30])=[CH:28][CH:29]=4)[N:21]=3)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)CCC1(c2cc(F)cc(F)c2)CCCCC1
Reactant: Cc1ccc(/C(N)=N/O)c(=O)[nH]1
Agent: CC(C)N=C=NC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Nc1noc(C2CN3CCC2C3)n1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2noc(CCC3(c4cc(F)cc(F)c4)CCCCC3)n2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 26.7 %

Procedure:
To a solution of 3-(1-(3,5-difluorophenyl)cyclohexyl)propanoic acid (20 mg, 0.075 mmol) and (Z)—N′-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3-carboximidamide (12.46 mg, 0.075 mmol) in acetonitrile (1 mL) was added N,N′-diisopropylcarbodiimide (0.013 mL, 0.082 mmol), and the mixture was stirred for 2.5 hrs at room temp. TBAF (0.112 mL, 0.112 mmol) was added and the mixture was stirred at room temperature. The oxadiazole formation was very slow. After 1 day of stirring, an additional 0.112 mL of 1M TBAF was added and the mixture was stirred for 5 more days. The mixture was diluted with EtOAc and washed with water and brine. The organic extract was dried over Na2SO4 and evaporated to give an oily residue which was purified by Combiflash (12 g silica gel). Elution with 7:93 MeOH—CH2Cl2 afforded a white solid which was repurified by prep HPLC to give pure 3-(5-(2-(1-(3,5-difluorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)-6-methylpyridin-2(1H)-one (8.0 mg, 26.7% yield) as a white solid. HPLC: tR=3.95 min, Waters Sunfire C18 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH-0.1% TFA; Final solvent: 90% aq. MeOH-0.1% TFA. LC/MS: m/e 400.12 (M+H)+. 1H NMR (400 MHz, CDCl3): δ ppm 8.19 (1 H, d), 6.84-6.86 (2 H, m), 6.65 (1H, m), 6.21 (1H, d), 2.44-2.54 (5 H, m), 2.04-2.06 (4 H, m), 1.39-1.61 (8 H, m).
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([OH:32])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:35]([O:37][CH3:38])=[O:36].C(N(CC)CC)C>O1CCCC1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([O:32][C:35]([O:37][CH3:38])=[O:36])[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)OC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a stirred solution of p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-hydroxyethylidene)acetate (500 mg) in tetrahydrofuran (20 ml) are added dropwise methyl chloroformate (200 mg) and triethylamine (216 mg) under ice cooling. After 1 hour, the reaction mixture is poured into ice water, and is extracted with ethyl acetate. The extract solution is washed with water, dried, and evaporated to give p-nitrobenzyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methoxycarbonyloxyethylidene)acetate (546 mg). Foam. Yield: 97%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.O>C(O)(C)C>[CH2:15]([N:22]1[C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[CH2:12][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc2ccnn2c(Cl)c1CCCl
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1nc2ccnn2c2c1CCN2Cc1ccccc1
Yield: 59.6 %

Procedure:
A solution of 1.15 g (5 mmoles) of 7-chloro-6-(2-chloroethyl)-5-methylpyrazolo[1,5-a]pyrimidine (prepared as described in Example 3), 643 mg (6 mmoles) of benzylamine and 2 ml of triethylamine dissolved in 5 ml of isopropanol was heated under reflux for 7 hours, with stirring. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was extracted with 5% by volume aqueous sulfuric acid, and the extract was made basic by the addition of sodium carbonate. The crystals which precipitated were collected by filtration and washed with water. They were then purified by column chromatography through silica gel (eluted with chloroform) and recrystallized from a mixture of ethyl acetate and chloroform, to afford 788 mg (yield 60%) of the title compound as colorless needles, melting at 130°-130.5° C.
Reaction SMILES: [C:1]([CH2:8][NH:9][C:10]1[C:11](=[CH:22][C:23]([O:26]CC2C=CC=CC=2)=[CH:24][CH:25]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>C1COCC1.C(OCC)(=O)C>[C:1]([CH2:8][NH:9][C:10]1[C:11](=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[C:12]([OH:14])=[O:13])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)CNc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNc1ccc(O)cc1C(=O)O
Yield: 100.4 %

Procedure:
N-(Carbo-t-butoxymethyl)-5-benzyloxyanthranilic acid, benzyl ester (45.0 g, 101 mmol) was dissolved in 1:1 THF/ethyl acetate (1200 mL) in a 2 liter round bottom flask. The atmosphere was flushed with argon and 10% Pd/C (4.0 g) was added. The reaction atmosphere was replaced with hydrogen gas (4 purge-fill cycles) and the reaction mixture stirred under a balloon of hydrogen for 23 hours. The atmosphere was replaced with argon and the reaction mixture filtered through a pad of Celite, washing the Celite pad with methanol (250 mL). The solvents were removed in vacuo and the resulting yellow solid placed under high vacuum overnight to yield N-(carbo-t-butoxymethyl)-5-hydroxyanthranilic acid (27.1 g, 100% yield).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]([NH2:42])[CH2:40][CH3:41].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH:39]([NH:42][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:31])[F:32])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])[CH2:40][CH3:41]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: CCC(N)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 1-(2-pyridyl)-propylamine (31 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with 4% methanol in dichloromethane. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 65 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12.[Li]CCCC.[Cl:33]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:33][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN1CCn2c(C(F)(F)F)cc(Br)c2C12CCN(C(=O)OC(C)(C)C)CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCn2c(C(F)(F)F)cc(Cl)c2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5.00 g, 11.1 mmol) in anhydrous THF (125 mL) at −78° C. was added nBuLi (8.84 mL of 2.5 M, 22.1 mmol) slowly. The reaction mixture was allowed to stir at −78 for 20 minutes before 1,1,1,2,2,2-hexachloroethane (5.36 g, 22.7 mmol) was added dropwise as a solution in THF (12 mL). The reaction mixture was allowed to slowly warm to room temperature and was stirred overnight. The reaction mixture was quenched with the addition of saturated aqueous ammonium chloride (100 mL). The volatiles were removed under reduced pressure to half volume. The remaining aqueous suspension was extracted with EtOAc (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a thick brown oil. The crude product was purified by silica gel column chromatography: 10-20% EtOAc/hexane gradient to provide tert-butyl 8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (2.40 g, 53%) as a yellow oil that crystallized upon standing. ESI-MS m/z calc. 407.2, found 407.9 (M+1)+; Retention time: 1.70 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 3.97 (t, J=5.5 Hz, 4H), 3.28 (s, 2H), 3.13 (s, 2H), 2.51-2.28 (m, 5H), 1.93 (d, J=13.7 Hz, 2H), 1.47 (d, J=9.5 Hz, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:12](=[O:14])[CH:13]=[CH:17][N:18]([CH3:20])[CH3:19])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1Cl
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=CC(=O)c1ncc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
5.0 g of 3-chloro-5-trifluoromethyl-2-acetylpyridine (Example P8) are introduced into 30 ml of toluene and 3.60 ml of N,N-dimethylformamide-dimethylacetal are added. The resulting yellow solution is stirred overnight at 100° C. After cooling to 25° C., the mixture is concentrated to dryness in vacuo, yielding 6.17 g of the desired target compound in the form of a dark-yellow oil which later solidifies.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[O:19]=[C:20]1[NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:22][CH:21]1[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[CH:5]1([C:3]([CH2:2][N:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[CH2:22][CH:21]([NH:37][C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[C:20]2=[O:19])=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CBr)C1CCCCC1
Reactant: CC(C)(C)OC(=O)NC1CN(C2CCCCC2)c2ccccc2NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CN(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.2 %

Procedure:
Bromomethylcyclohexylketone (861 mg), potassium iodide (23 mg), tetra n-butylammonium bromide (27 mg) and potassium carbonate (464 mg) were added to a solution of 2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1 g) in dimethylsulfoxide (10 ml), the mixture was stirred overnight at room temperature. Ice-water was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:5) and subsequently purified by silica gel column chromatography(silica gel NH-DM1020, produced by Fujisilicia Co. Ltd., ethyl acetate:n-hexane=1:5), to thereby obtain 500 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:12]([O:13][C:14]2[C:22]3[CH2:21][CH2:20][CH2:19][C:18]=3[C:17](C=O)=[CH:16][C:15]=2[CH3:25])=[CH:11][C:10]=1[CH:28]([CH3:30])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](=O)([O-:33])[OH:32].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH:31]([O:33][C:17]1[CH:16]=[C:15]([CH3:25])[C:14]([O:13][C:12]2[CH:26]=[CH:27][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([CH:28]([CH3:29])[CH3:30])[CH:11]=2)=[C:22]2[C:18]=1[CH2:19][CH2:20][CH2:21]2)=[O:32]
Reactant: O=C([O-])O
Reactant: Cc1cc(C=O)c2c(c1Oc1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(OC=O)c2c(c1Oc1ccc(OCc3ccccc3)c(C(C)C)c1)CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
7-(4-benzyloxy-3-isopropylphenoxy)-6-methylindan-4-carbaldehyde (712 mg) was dissolved in dichloromethane (10 mL). To the solution were added sodium hydrogen carbonate (582 mg) and m-chloroperbenzoic acid (399 mg), and the resulting mixture was stirred at room temperature overnight. Adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (694 mg).