Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[C:10](=[O:20])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2].[BH3-]C#N.[Na+].[OH-].[NH4+]>CCO.CC(O)=O>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([OH:20])[CH2:9][N:8]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(=O)c2c1[nH]c1ccccc21
Agent: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(O)c2c1[nH]c1ccccc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a suspension of 3-(4-fluorobenzoyl)-1-oxo-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (784 mg, 2 mmol) in EtOH (11 mL) and AcOH (3 mL) was added NaBH3CN (500 mg, 8 mmol) and the mixture was stirred at 20° C. overnight. It was then basified with 28% ammonium hydroxide and extracted with DCM. The combined organic layer was washed with water and dried over MgSO4. Evaporation of solvent gave a crude product, which was purified by column chromography on silica gel and eluted with MeOH-DCM (1:19) to give the title compound (450 mg); 1H-NMR (CDCl3): δ 9.61 (1H, s), 8.41 (1H, m), 7.41 (1H, m), 7.25-7.36 (5H, m), 7.05 (2H, m), 4.93 (1H, m), 4.57 (1H, d), 4.42 (3H, m), 3.85 (1H, m), 1.35 (3H, d). MS (ES): 395 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:8][CH2:9][CH2:10][C:11]#[N:12])([CH3:4])([CH3:3])[CH3:2].[NH4+].[OH-]>C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCN(CCCC#N)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCCN(CCCCN)C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
The nitrile 11 (2.00 g, 5.6 mmol) was dissolved in ethanol (100 mL). NH4OH (10 mL) and Raney nickel (8 g) were added and ammonia gas was bubbled through the solution for 20 minutes at 0° C. The suspension was hydrogenated at 50 parr for 24 hours. Air was bubbled through the solution and the Raney nickel was removed by filtering through a sintered glass funnel keeping the Raney nickel residue moist at all times. The ethanol and NH4OH were removed in vacuo and the oily residue dissolved in CH2Cl2 and washed with 10% aq, Na2CO3 (3×50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and the solvent removed in vacuo to give the product 12 as a clear oil without further purification (1.92 g, 95%), Rf=0.4 (1:10:89 NH4OH:MeOH:CHCl3); 1H NMR (CDCl3) d 4.65 (br s, 1H, NHCO), 3.14 (m, 6H, 3×CH2), 2.69 (t, 2H, CH2), 2.35 (t, 2H, CH2), 1.58-1.26 (m, 26H, 4×CH2, 6×CH3).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([CH3:12])[CH:6]=1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>C(O)C.O>[CH3:1][NH:2][C:3](=[O:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]([CH3:12])[CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)Nc1ccc(OC(=O)NC)cc1C

Procedure:
The reaction of 3-methyl-4-aminophenyl N-methylcarbamate (3.6g., 0.02 mole) with ethyl chloroformate (2.28g., 0.021 mole) and triethylamine (2.23g., 0.022 mole) yielded a beige solid (3.6g., m.p. 153°-55° C. from ethanol/water).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:46]>>[NH2:46][C:6]1[C:5]2[N:14]=[C:2]([CH3:1])[N:3]([CH2:15][CH2:16][C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18])[C:4]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCCNC(=O)CCn1c(C)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCNC(=O)CCn1c(C)nc2c(N)nc3ccccc3c21

Procedure:
3-(2-Methyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide (610 g, 20.2 mmol) was treated with mCPBA (8.15 g, 35.4 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (7.52 g, 39.5 mmol) according to a modification of the method described in Part D of Example 8. The reaction was not washed with 10% aqueous sodium hydroxide prior to the addition of ammonium hydroxide. The crude product was twice triturated with ethyl acetate and isolated by filtration. The solid was then purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol). The product was then triturated sequentially with 10% aqueous sodium hydroxide and acetone (2×). The solid was then purified again by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 95:5 to 90:10). The resulting solid was triturated with 10% aqueous sodium hydroxide, isolated by filtration, washed with water, and dried overnight to provide 0.477 g of 3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide as an off-white powder, mp 188-189° C.
Reaction SMILES: [F:1][C:2]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][N:8]1[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45].C([SiH](C(C)C)C(C)C)(C)C>C(Cl)Cl>[F:47][C:46]([F:49])([F:48])[C:44]([OH:50])=[O:45].[N:33]1[CH:34]=[CH:35][CH:36]=[N:37][C:32]=1[N:8]1[C@H:7]([CH2:6][O:5][CH2:4][C:3]2[CH:38]=[C:39]([F:43])[C:40]([F:42])=[CH:41][C:2]=2[F:1])[CH2:11][C@@H:10]([SH:12])[CH2:9]1
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2c2ncccn2)cc1F
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(F)c(COC[C@@H]2C[C@@H](S)CN2c2ncccn2)cc1F
Yield: 80 %

Procedure:
A solution of 1.7 g (2.84 mmol) (2S,4R)-2-[2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidin-1-yl]-pyrimidine in 30 ml CH2Cl2 was treated at 0° C. with 8 ml TFA and 5.82 ml (28 mmol) triisopropylsilane. After 30 min at RT the solution was completely evaporated and the compound precipitated twice from Et2O/pentane to give 1.06 g (80%) (3R,5S)-1-pyrimidin-2-yl-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol trifluoro-acetate (1:1) as colourless oil, MS: 356 (MH+).
Reaction SMILES: C([O:8][C:9](=[O:37])[CH2:10][C@@H:11]([N:24]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[CH:25]1)[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])C1C=CC=CC=1>CO.CCOC(C)=O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][N:24]([C@@H:11]([C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:17])[CH3:18])=[O:13])[CH2:10][C:9]([OH:37])=[O:8])[CH:25]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(C#N)cc2)c1)C(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(C#N)cc2)c1)C(C)(C)C
Yield: 90 %

Procedure:
According to the procedure described in Example 1(a), 3(R)-[3-(4-cyanophenyl)-1H-pyrrol-1-yl]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid benzyl ester in MeOH and EtOAc was hydrogenolyzed to provide 1.2 g (90%) of 3(R)-[3-(4-cyanophenyl)-1H-pyrrol-1-yl ]-N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]succinamic acid as a yellow powder, mp 138-40° C. 1H NMR (CD3OD): δ 7.98 (bs, 1H), 7.82 (bd, 1H, J=8.4 Hz), 7.68 (d, 2H, J=8.7 Hz), 7.50 (d, 2H, J=8.4 Hz), 7.38 (t, 1H, J=1.6 Hz), 6.92 (t, 1H, J=8.4 Hz), 6.55 (t, 1H, J=2.2 Hz), 5.28 (t, 1H, J=7.5 Hz), 4.19 (d, 1H, J=9.0 Hz), 2.98 (dd, 1H, J=6.9, 16.5 Hz), 2.64 (d, 3H, J=4.7 Hz), 0.98 (s, 9H). IR (KBr): 3317, 2963, 2225, 1648, 1550, 1410, 1180 cm-1. HRFABMS: Calculated for C22H26N4O4Cs (M+Cs+): 543.1008. Found 543.1021. Anal. Calculated for C22H26N4O4.0.4 EtOAc: C, 63.60; H, 6.60; N, 12.57. Found: C, 63.80; H, 6.77; N, 12.57.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18]CC)=[O:17])=[CH:8][N:9]2[C@@H:12]2[CH2:14][C@@H:13]2[F:15])=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([OH:18])=[O:17])=[CH:8][N:9]2[C@@H:12]2[CH2:14][C@@H:13]2[F:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)ccc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2cc(F)ccc2c1=O
Temperature: 0 °C
Yield: 95.2 %

Procedure:
A mixture of ethyl 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.08 g, 13.9 mmol), acetic acid (9 ml) and concentrated hydrochloric acid (9 ml) was heated under reflux for 21 hour. After cooling the reaction solution with ice, ice water (50 ml) was poured into the reaction solution, the precipitated crystals were filtered out, and after washing with excess water, a small amount of cold ethanol and excess diethyl ether, the crystals were dried under a reduced pressure at 80° C. for 16 hours. 3.51 g (95%) of the title compound was thereby obtained in the form of a white powder.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>>[CH3:15][O:16][C:17]1[CH:26]=[C:25]([NH:27][C:12]([C:6]2[S:7][C:8]([CH:9]([CH3:10])[CH3:11])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:14])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Reactant: COC(=O)c1ccc(N)cc1OC
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1OC
Yield: 32.5 %

Procedure:
In the same manner as that of Example 24, 4,5-diisopropylthiophene-2-carboxylic acid (80 mg, 0.377 mmol) and methyl 2-methoxy-4-aminobenzoate (123 mg, 0.679 mmol) were condensed, the reaction mixture was treated in a conventional manner, and then the residue was purified by silica gel chromatography [n-hexane-ethyl acetate (40:1)] and recrystallized to obtain methyl 2-methoxy-4-[(4,5-diisopropylthiophene-2-carbonyl)amino]benzoate (46 mg, 32%) as colorless prisms.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:15]=[C:16]([C:20]([C:22]3[N:23]([CH3:40])[CH:24]=[C:25]([C:27]4[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[C:30]([O:36]C)=[C:29]([O:38]C)[CH:28]=4)[N:26]=3)=[O:21])[N:17]([CH3:19])[CH:18]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.[BrH:41]>>[BrH:41].[OH:2][C:3]1[CH:4]=[C:5]([C:14]2[N:15]=[C:16]([C:20]([C:22]3[N:23]([CH3:40])[CH:24]=[C:25]([C:27]4[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[C:30]([OH:36])=[C:29]([OH:38])[CH:28]=4)[N:26]=3)=[O:21])[N:17]([CH3:19])[CH:18]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:9]
Reactant: COc1cc(-c2cn(C)c(C(=O)c3nc(-c4cc(OC)c(OC)c([N+](=O)[O-])c4)cn3C)n2)cc([N+](=O)[O-])c1OC
Agent: Br
Product: Cn1cc(-c2cc(O)c(O)c([N+](=O)[O-])c2)nc1C(=O)c1nc(-c2cc(O)c(O)c([N+](=O)[O-])c2)cn1C

Procedure:
5.0 g of 3,4-dimethoxy-5-nitrophenyl(1-methylimidazol-2-yl)ketone are treated with 50 ml of hydrobromic acid (48%), whereupon the mixture is stirred under reflux temperature for 2 hours. After cooling the separated precipitate is filtered under suction, washed with ice-water and recrystallized from ethanol. There is obtained 3,4-dihydroxy-5-nitrophenyl(1-methyl-imidazol-2-yl)ketone hydrobromide in the form of yellow crystals of decomposition point>240°.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC[CH:11]1[CH2:20][CH2:19][CH2:18][CH2:17][C:12]21OCC[O:13]2>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][CH:11]1[CH2:20][CH2:19][CH2:18][CH2:17][C:12]1=[O:13])(=[O:7])[CH3:6]
Reactant: OCCC1CCCCC12OCCO2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OCCC1CCCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
Under an argon atmosphere, DMAP (259 mg, 2.12 mmol) and acetic anhydride (3 ml, 31.75 mmol) were added to a solution of (±)-6-(2'-hydroxyethyl)-1,4-dioxaspiro [4.5)decane (3.94 g, 21.17 mmol) in pyridine (106 ml). The mixture was stirred at room temperature for 1 h. The pyridine was evaporated under reduced pressure and the residue was diluted with methanol (100 ml). The mixture was cooled to 0° C. and 2 M hydrochloric acid (250 ml) was added. The mixture was stirred at room temperature for 1 h and then extracted with chloroform (3×200 ml). The combined organic extracts were washed with 2 M hydrochloric acid (200 ml) and brine (300 ml). The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with hexane-ethyl acetate (3:1) to give (±)-2-(2'acetoxyethyl)cyclohexanone (3.45 g, 88% yield) as a colourless oil. Rf 0.34 (hexane-ethyl acetate, 7:3).
Reaction SMILES: [OH:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].[CH2:22]([O:24][P:25]([CH2:30][S:31][CH2:32][CH2:33]O)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:22]([O:24][P:25]([CH2:30][S:31][CH2:32][CH2:33][O:1][N:2]1[CH:10]=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])([O:26][CH2:27][CH3:28])=[O:29])[CH3:23]
Reactant: CCOP(=O)(CSCCO)OCC
Reactant: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(CSCCOn1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)OCC
Yield: 45.8 %

Procedure:
A mixture of 9-hydroxy-6-phthalimidopurine (0.5 g, 2.2 mmol). diethyl-2-hydroxyethylthiomethylphosphonate (0.45 g. 2 mmol) and triphenylphosphine (0.52 g, 2 mmol) was dissolved in dry tetrahydrofuran (20 ml) and cooled to 0°-5° C. A solution of diethylazodicarboxylate (0.348 g, 2.0 mmol) in dry tetrahydrofuran (10 ml) was added dropwise with stirring, and after the addition was completed the reaction was stirred at room temperature for 18 hours. The solvent was then removed in vacuo, and the residue was purified by column chromatography on silica using ethyl acetate: methanol (98:2) as eluent to give 9-[2-(diethoxyphosphorylmethylthio)ethoxy]-6-phthalimidopurine (0.45 g 56%) as a white solid after crystallisation from acetone/diethyl ether, m.p. 115°-116° C.; γmax (EtOH) 271mm (s 14020) υmax (KBr) 3100, 3060, 2960, 2900, 1780, 1725, 1650, 1600, 1580, 1453, 1400, 1380, 1360, 1320, 1280, 1240, and 1200 cm-1 ; δH [(CD3)2SO] 1.25 (6H, t, J 7Hz 2 × CH3), 3.0 (2H, d, J 13Hz, PCH2S), 3.1 (2H, t, J 7Hz CH20, 4.0 (4H, m, 2 × CH2), 4.7 (2H, t, J 7Hz, CH2S), 8.1 (4H, m, Ar H), 9.0 (1H, s, 2H), 9.1 (1H, s, 8-H). (Found C, 48.65; H, 4.55; N, 14.23%. C20H22N5O6PS requires C,48.87; H, 4.51; N, 14.25%).
Reaction SMILES: O.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 3-neck flask equipped with an internal thermometer was added sulfuric acid and cooled to −10° C. in an ice/salt/water batch. 2′-fluoroacetophenone(1 eq) in sulfuric acid was added dropwise over 10 minutes via addition funnel to produce a solution of 0.2M. Nitric acid (1.15 eq) in sulfuric acid was then added dropwise at a rate not to exceed 5° C. After complete addition resulting solution was allowed to stir at for 30 minutes. Solution was poured onto ice and extracted with ethyl acetate. Organics were washed with a saturated solution of sodium bicarbonate, brine, dried with sodium sulfate and concentrated. Crude product was purified using flash chromatography (85% Hex:15% EtoAc) on silica to afford 1-(2-fluoro-5-nitrophenyl)ethanone.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:23][O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[OH:27].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl.C([O-])(O)=O.[Na+].CCOCC>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH:5]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[O:27][C@@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:25]([O:24][CH3:23])=[O:32])=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](O)CC(C)C
Reactant: N=C(OC(c1ccc(F)cc1)c1ccc(Br)cc1)C(Cl)(Cl)Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](CC(C)C)OC(c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the (4-bromophenyl)(4-fluorophenyl)methyl 2,2,2-trichloroethanimidoate of step 2 (1.18 mmol, 500 mg) in CH2Cl2 (5 mL) was added L-leucic acid methyl ester 2 (1.18 mmol, 146 mg) and then camphor sulfonic acid (0.12 mmol, 27 mg). The mixture was stirred at r.t. for 18 h. A few drops of saturated NaHCO3 was added, The mixture was diluted with ether and filtered. The filtrate was concentrated under reduced pressure and the crude product was chromatographed to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH3:15].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21](Cl)=[O:22]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH3:15])[C:21](=[O:22])[C:20]1[CH:19]=[C:18]([C:17]([F:32])([F:31])[F:16])[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=1
Reactant: CNc1cnccc1-c1ccncc1F
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccncc1F

Procedure:
The title compound was prepared in analogy to example 55, from (3′-fluoro-[4,4′]bipyridinyl-3-yl)-methyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using preparative HPLC for the chromatographic purification. Off-white solid (5%). MS (ESI): m/z=444.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH:16]([O:18]C(=O)C)[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH:16]([OH:18])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11]
Reactant: CC(=O)OC1CC(N2Cc3c(N)cccc3C2=O)C(=O)NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Nc1cccc2c1CN(C1CC(O)C(=O)NC1=O)C2=O

Procedure:
A solution of 3-(4-amino-1-oxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (0.96 g, 3.5 mmol) and p-toluenesulfonic acid (0.33 g, 1.8 mmol) in methanol (10 mL) is heated at reflux for 5 hours. The solvent is removed in vacuo to give 4-amino-2-(5-hydroxy-2,6-dioxopiperid-3-yl)isoindoline-1-one which is further purified by column chromatography.
Reaction SMILES: [O:1]1CCCC1.ClCl.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]([OH:15])[CH3:14].BrBr>O>[CH3:14][C:13]1[O:15][CH:12]=[CH:11][C:10](=[O:1])[C:9]=1[OH:8]
Reactant: CC(O)c1ccco1
Reactant: C1CCOC1
Agent: BrBr
Agent: ClCl
Solvent: O
Product: Cc1occc(=O)c1O
Temperature: 0 °C

Procedure:
In a 3-neck round bottom flask equipped with a magnetic stirring bar, a gas inlet tube, a thermometer and an additional funnel was added 50 ml of tetrahydrofuran and 50 ml of water. This solution was then cooled to 0° C. and chlorine (0.10 mole) was added slowly to the reaction flask while 1(2-furyl)-1-ethanol (0.09 mole) was added dropwise. The temperature of the reaction mixture was not allowed to exceed 10° C. Bromine (0.10 mole) was then added and the reaction mixture heated to reflux. Following the isolation procedure of Example 1, a yield of 5.7 g of maltol was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([Li])CCC.[Cl:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23](=[O:24])[C:18]=2[CH:17]=1.Cl>C1COCC1.CCOC(C)=O>[Cl:15][C:16]1[CH:32]=[CH:31][C:19]([NH:20][C:21](=[O:22])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:18]([C:23](=[O:24])[C:3]2[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:17]=1
Reactant: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Reactant: COc1cccc(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(F)c1C(=O)c1cc(Cl)ccc1NC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a solution of 1-fluoro-3-methoxy-benzene (19.6 g, 155 mmol) in THF (180 mL), at −78° C., was added dropwise 2.5 M n-butyllithium in hexanes (62 mL, 155 mmol). The solution was stirred at −78° C. for 3 h and then added to a suspension of 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one (38.8 g, 150 mmol) in THF (280 mL) at −20° C. The mixture was allowed to gradually warm until the solution became homogenous. 1N HCl (150 mL) followed by EtOAc (250 mL) were then added and the solution allowed to warm to room temperature. The organic portion was collected and washed with H2O (250 mL), saturated NaHCO3 (2×250 mL) and H2O (250 mL). The organic portion was then dried over Na2SO4 and evaporated to dryness, in vacuo, to provide the N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide as an orange solid (42.7 g). To a solution of N-[4-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-phenyl]-benzamide (42.7 g, 110 mmol) in MeOH (540 mL) was added KOH (56.4 g, 1 mole) in H2O (100 mL). The solution was allowed to reflux for 16 h. The solution was then allowed to cool to room temperature and the resulting precipitate removed by filtration. The filtrate was concentrated in vacuo, diluted with EtOAc (250 mL) and washed with H2O (3×100 mL). The organic portion was then dried over Na2SO4, concentrated in vacuo and then purified by column chromatography (silica gel, 0 to 15% EtOAc/hexanes) to provide 1ac (19.6 g, 47%) MS m/z=280 (M+H).
Reaction SMILES: [F:1][C:2]1([F:13])[CH:10]([F:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[NH3:14].[BH4-].[Na+].Cl.[OH-].[Na+]>CCO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CCOCC>[NH2:14][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([F:11])[C:2]1([F:13])[F:1]
Reactant: O=C1c2ccccc2C(F)C1(F)F
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: NC1c2ccccc2C(F)C1(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2,2,3-trifluoro-indanone (282 mg, 1.5 mmol), titanium isopropoxide (0.886 ml, 2.99 mmol) and ammonia (2M in EtOH, 2.5 ml) in EtOH was stirred for 5 hours. The mixture was cooled to 0° C. and NaBH4 (85 mg, 2.25 mmol) added. After stirring for 2 hours the mixture was left at room temperature overnight, then poured onto NH4OH (25%, 10 ml) and extracted with EtOAc. The organic phase was washed with water, dried, and evaporated to yield the crude product (205 mg) as a brown oil. This was shaken between ether and HCl (2M aq.), basified with NaOH (2M) and extracted into ether. Evaporation yielded 1-amino-2,2,3-trifluoro-indane (90 mg) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:38](Cl)(=[O:40])=[O:39])[CH2:36][CH3:37]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:38]([CH2:35][CH2:36][CH3:37])(=[O:40])=[O:39])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, propanesulfonyl chloride.