Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([N:13]1[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[F:32])([C:23]#[N:24])[C@H:14]1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[F:40])=[O:12].[Li+].[OH-]>C1COCC1.O>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][N:13]2[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:41])=[O:2])=[O:12])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccccc1NC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1CN(C(=O)Nc2ccccc2C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 23 h
Yield: 94.8 %

Procedure:
To a mixture of rac-2-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-benzoic acid methyl ester (53.0 mg, 0.0883 mmol, Example C3) in THF (3 mL) was added a solution of LiOH (Aldrich, 21.8 mg, 0.52 mmol) in water (2 mL) and the reaction mixture was stirred at rt for 23 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 4-5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give 2-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid (49.1 mg, 95%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O3+H [(M+H)+]: 586.1471; Found: 586.1474.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Li+].[O:7]1[C:9]([CH3:11])([CH3:10])[CH2:8]1.[Br:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].O>C(OCC)C>[Br:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][CH2:8][C:9]([CH3:11])([OH:7])[CH3:10]
Reactant: CC1(C)CO1
Reactant: Cc1cccc(N)c1Br
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(NCC(C)(C)O)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of lithium perchlorate (2.13 g, 20 mmol) in diethyl ether (4 mL) was added 1,2-epoxy-2-methylpropane (0.195 mL, 2.2 mmol), followed by 2-bromo-3-methylaniline (0.250 mL, 2 mmol) under an atmosphere of nitrogen gas. The reaction mixture was stirred overnight at RT. Water was added dropwise, and the product was extracted from the reaction mixture with DCM. The organic phase was dried over MgSO4. The solvent was removed under reduced pressure and the remaining residue was purified by flash chromatography (10-40% hexanes/EtOAc). 1-(2-bromo-3-methylphenylamino)-2-methylpropan-2-ol was obtained as a clear colorless oil.
Reaction SMILES: [NH2:1][C:2](=[O:29])[CH2:3][O:4][CH2:5][C:6]1[N:10]=[C:9]([C@H:11]([CH2:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[O:8][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2](=[O:29])[CH2:3][O:4][CH2:5][C:6]1[N:10]=[C:9]([C@H:11]([CH2:20][CH2:21][CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][C:13]([OH:15])=[O:14])[O:8][N:7]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(COCC(N)=O)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
A solution of tert-butyl (3R)-3-{3-[(2-amino-2-oxoethoxy)methyl]-1,2,4-oxadiazol-5-yl}-6-cyclohexylhexanoate (Preparation 90) (280 mg, 0.86 mmol) in dichloromethane (7 ml) was treated with trifluoroacetic acid (3 ml) and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene and dichloromethane. The oil was purified by column chromatography on silica gel eluting with a gradient system of 100:0:0 (dichloromethane:methanol:acetic acid) gradually changing to 90:10:1 (dichloromethane:methanol:acetic acid) to afford a colourless oil which was triturated with diethyl ether and filtered to afford the title compound (155 mg).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.O.[NH2:15][NH2:16]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:10]([NH2:11])=[N:15][NH:16][C:8]=2[NH2:9])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)Cc1ccc(F)cc1
Reactant: NN
Solvent: O
Product: Nc1n[nH]c(N)c1Cc1ccc(F)cc1

Procedure:
The product from Example 5A (1.5 g, 8.61 mmol) and hydrazine monohydrate (2.111 mL, 43.1 mmol) was processed using the method analogous to that described in Example 1B to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.96 (s, 1H) 7.15-7.51 (m, 2H) 6.79-7.11 (m, 2H) 4.30 (s, 4H) 3.48 (s, 2H). MS (ESI) m/z 259.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[S:3]([NH:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][O:12][C:11]1=[O:16])(=[O:5])=[O:4].C(=O)([O-])O.[Na+].Cl[C:29]([O:31][CH2:32][CH2:33][CH3:34])=[O:30].O>C(#N)C>[CH2:32]([O:31][C:29]([N:6]([C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][O:12][C:11]1=[O:16])[S:3]([C:2]([F:1])([F:21])[F:22])(=[O:5])=[O:4])=[O:30])[CH2:33][CH3:34]
Reactant: O=C1OCCCN1Cc1ccccc1NS(=O)(=O)C(F)(F)F
Reactant: CCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCOC(=O)N(c1ccccc1CN1CCCOC1=O)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 68.2 %

Procedure:
3-[2-(Trifluoromethanesulfonylamino)benzyl]-[1,3]-oxazinan-2-one (0.13 g, 0.38 mmol) and sodium hydrogen carbonate (0.06 g, 0.71 mmol) was suspended in acetonitrile (15 ml), added with propyl chloroformate (0.09 g, 0.77 mmol) and heated to reflux for six hours. After cooling to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to obtain 3-{2-[N-(propoxycarbonyl)-N-(trifluoromethanesulfonyl)amino]benzyl)-[1,3]-oxazinan-2-one (0.11 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([O:28][C:29]3[C:36]([CH3:37])=[CH:35][C:32]([C:33]#[N:34])=[CH:31][C:30]=3[CH3:38])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN1C=CC=CC1=O>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([O:28][C:29]3[C:30]([CH3:38])=[CH:31][C:32]([C:33]#[N:34])=[CH:35][C:36]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(F)nc2c1ccn2Cc1ccccc1
Agent: Cn1ccccc1=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To a solution of 4-aminobenzonitrile (54 mg, 0.46 mmol) in 1-methyl-2-pyridone (1 mL) was added NaH (18 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 4-(7-benzyl-2-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3,5-dimethyl-benzonitrile (34 mg, 0.091 mmol) in 1-methyl-2-pyridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water, and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 28 mg (65%) of 4-[7-benzyl-2-(4-cyano-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3,5-dimethyl-benzonitrile.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12](OC)=[O:13])[CH3:8]>C1COCC1>[CH2:7]([C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:16]=[CH:17][CH:18]=1)[CH3:8]
Reactant: CCc1cccc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (3.1 mL of 1.0 M solution in THF, 3.1 mmol) was added to a solution of methyl 3-ethylbenzoate (500 mg, 3.05 mmol) in THF (12 mL) at 0° C. After 2 h at 0° C., the reaction was quenched by the addition of saturated aqueous Rochelle's salt (50 mL) and stirred vigorously overnight at room temperature. The reaction mixture was extracted with Et2O (3×100 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford (3-ethylphenyl)methanol which was shown to be ˜90% pure by 1H NMR analysis and was taken on without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[CH2:6].[O:11]1[CH:15]=[CH:14][CH2:13][CH2:12]1>Cl.C(OCC)C>[O:11]1[CH2:12][CH2:13][CH2:14][CH:15]1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:12]1[CH2:13][CH2:14][CH2:15][O:11]1)[CH:5]=[CH2:6]
Reactant: C=Cc1ccc(O)c(O)c1
Reactant: C1=COCC1
Agent: Cl
Solvent: CCOCC
Product: C=Cc1ccc(OC2CCCO2)c(OC2CCCO2)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To 38.1 g (0.28 mol) of 3,4-dihydroxystyrene and 118 g (1.68 mol) of 2,3-dihydrofuran are added 5 drops of concentrated hydrochloric acid, whereupon an exothermic reaction ensues. The solution is stirred for 4 h at 50° C. and then poured on to a mixture of ice-water and diethyl ether. After two extractions with diethyl ether, the organic phase is washed three times at 0° C. with 1N NaOH and dried over Na2SO4. The solvent is removed by evaporation to leave a clear liquid which is purified by distillation in a bulb tube (155° C./0.02 torr) or by column chromatography (silica gel, hexane/ethyl acetate 4:1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[C:7]([CH2:9]Br)=[CH2:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[C:1]([O:5][C:6](=[O:11])[C:7]([CH2:9][N:25]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH2:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: C=C(CBr)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(CN(Cc1ccccc1)Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
A solution of 2-(bromomethyl)propenoic acid t-butyl ester (20 g, 90.5 mmole) in dry acetonitrile (360 ml), cooled to 0° C., was treated with solid potassium carbonate (15.63 g, 113 mmole), followed by a solution of dibenzylamine (17.83 g, 90.5 mmole), in dry acetonitrile (600 ml), producing a 10° C. exotherm. The reaction was stirred at 0° C. for 0.5 hours, followed by 1 hour at room temperature, and then partitioned between water and diethyl ether. The ether phase was washed again with water, dried (sodium sulphate) and evaporated to yield the crude product (31 g) which was filtered through a pad of silica, eluting with hexane/CH2Cl2 (1:1), to yield 2-(dibenzylaminomethyl)propenoic acid t-butyl ester (23.8 g, 78%) as a solid, m.p. 62°-63° C. Found: C,78.09; H,8.20; N,4.18. C22H27NO2 requires C,78.3; N,8.06; N,4.15 %.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](Cl)=[O:10].C(=O)=O.[CH3:15][C:16](C)=O.C(OCC)C>ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][C:9](=[O:10])[CH2:16][CH2:15]2
Reactant: O=C(Cl)Cc1ccccc1Cl
Reactant: CC(C)=O
Agent: O=C=O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C1CCc2cccc(Cl)c2C1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
To a slurry of 46.5 gm (0.348 mole) AlC3 in 400 mL dichloromethane at -78° C. was added a solution of 32.76 gm (0.174 mole) of the previously prepared o-chlorophenylacetyl chloride in 100 mL dichloromethane dropwise over 1 hour. The dry ice/acetone bath then was replaced with an ice/water bath and ethylene was bubbled into the reaction mixture during which time the temperature rose to 15° C. The ethylene addition was discontinued at the end of the exotherm and the reaction mixture was stirred at about 5° C. for 4 hours. Ice was then added to the reaction mixture to destroy aluminum complexes. Upon termination of the exotherm, the reaction mixture was diluted with 500 mL of water and stirred vigorously until all solids had dissolved. The phases were separated and the organic phase was washed with 3×400 mL 1N hydrochloric acid and 2×400 mL saturated aqueous sodium bicarbonate. The remaining organic phase was then dried over sodium sulfate and concentrated in vacuo to give a pale orange residue. The residue was dissolved in 1:1 hexane:diethyl ether and was poured over a flash silica column which was then eluted with 1:1 hexane:diethyl ether to give a light yellow residue which was crystallized from 4:1 hexane:diethyl ether to give 10.55 gm of the title compound.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[S:18][CH2:17][C:16]3[CH:15]=[N:14][NH:13][C:12]=3[C:10]=2[CH:11]=1)([O-])=O>O.C(O)C.[Fe]>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]2[S:18][CH2:17][C:16]3[CH:15]=[N:14][NH:13][C:12]=3[C:10]=2[CH:11]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)-c1[nH]ncc1CS2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)-c1[nH]ncc1CS2
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
To a stirred mixture of iron powder (8.53 g) and ammonium chloride (0.85 g) in water (22 ml) and ethanol (66 ml) was added portionwise 8-nitro-1,4dihydro[1]benzothiopyrano[4,3-c]pyrazole (6.6 g) under reflux over a period of 15 minutes. After being stirred for 30 minutes under reflux, the mixture was filtered and the filtrate was evaporated in vacuo. To the residue were added aqueous sodium bicarbonate and ethyl acetate and the mixture was stirred at room temperature. The resulting precipitate was collected by filtration, washed with water, and recrystallized from a mixture of tetrahydrofuran and methanol to give 8-amino-1,4-dihydro[1]benzothiopyrano[4,3-c]pyrazole (3.79 g).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[CH2:10][O:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][CH:12]([OH:15])[CH2:13][CH3:14]>CN(C=O)C.[H-].[Na+]>[CH:12]([O:15][CH2:10][CH:8]([OH:9])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH2:13][CH3:14])[CH3:11]
Reactant: C1CCC(C[C@H]2CO2)CC1
Reactant: CCC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)OCC(O)CC1CCCCC1
Yield: 55.2 %

Procedure:
The product from Example 1308C (420 mg, 3.0 mmol) in DMF (3.0 mL), 2-butanol (1.1 mL, 12.0 mmol) in DMF (6.0 mL) and NaH, 60% dispersion in mineral oil, (240 mg, 6.0 mmol) in DMF (12 mL) were allowed to react in a manner similar to that described in Example 1308D. The residue was chromatographed (silica gel; EtOAc/hexanes, 1:12) to afford a clear oil (355 mg, 55%). MS (CI/NH3) m/z: (M+NH4)+ 232.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].Cl[CH:6]1[C:14]2[C:9](=CC=[CH:12][CH:13]=2)[C:8]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:7]1>[O-2].[O-2].[O-2].[Cr+6].O>[C:8]12([CH2:15][CH2:16][CH2:17][CH2:18]1)[C:7]1[C:2](=[CH:12][CH:13]=[CH:14][CH:6]=1)[C:1](=[O:4])[CH2:9]2
Reactant: ClC1CC2(CCCC2)c2ccccc21
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Product: O=C1CC2(CCCC2)c2ccccc21

Procedure:
To a mixture of acetic acid (75 ml), water (75 ml) and chromium trioxide (75 g; 0.75 moles) there are added dropwise under agitation 3'-chlorospiro(cyclopentane-1,1'-indan) (103 g; 0.5 moles), the temperature being held at 30°-40° C. by external cooling.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1>>[O-:35][N+:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[N:1]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])[CH:2]=[N:3][C:4]=2[CH:5]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(CCCCCn1cnc2cnc3ccccc3c21)c1ccccc1
Product: O=C(CCCCCn1cnc2c[n+]([O-])c3ccccc3c21)c1ccccc1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 6-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one (2.0 g, 5.8 mmol) by reaction with m-CPBA (1.44 g, 6.41 mmol) to provide 6-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one followed by reaction with p-toluenesulfonyl chloride (1.22 g, 6.41 mmol) and ammonium hydroxide solution (10 mL) to provide 6-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylhexan-1-one (0.29 g) as an off-white solid after chromatography on silica gel (elution with 5% methanol in dichloromethane) and recrystallization from dichloroethane, mp 163-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[N:32]=[C:33]=[O:34]>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[NH:32][C:33]([NH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20])=[O:34]
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F)Nc1cc(C(F)(F)F)ccc1F
Yield: 80 %

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 2-fluoro-5-trifluoromethyl-phenylisocyanate to afford the title compound, yield=80%.
Reaction SMILES: N[C@@H](C(C)C)[C@@H](C1C=CC=CC=1)O.[NH2:14][C@@H:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17].BrCCCCBr.[O:36]([CH2:40][CH2:41]Br)[CH2:37][CH2:38]Br>CCOC(C)=O.CCCCCC>[C:18]1([C@@H:16]([OH:17])[C@H:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:14]2[CH2:41][CH2:40][O:36][CH2:37][CH2:38]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H](c1ccccc1)[C@H](O)c1ccccc1
Reactant: BrCCOCCBr
Agent: CC(C)[C@H](N)[C@H](O)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: BrCCCCBr
Product: O[C@H](c1ccccc1)[C@H](c1ccccc1)N1CCOCC1
Yield: 95 %

Procedure:
Repeat Step (a) of EXAMPLE 6, but replace (1R,2S)-2-amino-1-phenyl-3-methyl-butanol with (1R,2S)-2-amino-1,2-diphenylethanol, and replace 1,4-dibromobutane with (BrC2H4)2O. Column chromatography (Silica gel 50 g, eluent is n-Hexane:EtOAc=4:1) is used to purify the coarse product and a white solid (1.34 g) is obtained. The yield is 95% and the other analysis includes:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:42]([CH3:43])=[N:41][C:40]2=[CH:44][C:37]3=[N:38][N:39]2[C:12]=1[C:13]1[CH:47]=[C:46]2[C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[CH:45]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[C:15]([F:48])[CH:14]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:42]([CH3:43])=[N:41][C:40]2=[CH:44][C:37]3=[N:38][N:39]2[C:12]=1[C:13]1[CH:47]=[C:46]2[C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[CH:45]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[C:15]([F:48])[CH:14]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1-c1cc(F)c2c(c1)N(CCCCCc1ccccc1-c1cccc-3c1)CCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)-c1cc(F)c2c(c1)N(CCCCCc1ccccc1-c1cccc-3c1)CCO2
Temperature: 70 °C
Yield: 45.4 %

Procedure:
A solution of methyl (2S)-2-(tert-butoxy)-2-{31-fluoro-4-methyl-29-oxa-5,7,8,26-tetraazaheptacyclo[24.6.2.16,9.110,14.02,7.015,20.030,34]hexatriaconta-1(32),2,4,6(36),8,10(35),11,13,15(20),16,18,30,33-tridecaen-3-yl}acetate (0.063 g, 0.097 mmol) in MeOH (2 mL) was treated with NaOH (0.24 mL, 0.48 mmol) and the reaction was heated (70° C. oil bath) for 2.5 hrs. The reaction was cooled and then purified by prep-HPLC to afford the desired product (0.0278 g, 0.044 mmol, 45.2% yield). LCMS (M+H)=635.5.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)=[O:38]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCNC4)c[nH]c23)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide hydrochloride (example A168) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH:15]=[N:16][CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.C(OCC)(=O)C.C(Cl)Cl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][NH:16][CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)N=CSC12
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)NCSC12
Temperature: 10 °C
Reaction time: 1.25 h
Yield: 87.6 %

Procedure:
To a solution of benzyl 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]oct-3-ene-2-carboxylate (3.0 g.) in tetrahydrofuran (22 ml.) was added alminum amalgam at 4° C., which was prepared by alminium power (1.8 g.) and 0.5% mercuric chloride (4 ml.), and water (0.75 ml.) was added dropwise thereto. After the mixture was stirred at 10° C. for 75 minutes under nitrogen atmosphere, the reaction mixture was diluted with ethyl acetate (50 ml.) and filtered through a pad of Celite. The filter cake was washed with ethyl acetate, and the filtrate and washings were combined, washed twice with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to leave an oil (2.7 g.). Chromatography on silica gel (15 g.) with a mixed solvent of methylene chloride and ethyl acetate (5:1 by volume) as an eluent gave an amorphous solid (2.64 g.) of benzyl 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate.