Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[N:11]([CH2:15][CH2:16][CH3:17])[CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][NH2:22].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:20][O:21]/[N:22]=[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)\[CH2:9][C:10]1[N:11]([CH2:15][CH2:16][CH3:17])[CH:12]=[CH:13][N:14]=1
Reactant: CCCn1ccnc1CC(=O)c1ccc(N)cc1
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCn1ccnc1C/C(=N\OC)c1ccc(N)cc1
Yield: 34.2 %

Procedure:
A solution of 1-(4-aminophenyl)-2-(1-propylimidazol-2-yl)ethanone (600 mg) and O-methylhydroxylamine hydrochloride (227 mg) in ethanol (20 ml) was refluxed for 8 hours. After the mixture was allowed to be at room temperature, and saturated sodium bicarbonate solution was added to the mixture, the mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1), and washed with diisopropyl ether to give (1E)-1-(4-aminophenyl)-2-(1-propylimidazol-2-yl)ethanone O-methyloxime (230 mg) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH:44][NH2:45])(=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CC1C=CC(C)=CC=1>[C:37]1([C:36]2[N:26]3[C:21]4[CH:20]=[C:19]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:18]([C:15]5[CH:16]=[CH:17][C:12]([C:8]6([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]6)=[CH:13][CH:14]=5)=[N:28][C:22]=4[O:23][CH2:24][C:25]3=[N:45][N:44]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccccc3)CO4)cc2)CCC1
Temperature: 150 °C
Yield: 39.3 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.205 mmol) and benzoic acid hydrazide (84 mg, 0.615 mmol) in p-xylene (2 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexane) to give the title compound (46 mg, 40%). LCMS (Method D): RT=1.546 min, M+1=572. 1H NMR (500 MHz, CDCl3): 7.77-7.69 (2H, m), 7.64-7.57 (2H, m), 7.56-7.50 (1H, t), 7.49-7.41 (2H, t), 7.34-7.30 (2H, m), 7.28 (1H, s), 7.22-7.14 (3H, m), 6.95-6.90 (2H, dd), 5.65 (2H, s), 2.55-2.40 (3H, m), 2.15-2.01 (2H, m), 1.89-1.77 (1H, m), 1.46-1.24 (9H, bs).
Reaction SMILES: [CH:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:25]=[C:24]([CH3:26])[O:23][N:22]=3)[CH:16]=2)[C:7]2[C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28]>ClCCl>[CH:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:25]=[C:24]([CH3:26])[O:23][N:22]=3)[CH:16]=2)[C:7]2[C:8](=[O:12])[N:9]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:27]#[N:28])[CH:34]=3)[CH:10]=[CH:11][C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cccc(Cn3c(C(C)C)nc4cc[nH]c(=O)c43)c2)no1
Reactant: N#Cc1cccc(B(O)O)c1
Solvent: ClCCl
Product: Cc1nc(-c2cccc(Cn3c(C(C)C)nc4ccn(-c5cccc(C#N)c5)c(=O)c43)c2)no1

Procedure:
By reaction of 2-isopropyl-3-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzyl]-3,5-dihydroimidazo[4,5-c]pyridin-4-one with 3-cyanophenylboronic acid under copper acetate catalysis in dichloromethane, 2-isopropyl-3-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzyl]-5-(3-cyanophenyl)-3,5-dihydroimidazo[4,5-c]pyridin-4-one is obtained. By subsequent reaction in ethanol NaHCO3 and then with hydroxylammonium chloride, 2-isopropyl-3-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)benzyl]-5-(3-N-hydroxyamidinophenyl)-3,5-dihydroimidazo[4,5-c]pyridin-4-one is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH:10]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:14])[CH:13]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:7][C:8]1[N:9]([C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)[CH:10]=[C:11]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12](=[O:14])[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(=O)c(OCc2ccccc2)cn1-c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl[5-(benzyloxy)-1-(biphenyl-3-yl)-4-oxo-1,4-dihydropyridin-2-yl]carbamate (4.68 g, 10 mmol) was added TFA-DCM (1:1, 60 mL), and the resulting solution was stirred for 1 h at rt. The solution was then concentrated and treated with saturated aq. NaHCO3-EtOAc. The organic layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated to give 2-amino-5-(benzyloxy)-1-(biphenyl-3-yl)pyridin-4(1H)-one as a slightly yellow solid 1H NMR (500 MHz, DMSO): ä 7.82 (ddd, J=7.8, 1.8, 1.0 Hz, 1 H); 7.76-7.73 (m, 2 H); 7.67-7.61 (m, 2 H); 7.53-7.47 (m, 2 H); 7.43-7.34 (m, 6 H); 7.33-7.29 (m, 1 H); 7.04 (s, 1 H); 5.65 (s, 2 H); 5.49 (s, 1 H); 4.89 (s, 2 H).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[C:7]1[S:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(#N)C>[NH:16]([C:7]1[S:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Reactant: Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1sc(Nc2ccccc2)nc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
252 g (3.0 mols) of sodium bicarbonate are added to a solution of 360 g (1.8 mols) of 2,4-dichloro-5-nitrothiazole in 1.5 l of acetonitrile. A mixture of 139.5 g (1.5 mols) of aniline and 1,500 ml of acetonitrile is then added dropwise at -10° C. to -15° C. in the course of about 4.5 hours and the mixture is subsequently stirred at the same temperature for a further 4 hours. It is then stirred into 15 l of ice-water and the precipitate is filtered off, washed with water and dried. To remove excess 2,4-dichloro-5-nitrothiazole, the product is stirred into 2.4 l of petroleum ether at room temperature, filtered off, washed with petroleum ether and dried. 361.7 g (94.4% of theory) of 2-anilino-4-chloro-5-nitrothiazole of melting point 186° C. to 187° C. (decomposition) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C@H:5]([C:9](=[O:28])[N:10]1[C@@H:14](C2C=CC=CC=2)[C@@H:13]([C:21]2C=C[CH:24]=[CH:23][CH:22]=2)O[C:11]1=O)[CH2:6]C=O.C1(N)CCCCC1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:3]=1[CH2:4][C@H:5]1[CH2:6][CH2:11][N:10]([CH:14]2[CH2:13][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:9]1=[O:28]
Reactant: O=CC[C@H](Cc1c(F)cccc1Cl)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: NC1CCCCC1
Solvent: C1CCOC1
Product: O=C1[C@@H](Cc2c(F)cccc2Cl)CCN1C1CCCCC1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
Dissolve (S)-3-(2-Chloro-6-fluoro-benzyl)-4-oxo-4-((4S,5R)-2-oxo-4,5-diphenyl-oxazolidin-3-yl)-butyraldehyde (Preparation 85) (0.384 g, 0.825 mmol) in THF (20 mL). Add cyclohexanamine (0.098 g, 0.99 mmol) and AcOH (0.049 g, 0.82 mmol). Stir the mixture for one hour and then add NaBH(OAc)3 (0.262 g, 1.24 mmol). Stir the reaction mixture for 24 hours until LC-MS shows the starting material has been gone. Add water (20 mL) and extract the aqueous with CH2Cl2 (3×50 mL). Combine the organic layers and dry over Na2SO4. Concentrate and purify by chromatography (Silica gel) to afford (S)-3-(2-Chloro-6-fluorobenzyl)-1-cyclohexylpyrrolidin-2-one (0.172 g, 67%). MS (APCI-pos mode) m,/z (rel intensity) 310 (100), 312 (35).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:12]1([O:17][C:18]2[C:19]([O:47][CH3:48])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]([CH2:28][CH2:29][O:30]C2CCCCO2)[C:25](=[O:37])[CH:24]=[C:23]3[NH:38][C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[CH:41][C:40]=2[Cl:46])[CH2:16][CH2:15][CH2:14][CH2:13]1>CO>[CH:12]1([O:17][C:18]2[C:19]([O:47][CH3:48])=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]([CH2:28][CH2:29][OH:30])[C:25](=[O:37])[CH:24]=[C:23]3[NH:38][C:39]2[C:40]([Cl:46])=[CH:41][N:42]=[CH:43][C:44]=2[Cl:45])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)n(CCOC3CCCCO3)c2c1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)n(CCO)c2c1OC1CCCC1
Reaction time: 8 h

Procedure:
p-Toluenesulfonic acid (172 mg, 1.0 mmol) was added to a solution of 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)quinolin-2(1H)-one (2.4 g, 4.4 mmol) and methanol (100 mL). After stifling overnight, the reaction was concentrated, diluted with dichloromethane (100 mL), and then washed with sat'd NaHCO3 (20 mL) followed by water (20 mL). The organic layer was dried, filtered, concentrated, and recrystallized from dichloromethane/petroleum ether (1:2) to give 8-(cyclopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-1-(2-hydroxyethyl)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 2H), 8.73 (s, 1H), 7.91 (d, 1H), 7.11 (d, 1H), 4.92 (s, 1H), 4.65 (t, 2H), 4.59 (m, 1H), 4.50 (t, 1H), 3.90 (s, 3H), 3.32 (m 2H), 1.80-1.48 (m, 8H); MS (ESI): 463.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:20]([CH3:26])([CH2:23][CH:24]=[CH2:25])[CH:21]=[O:22])=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:7]=[CH:6]2.CC(=CC)C.P([O-])(O)(O)=[O:33].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.CCOC(C)=O>[C:16]([O:15][C:13]([N:8]1[C:9]2[C:5](=[C:4]([C:20]([CH3:26])([CH2:23][CH:24]=[CH2:25])[C:21]([OH:33])=[O:22])[C:3]([O:2][CH3:1])=[CH:11][C:10]=2[CH3:12])[CH:6]=[CH:7]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: O=P([O-])(O)O
Reactant: C=CCC(C)(C=O)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: C=CCC(C)(C(=O)O)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To (±)-tert-butyl 5-methoxy-7-methyl-4-(2-methyl-1-oxopent-4-en-2-yl)-1H-indole-1-carboxylate (Example 156-C) (2 g, 5.60 mmol) in tert-butanol (37.3 mL) and water (18.65 mL) was added 2-methyl-2-butene (5.93 ml, 56.0 mmol), sodium dihydrogen phosphate (2.69 g, 22.38 mmol) and then sodium chlorite (2.53 g, 22.38 mmol). The reaction was allowed to stir at room temperature overnight for 17 hours. At this point the reaction was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated to obtain the title compound that was use in the next step without further purification. MS (ESI+) m/z 374.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:27])[CH2:17][CH2:16][C:15]([CH2:25][NH2:26])([C:18]2[CH:19]=[N:20][C:21]([CH3:24])=[N:22][CH:23]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:15]1([C:18]2[CH:23]=[N:22][C:21]([CH3:24])=[N:20][CH:19]=2)[CH2:16][CH2:17][C:12]([F:11])([F:27])[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: Cc1ncc(C2(CN)CCC(F)(F)CC2)cn1
Product: Cc1ncc(C2(CNC(=O)c3ccccc3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2-chlorobenzoic acid and C-[4,4-difluoro-1-(2-methyl-pyrimidin-5-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=380.1, tR (minutes, Method F)=2.37
Reaction SMILES: [Na].CS(C)=O.[OH:6][C:7]1[N:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1.Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CO>[CH2:24]([O:23][C:21]([CH:20]([O:6][C:7]1[N:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:8]=1)[CH3:26])=[O:22])[CH3:25]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1nc(O)nn1-c1ccccc1
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1nc(C)n(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A 3.2 g portion of sodium was dissolved in 50 ml of methanol, and the solution was added to 100 ml of dimethylsulfoxide. To it was added 24.6 g of 3-hydroxy-5-methyl-1-phenyl-1,2,4-1H-triazole, and the solution was heated on the steam bath for 2 hours, adding 100 ml of additional dimethylsulfoxide. To the solution was then added 25.4 g of ethyl 2-bromopropionate, and heating was continued for 2 hours more. The reaction mixture was then cooled, poured over ice-water, and extracted with 300 ml of chloroform. The extract was washed with water and with saturated brine, and was dried with sodium sulfate and phase separation paper. The solvent was removed under vacuum, and the product was distilled at 1.2 mm of mercury and 192° to obtain 20 g of the desired product, an oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:18]1([CH2:21][C:22]([NH2:30])([CH3:29])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1.CO>CCCCCCC>[CH:18]1([CH2:21][C:22]([NH:30][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([CH3:29])[C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH2:20][CH2:19]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CO
Solvent: CCCCCCC
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 357e) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/10% 2-propanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 397.2244 (M+H)+, αD20 (MeOH)=−22.3°.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:5][C@@H:4]([NH:29][S:30](N2CCOC2=O)(=[O:32])=[O:31])[CH2:3]1.Cl.CN.C(N[C@@H]1C[C@H](C(O)=O)[C@H](C)C1)(=O)C.[F:55][C:56]([F:63])([F:62])[C@H:57]1[CH2:61][CH2:60][CH2:59][NH:58]1>CC#N>[CH3:1][C@H:2]1[C@@H:6]([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:20])=[O:21])[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][N:8]=2)[CH2:5][C@@H:4]([NH:29][S:30]([N:58]2[CH2:59][CH2:60][CH2:61][C@@H:57]2[C:56]([F:63])([F:62])[F:55])(=[O:32])=[O:31])[CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@H]4C[C@@H](NS(=O)(=O)N5CCOC5=O)C[C@H]4C)n23)cc1
Reactant: FC(F)(F)[C@H]1CCCN1
Agent: CC(=O)N[C@H]1C[C@@H](C)[C@@H](C(=O)O)C1
Agent: CN
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@H]4C[C@@H](NS(=O)(=O)N5CCC[C@@H]5C(F)(F)F)C[C@H]4C)n23)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
To a solution of N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)-2-oxooxazolidine-3-sulfonamide (0.200 g, 0.261 mmol, prepared from 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (WO2009152133) and (1S,2R,4S)-4-acetamido-2-methylcyclopentanecarboxylic acid [prepared from ethyl 4-amino-2-methyl-cyclopentanecarboxylate (WO2009152133) using G, AA, and Z] using H, OO, BB, and ZZ) and (R)-2-trifluoromethylpyrrolidine (0.055 g, 0.392 mmol) in MeCN (1.4 mL) was added TEA (0.073 mL, 0.523 mmol). The reaction was irradiated in a CEM microwave at about 120° C. for about 0.5 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure to afford a residue. The crude material was purified by silica gel chromatography eluting with a gradient of 0-70% EtOAc in DCM to afford (R)-N-((1S,3R,4S)-3-methyl-4-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)cyclopentyl)-2-(trifluoromethyl)pyrrolidine-1-sulfonamide (0.12 g, 75%, 72% purity) as an off-white solid: LC/MS (Table 1, Method a) Rt=2.79 min; MS m/z: 611 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=2[F:27])=[O:18])=[N:5][CH:4]=1.Cl.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:27][C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:17]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:3]([CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:4][N:5]=1)=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(F)c(C(=O)c2ncc(CN)c3cc(OC)c(OC)cc23)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(F)c(C(=O)c2ncc(CNS(C)(=O)=O)c3cc(OC)c(OC)cc23)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
(4-Aminomethyl-6,7-dimethoxy-isoquinolin-1-yl)-(2-fluoro-5-methoxy-phenyl)-methanone (Example 27) (100.5 mg, 0.2269 mmol) was suspended in 5 ml of methylene chloride. The solution was cooled to −78° C. and methanesulfonyl chloride (0.0195 ml, 1.10 eq) was added followed by the addition of N,N-diisopropylethylamine (0.122 ml, 3.0 eq). The mixture was stirred at −78° C. for 1 hr and then at room temperature overnight. The mixture was evaporated and the residue was purified through a flash column chromatography using ethyl acetate and hexane (4/1 ratio) to give N-[1-(2-Fluoro-5-methoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-ylmethyl]-methanesulfonamide (70 mg, 69%). ES-MS calcd for C21H21N21O6S (m/e) 448.47, obsd 449.0 (M+H).
Reaction SMILES: [C:1]([O:4][CH:5](Cl)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O-:27])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15].[K+].[I-].[Na+]>CN(C=O)C>[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O:27][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: CC(=O)OC(Cl)Cc1ccccc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(Cc2ccccc2)OC(C)=O)c(I)c(N(C)C(C)=O)c1I
Reaction time: 21 h

Procedure:
1-Chloro-2-phenylethyl acetate (Intermediate 9) (4.20 g, 21.1 mmol) in dry DMF (25 ml) is added dropwise at 50° C. to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (15.5 g, 23.2 mmol) and sodium iodide (158 mg, 1.0 mmol) in dry DMF (300 ml). The precipitate is removed by filtration after stirring for 21 hours and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (200 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>CC(C)=O>[C:35]([O:41][CH2:42][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To (+)-3-hydroxy-N-(benzyloxycarbonyl)morphinan (12.0 g, 31.8 mmol) from Example 1 and cesium carbonate (11.4 g, 35.0 mmol) in acetone (150 mL) was added iodomethyl pivalate (8.46 g, 35.0 mmol) (see Bristol-Myers Squibb Company, U.S. Pat. No. 5,470,845 A1 (1995/11/28), Appl.; US1994-266843 (1994 Jul. 5)) at room temperature. The reaction mixture was stirred vigorously at room temperature overnight. The acetone was then removed by rotary evaporation under vacuum. To the residue was added saturated NaHCO3 solution. The mixture was extracted with EtOAc (150 mL×2). The combined organics were washed with 1N HCl solution (100 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide the crude product, which was further purified by prep reverse-phase HPLC to afford the title compound (13.2 g, 84%) as a yellow gum.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])C.[K+].[CH3:7][C:8]([CH:10]1[CH2:12][CH2:11]1)=[O:9].C(OCC)(=O)C>C1COCC1>[CH:10]1([C:8](=[O:9])[CH2:7][C:2](=[O:4])[CH3:1])[CH2:12][CH2:11]1
Reactant: CC(=O)C1CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CC(=O)C1CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a stirring solution of THF (100 mL) was added potassium tert-butoxide (5.60 g, 49.5 mmol), followed by a mixture of cyclopropyl methyl ketone (3.27 mL, 33 mmol) and ethyl acetate (9.69 mL, 99 mmol) in 30 mL THF at 35° C., via addition funnel over a 25 min period. The contents were heated and stirred at 60° C. After 3 h, the contents were removed from heating, and allowed to cool to room temperature. The reaction mixture was carefully diluted with 30 mL 2 N HCl and stirred for 10 min. The mixture was extracted with diethyl ether (3×50 mL), and the combined organic layers washed with brine (1×50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (eluent: 0 to 15% EtOAc in hexanes) with good separation afforded 1-cyclopropyl-1,3-butanedione as a light yellow colored oil, 3.9 g in ˜75% purity (residual solvent), for an overall yield of 70%. 1H NMR (400 MHz, CDCl3) δ ppm 0.89-0.96 (m, 2H), 1.09-1.15 (m, 2H), 1.59-1.69 (m, 1H), 2.04 (s, 3H), 5.63 (s, 1H), 15.5-16.0 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:4]=2[N:3]=1>N.CO>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3cc(F)c(F)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3cc(F)c(F)cc32)[C@H](O)[C@@H]1O

Procedure:
Compound 64 (0.894 g, 2 mmole) was treated with 20 mL of NH3 /MeOH in a pressure bottle at room temperature for 3 hr. The reaction mixture was evaporated and coevaporated with MeOH to give a solid. This was recrystallized from MeOH to give 0.573 g (3 crops, 89%) of 65 as a crystalline compound. MP ~215° C. (dec.); MS m/e 320.0385 (20%, M+ =320.0375); 1H NMR (DMSO-d6): d 8.34 (dd, 1, 7-H, 3JF-H =11.5 Hz, 4JF-H =7.5 Hz), 7.77 (dd, 1, 4-H, 3JF-H =11.0 Hz, JF-H =7.5 Hz), 5.88 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.50 (d, 1, 2'-OH, J2-2-OH =6.5 Hz), 5.45 (t, 1, 5'-OH, J5'-5'OH =4.5 Hz), 5.30 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.40 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.14 (m, 1, 3'-H, J3'-4' =1.5 Hz), 4.01 (m, 1, 4'-H), 3.72 (m, 2, 5'-H, J5'-4' =2.5 Hz, J5'-5" =12.0 Hz); 13C NMR (DMSO-d6): d 148.53, 148.42, 148.37, 148.26, 145.88, 145.76, 145.72, 145.60 (C5 and C6, 1JF-C =241 Hz, 2JF-C =16 Hz), 140.84 (C2), 137.16, 137.04 (C3a, 3JF-C =11 Hz), 128.55, 128.42 (C7a, 3JF-C =12 Hz), 106.77, 106.54 (C4, 2JF-C =20 Hz), 102.12, 101.84 (C7, 2JF-C =25 Hz), 89.10 (C1'), 86.39 (C4'), 71.55 (C2'), 69.81 (C3'), 6.12 (C5').