Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[S:16][C:10]=3[C:9]2=[O:24])=[CH:4][C:3]=1[O:25][CH3:26].[CH2:27]([N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:28]#[CH:29].C(N(CC)CC)C.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[S:16][C:10]3[C:9](=[O:24])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:29]#[C:28][CH2:27][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[C:3]([O:25][CH3:26])[CH:4]=4)[CH2:13][CH2:12][C:11]=3[N:14]=2)=[CH:18][CH:19]=1
Reactant: C#CCN1CCCC1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1C#CCN1CCCC1
Temperature: 80 °C
Reaction time: 48 h
Yield: 11.2 %

Procedure:
Treat a suspension of 5-(4-bromo-3-methoxy-phenyl)-2-(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (0.25 mg, 0.56 mmol), 1-prop-2-ynyl-pyrrolidine (0.12 g, 1.10 mmol), dichlorobis(triphenylphosphine)palladium (II) (12.0 mg, 0.02 mmol), triethylamine (0.5 mL) in DMF with CuI (4.0 mg, 0.02 mmol). Stir at 80° C. under nitrogen for 2 days. Dilute the reaction with water and extract with CH2Cl2 (2×). Dry, filter, and concentrate the organic solution and purify the crude material by flash chromatography, using a gradient of 0-10% MeOH in CH2Cl2 to give the title compound (30.0 mg, 12%). MS (ES+) 478.0 (M+1)+. 1H NMR (400 MHz, CDCl3): δ 7.89 (d, 2H, J=8.8 Hz), 7.40 (m, 3H), 6.95 (d, 1H, J=2.2 Hz), 6.82 (dd, 1H, J=8.1, 2.0 Hz), 4.10 (t, 2H, J=6.8 Hz), 3.84 (m, 5H), 3.26 (t, 2H, J=6.8 Hz), 2.88 (m, 4H), 1.89 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3](CBr)=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C-:14]#[N:15].[Na+].[CH3:17]S(C)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:17][C:14]#[N:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: [C-]#N
Reactant: BrCc1cc2ccccc2cc1Br
Reactant: CS(C)=O
Agent: [Na+]
Product: N#CCc1cc(Br)cc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3-bromo-2-bromomethylnaphthalene (6.0 g, 0.020 mol), DMSO (150 mL) and sodium cyanide (1.0 g, 0.020 mol) was stirred for 2 hours at room temperature. The resulting solution was added to ice/H2O and extracted well with ethyl acetate. The organic phase was dried over MgSO4, concentrated and dried in vacuo for 16 hours. Treatment of the resulting solid with diethyl ether/hexane afforded 3-bromo-2-naphthalenylacetonitrile (3.6 g), m.p. 116°-117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]([CH2:17][CH3:18])[C:13]([O:15]C)=[O:14])=[CH:8][CH2:9]2)=[CH:5][CH:4]=1.[OH-].[K+]>CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]([CH2:17][CH3:18])[C:13]([OH:15])=[O:14])=[CH:8][CH2:9]2)=[CH:5][CH:4]=1
Reactant: CCC(C(=O)OC)C1=CCc2cc(OC)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C(=O)O)C1=CCc2cc(OC)ccc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of the ester prepared in Example 1 (14.0 g, 58.9 mmol) in 140 mL MeOH, was added a solution of KOH (6.4 g, 113.8 mmol) in 5 mL water. The reaction mixture was stirred at 60° C. (pot temperature) for 2 hours. TLC showed 70% conversion. A solution of KOH (3.0 g, 53.6 mmol) in 100 mL water was then slowly added to the pot. After 1 hour, the reaction was completed. After cooling to room temperature, the solvents were removed at a reduced pressure. The residue was dissolved in 500 mL water, and then washed with EtOAc. The aqueous layer was cooled in an ice-water bath, and then acidified with conc. HCl to pH<3.0. The product was extracted into 300 mL CH2Cl2, washed with water (2×100 mL), then dried over Na2SO4. After Na2SO4was filtered off, the CH2Cl2 solution was stirred with 3.0 g of charcoal for 2 hours. The charcoal was removed by filtration through a pad of Celite®. The title product (12.5 g, 95%) was obtained as a light brown solid after solvent removal and vacuum drying. 1H NMR (DMSO-d6) 612.20(b, 1H), 7.30(d, 1H), 7.06(d, 1H), 6.82(dd, 1H), 6.22(s, 1H), 3.75(s, 3H), 3.45(t, 1H), 3.30(s, 2H), 1.90(m, 1H), 1.78(m, 1H), 0.90(t, 3H).
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.[O-:11][P:12]([O:15][P:16]([O-:19])([O-:18])=[O:17])(=[O:14])[O-:13].[Na+].[Na+].[Na+].[Na+].[CH2:24]([N:28]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>O.[NH+]1C=CC=CC=1.CO>[O-:13][P:12]([O:15][P:16]([O-:19])([O-:18])=[O:17])(=[O:11])[O-:14].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36].[CH2:33]([NH+:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCN(CCCC)CCCC
Agent: O=P([O-])([O-])OP(=O)([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: CCCC[NH+](CCCC)CCCC

Procedure:
Tetrasodium diphosphate decahydrate (2.23 g, 5 mmol) was dissolved in water (50 mL), the solution was applied to a column of Dowex 50WX8 (100 mL) in the pyridinium form, and the column was washed with 300 mL water-methanol (1:1). The eluate was directly dropped into a cooled (ice water) and stirred solution of tri-n-butylamine (2.38 mL, 10 mmol) in methanol. The solution was evaporated to dryness and re-evaporated twice with methanol and finally with anhydrous DMF (30 mL) on an oil pump.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[C:4]([CH3:10])[N:3]=1.[Br:11]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([Br:11])=[C:4]([CH3:10])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(C#N)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N)c(C#N)nc1Br
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A stirred solution of 8.5 grams (0.063 mole) of 2-amino-3-cyano-6-methylpyrazine [prepared by the method of Taylor and Kobayashi; JOC, 41, 299 (1976)]in 125 mL of N,N-dimethylformamide is cooled in an ice bath, and a solution of 11.2 grams (0.063 mole) of N-bromosuccinimide in 125 mL of N,N-dimethylformamide is added dropwise during a 30 minute period, while maintaining the reaction mixture temperature at about 15°-25° C. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours. After this time, the reaction mixture is poured into 1 liter of aqueous 3N sodium hydroxide. The mixture is then diluted to a volume of about 1700 mL with distilled water. A solid precipitate is collected by filtration and dried under reduced pressure, yielding 2-amino-3-cyano-5-bromo-6-methylpyrazine.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][C:16]([NH2:18])=[O:17])[CH:10]=[CH:11][CH:12]=1.Cl.O.C[CH2:22][OH:23]>>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][N:15]2[C:2](=[O:3])[CH2:1][C:22](=[O:23])[NH:18][C:16]2=[O:17])[CH:10]=[CH:11][CH:12]=1
Reactant: CC[O-]
Reactant: COc1cccc(CCNC(N)=O)c1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cccc(CCN2C(=O)CC(=O)NC2=O)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of NaOEt (144 mmol, fleshly prepared from 3.3 g of Na) in EtOH (80 mL), a solution of ethyl malonate (2) (22 mL, 144 mmol) in EtOH (250 mL) was added. The mixture was refluxed then added a solution of [2-(3-methoxy-phenyl)-ethyl]-urea (2) (23.3 g, 120 mmol) in EtOH (300 mL). The reaction mixture was refluxed overnight, then cooled to room temperature. The mixture was acidified carefully with 1M HCl aq. then poured into water (1 L). The precipitate which was formed was collected by filtration, washed with water then dried under reduced pressure to give the title compound (23.2 g, 74%). MS (ESI) (M+H)+ 263.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([N:33](C(OC4C=CC=CC=4)=O)[C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]>CN(C)C=O>[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]([N:2]4[CH2:5][CH2:4][CH2:3]4)=[O:35])[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Reactant: C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC4)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.6 %

Procedure:
Azetidine hydrochloride (104 mg, 1.11 mmol) and triethylamine (0.155 ml, 1.11 mmol) were added to a dimethylformamide (1 ml) solution of phenyl N-(4-(1-(methylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (116 mg, 0.222 mmol) synthesized in Production example 5-2; and the reaction mixture was stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a solvent mixture of ether-hexane=1:1; and the resultant solid was filtered off to yield the title compound (50 mg) as crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[K+]>C1(C)C=CC=CC=1.O.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>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(C#N)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C#N)ccc1-c1ccc(C(F)(F)F)cc1
Yield: 94.8 %

Procedure:
A mixture of 4-bromo-3-methoxybenzonitrile (500 mg, 2.36 mmol), 4-(trifluoromethyl)phenyl boronic acid (671.9 mg, 3.54 mmol) and potassium fluoride (411 mg, 7.08 mmol) in toluene (11 mL) and water (3 mL) was purged with nitrogen. Pd(PPh3)4 (272.7 mg, 0.236 mmol) was added. The resulting mixture was heated at reflux overnight. The reaction mixture was washed with water (200 ml) and extracted with ethyl acetate (150 mL* 4). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 2-methoxy-4′-(trifluoromethyl)biphenyl-4-carbonitrile (620 mg) as a colorless solid. 1HNMR (400 MHz, CDCl3) δ 7.68 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.36-7.40 (m, 2H), 7.22 (s, 1H), 3.87 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)([O-])=O.[Cl-].[NH4+].C(OCC)(=O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1cc(N)ccc1Oc1ccccc1
Temperature: 80 °C
Yield: 62.9 %

Procedure:
To 52.1 g of N-(5-nitro-2-phenoxyphenyl)methanesulfonamide was added 51 ml of an aqueous solution containing 2.7 g of ammonium chloride, and then 42.5 g of an iron powder was added thereto with heating at 80° C. with stirring, followed by stirring for 2 hours. To the reaction cooled to 50° C. were added ethyl acetate and water. The insoluble substances were removed by filtration, and the filtrate was extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethanol to give 29.6 g of N-(5-amino-2-phenoxyphenyl)methanesulfonamide.
Reaction SMILES: C(O)(=O)[C:2]1([CH2:12][CH2:11][CH:7]([C:8](O)=O)[C:4]1([CH3:6])C)C.[CH2:15]([N:18]1[CH2:23][C@@H:22]([CH3:24])[NH:21][CH2:20][C@@H:19]1[CH3:25])[CH:16]=[CH2:17].C(=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C>[CH2:15]([N:18]1[CH2:23][C@@H:22]([CH3:24])[N:21]([CH2:8][C:7]2[CH:4]=[CH:6][CH:2]=[CH:12][CH:11]=2)[CH2:20][C@@H:19]1[CH3:25])[CH:16]=[CH2:17]
Reactant: C=CCN1C[C@@H](C)NC[C@@H]1C
Reactant: CC1(C(=O)O)CCC(C(=O)O)C1(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CCN1C[C@@H](C)N(Cc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of the camphoric acid salt of (+)-(2S,5R)-1-allyl-2,5-dimethylpiperazine from Preparation 1 (78.2 g) and benzaldehyde (26.5 g) in tetrahydrofuran (500 ml) containing glacial acetic acid (2 ml) was added sodium triacetoxyborohydride (93.3 g) portionwise over 10 minutes. The resulting mixture was stirred at room temperature for 4 hours. The reaction was partitioned between ethyl acetate (1500 ml) and aqueous sodium hydroxide (750 ml of 2N solution). The layers were separated and the organic phase was washed with 10% sodium metabisulphite solution (200 ml) and saturated brine solution. The organic layer was dried (MgSO4) and evaporated to dryness in vacuo to give the title compound, 52.1 g.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([CH:23]=O)[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1.Cl.[NH2:27][OH:28].N1C=CC=CC=1.CCOC(C)=O>CO>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([CH:23]=[N:27][OH:28])[C:9]3[C:14]([C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: NO
Reactant: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C=O
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)c2ccccc2n1C=NO
Temperature: 25 °C

Procedure:
2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbaldehyde (18 mg, 0.05 mmol) was dissolved in 5 ml MeOH. 5 eq hydroxylamine hydrochloride and 6 eq pyridine were added. The mixture was heated at reflux for 1.5 h and then allowed to cool to rt. 50 ml EtOAc were added, the resulting mixture was washed with brine 3× and then dried over Na2SO4. The solvent was concentrated and the crude product was purified using preparative HPLC. 3.5 mg 2-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbaldehyde oxime was obtained. The title compound was identified by 1H-NMR which showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 348.01 (M+H), 346.18 (M−H); 1H NMR (MeOD, 500 MHz): 8.38 (s, 1H), 8.26 (m, 1H), 7.66 (m, 1H), 7.35 (m, 1H), 7.25 (m, 1H), 7.11 (m, 2H), 6.80 (m, 2H), 2.13 (s, 3H) and 1.99 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([NH:16]C(=O)OCC1C=CC=CC=1)[CH3:15].B(Br)(Br)Br.O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:16][CH:14]([C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:6]2[C:7](=[O:8])[C:2]=1[Br:1])[CH3:15]
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c(=O)c1Br
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(N)c1nc2ccc(F)cn2c(=O)c1Br
Reaction time: 0.83 h
Yield: 104.9 %

Procedure:
E2 (312 mg, 0.74 mmol) was dissolved in 18 mL of anhydrous dichloromethane. BBr3 (3.7 mL, 1M in dichloromethane) was added dropwise at −10° C. under nitrogen. Stirring was continued at −10° C. for 50 min., then at room temperature for 45 min. Water was added to quench the reaction. The dichloromethane layer was set aside. The aqueous layer was adjusted to pH 8 with sodium bicarbonate and extracted with 30% isopropanol in chloroform 4 times. The dichloromethane layer was washed with brine and the brine layer was adjusted to pH 8 with sodium bicarbonate and extracted with 30% isopropanol in chloroform 1 times. The combined 30% isopropanol in chloroform extracts were dried and concentrated to give 222 mg of E3 as a solid, which was used directly for next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:5]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32](Cl)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[C:32]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[C:5]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:34])[CH3:33]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(N)ccc2c1=O
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 6-amino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (synthesized according to the method similar to that in Example 111 (1)) (0.1 g, 0.24 mmol), acetyl chloride (38 mg, 0.48 mmol), sodium hydrogencarbonate (81 mg, 0.96 mmol), water (0.5 ml) and ethyl acetate (5 ml) was stirred at room temperature for 2 h. The reaction mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give 6-acetylamino-3-tert-butoxycarbonylaminomethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (80 mg, 73%) as crystals.
Reaction SMILES: [I:1][C@@H:2]1[C@@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12][C@H:3]1[O:4][Si](CC)(CC)CC.C1COCC1.FC(F)(F)C(O)=O>O>[I:1][C@H:2]([C@H:15]([C@@H:14]([C@@H:13]([CH2:18][OH:19])[OH:12])[OH:17])[OH:16])[CH:3]=[O:4]
Reactant: CC[Si](CC)(CC)O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1I
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: O=C[C@H](I)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Mixture of 2-deoxy-2-iodo-1-O-triethylsilyl-β-D-glucopyranose (VI) (0.1 g), THF (2 mL), water (0.5 mL) and trifluoroacetic acid (0.1 mL) was prepared and stirred at room temperature. Progress of the reaction was monitored by TLC and after substrate disappearance reaction mixture was washed with dichloromethane (5×10 mL). The remaining water solution was lyophilized and such obtained crude solid residue was purified by column chromatography (SilicaGel 60, Merck) using chloroform, chloroform:methanol 9:1, 7:3 as eluents, to give (0.05 g) of 2-deoxy-2-iodo-D-glucose (VII). Yield 70%.
Reaction SMILES: [Br:1][C:2]1[C:3](N)=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[Cl:8].N([O-])=O.[Na+].N1C=CC=CC=1.[FH:21]>>[Br:1][C:2]1[C:3]([F:21])=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[Cl:8]
Reactant: Nc1ncc(Br)c(Cl)c1Br
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: Fc1ncc(Br)c(Cl)c1Br
Yield: 83 %

Procedure:
The reaction and post-treatment were carried out according to Example (8a) using 3,5-dibromo-4-chloropyridin-2-amine produced in Example (14a) (10.1 g, 35.4 mmol), sodium nitrite (3.66 g, 53.1 mmol) and hydrogen fluoride-pyridine (50 mL) to obtain the title compound (8.50 g, 83%) as a pale yellow oil.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].S([NH:23][N:24]=[CH:25][CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(C1C=CC(C)=CC=1)(=O)=O>O.Cl.C(O)C.N1C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([N:9]2[N:1]=[C:25]([CH:26]=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:24][NH:23]2)[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=N[O-]
Reactant: Cc1ccc(S(=O)(=O)NN=CC=Cc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: Clc1cccc(N2N=C(C=Cc3ccccc3)NN2)c1
Temperature: 0 °C
Yield: 19 %

Procedure:
An aqueous (5 mL) solution of sodium nitrite (540.9 mg, 7.839 mmol) was added to a solution of 3-chloroaniline in water (7 mL), concentrated hydrochloric acid (3 mL) and ethanol (7 mL) via dropping funnel. The reaction was allowed to stir at 0° C. for ten minutes. This solution was poured into a dropping funnel and ice was added. This was added dropwise to a solution of the product obtained in example 9.1 (2.3 g, 7.7 mmol) in pyridine (20 mL). This was allowed to stir overnight. An aqueous workup was done extracting with DCM three times. The combined layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (20% EtOAc/hexanes) to yield the title compound as a light purple solid (433 mg, 19%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)[CH:17]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][C:18]=2[C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(Cl)cc1-c1nccc2ccccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2nccc3ccccc23)cc1

Procedure:
The title compound was prepared according to the general procedure using 4-tert-butyl-benzenesulfonyl chloride and 4-chloro-2-isoquinolin-1-yl-phenylamine and purified by preparative HPLC. MS: (M+H)/z=451.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]([N:27]=C=O)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:30]([NH2:33])[CH:31]=[CH2:32]>>[CH2:30]([NH:33][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([NH:27][C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:7])=[O:18])[CH:31]=[CH2:32]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: C=CCN
Reactant: O=C=NC(=O)c1ccccc1
Product: C=CCNC(=O)[C@@H]1CC(=NOC)CN1C(=O)NC(=O)c1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, benzoyl isocyanate, and allylamine the title compound was obtained in 49% purity by LC/MS. MS(ESI+): m/z=345.0.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][N:15]=[CH:16][C:6]=2[O:5]1.[CH3:17][NH:18][CH3:19]>C(O)C>[ClH:1].[CH3:17][N:18]([CH3:19])[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:12])[C:7]2[CH:13]=[CH:14][N:15]=[CH:16][C:6]=2[O:5]1
Reactant: CN1CC(CCCl)Oc2cnccc2C1=S
Reactant: CNC
Solvent: CCO
Product: CN(C)CCC1CN(C)C(=S)c2ccncc2O1
Product: Cl

Procedure:
To a solution of 0.5 g (0.002 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[4,3-f][1,4]-oxazepine-5(4H)-thione in 20 ml of ethyl alcohol was added 2 ml of 40% aqueous dimethylamine. The mixture was heated in a steel bomb to 100° C. for 14 hr. The resulting solution was filtered and concentrated. The residue was dissolved in isopropyl alcohol and a few drops of ethereal hydrogen chloride were added. The hydrochloride salt crystals were recrystallized by dissolving in ethyl alcohol and boiling while replacing the ethyl alcohol with isopropyl alcohol. The yield of product was 0.3 g (47%), m.p.: decomp. above 200° C.