Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[CH:17]=[C:18]([N:26]([CH2:33][CH3:34])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:19]([CH3:25])=[C:20]([CH:24]=2)[C:21](O)=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl-].[CH3:43][C:44]1[CH:49]=[C:48]([CH3:50])[NH:47][C:46](=[O:51])[C:45]=1[CH2:52][NH3+:53].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CS(C)=O>[CH3:43][C:44]1[CH:49]=[C:48]([CH3:50])[NH:47][C:46](=[O:51])[C:45]=1[CH2:52][NH:53][C:21]([C:20]1[CH:24]=[C:16]([C:15]#[C:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:17]=[C:18]([N:26]([CH2:33][CH3:34])[CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:19]=1[CH3:25])=[O:22]
Reactant: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)O)c1C)C1CCOCC1
Reactant: Cc1cc(C)c(C[NH3+])c(=O)[nH]1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 5-((1-(tert-butoxycarbonyl)piperidin-4-yl)ethynyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoic acid (1.06 g, 2.25 mmol) in DMSO (5.8 mL) at rt was added triethylamine (0.90 mL, 6.44 mmol) and (4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methanaminium chloride (0.405 g, 2.15 mmol). The clear solution become heterogenous. Then HOBT (0.493 g, 3.22 mmol) and EDC (0.617 g, 3.22 mmol) were added and the resulting reaction mixture was stirred at rt overnight. The reaction was quenched with water (80 mL) and the slurry was stirred for 1 h at rt. The slurry was filtrated and the cake was washed with water (2×20 mL). The collected solid was dried under vacuum to give the titled compound (1.27 g, 98% yield). 1H-NMR (500 MHz, CD3OD) 8 ppm; 7.22 (s, 1H), 7.08 (d, J=1.0 Hz 1H), 6.11 (s, 1H), 4.45 (s, 2H), 3.92 (brd, J=10.8 Hz, 2H), 3.78 (dd, J=4.4, 5.4 Hz, 1H), 3.75 (dd, J=4.4, 5.4 Hz, 1H), 3.36 (t, J=11.7 Hz, 2H), 3.21 (br t, J=8.3 Hz, 2H), 3.07 (q, J=7.3 Hz, 2H), 3.01 (dddd, J=3.9, 3.9, 11.3, 11.3 Hz, 1H), 2.84 (dddd, J=3.4, 3.4. 3.9, 3.9 Hz, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 1.88 (m, 2H), 1.70 ((brd, J=12.2 Hz, 2H), 1.60 (m, 4H), 1.47 (s, 9H), 0.87 (t, J=7.3 Hz, 3H); MS (ESI) [M+H]+605.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[C:33]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:28]([C:27]1[CH:31]=[CH:32][C:33]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:34][C:26]=1[Cl:25])=[O:29]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Yield: 73 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(2-chloro-4-methylsulfonylphenyl)carbonyl]-L-phenylalanine methyl ester was prepared in 73% yield from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 2-chloro-4-methylsulfonylbenzoic acid using the general procedure described in example 3. HR MS: Obs. mass, 583.0263. Calcd. mass, 583.0264 (M+H).
Reaction SMILES: [C:1]12([C:11](=O)[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[O:8]1)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.C(O)C.Cl.[NH2:21][OH:22].Cl>N1C=CC=CC=1>[C:1]12([O:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3/[C:11]/1=[N:21]/[OH:22])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: O=C1c2ccccc2OC12CCCCCC2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O/N=C1/c2ccccc2OC12CCCCCC2
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of 10.81 g of spiro[benzofuran-2(3H),1'-cycloheptane]-3-one, 100 ml of absolute ethanol, 34.75 g of hydroxylamine hydrochloride and 100 ml of pyridine was heated at reflux overnight under nitrogen and thereafter cooled to room temperature. The mixture was poured into 500 ml of 2N aqueous hydrochloric acid and extracted with hexane (2×200 ml). The combined hexane extracts were washed with 2N hydrochloric acid (100 ml), distilled water (100 ml) and saturated sodium chloride solution (100 ml). After the last wash, the oxime began to crystallize out of the hexane extracts; dichloromethane was added to redissolve any crystallized solid and the solution was dried overnight over anhydrous sodium sulfate. Filtration and concentration in vacuo afforded a gum which was triturated to solid with hexane. This material was filtered off and recrystallized from 60 ml of boiling hexane to afford 7.28 g of needles, m.p. 98.5°-103.5° C. Recrystallization twice more from 60 ml portions of hexane afforded 5.01 g of pure major (Z) isomer as needles, m.p. 104°-106.5° C.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[C@@H:16]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[NH:15][C:14]1=[O:22].C(N(C(C)C)CC)(C)C.[I:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](Cl)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:35][CH:34]=1>CC(C)=O>[I:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([NH:12][C@H:13]2[C@@H:16]([O:17][CH2:18][CH:19]([CH3:20])[CH3:21])[NH:15][C:14]2=[O:22])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:37][CH:38]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccc(I)cc1
Reactant: CC(C)CO[C@H]1NC(=O)[C@H]1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: CC(C)CO[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccc(I)cc1
Reaction time: 6 h
Yield: 66.8 %

Procedure:
A solution of (3S,4R)-3-amino-4-(isobutoxy)azetidin-2-one para-toluenesulfonate (180 mg, 0.54 mmol) in acetone (8 mL) containing diisopropylethylamine ( 1.1 mmol) was treated with a solution of (4-iodophenyl)diphenylmethyl chloride (218 mg, 0.54 mmol), prepared as described by Tschitschibabin, Chem. Ber. 44, 450 (191 1), in acetone (98 mL). The solution was stirred for 6 h and partitioned between water and dichloromethane. The combined organic phases were dried (magnesium sulfate), concentrated, and the residue was chromatographed on silica gel eluted with 15% ethyl acetate:hexane to give the title compound (190 mg, 67%). MS(ES) m/e 527 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](OCC)(OCC)(OCC)[CH2:13][CH3:14]>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:13]([C:14]1[O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[N:1]=1)[CH3:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(CC)(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCc1nc2cc([N+](=O)[O-])ccc2o1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A solution of 2-amino-4-nitrophenol (2.00 g, 12.98 mmol) and triethyl orthopropionate (4.57 g, 25.95 mmol) in anhydrous ethanol (15 ml) was treated with p-toluenesulphonic acid (20 mg) and the resulting mixture refluxed for 3 h. On cooling to room temperature a precipitate formed which was filtered off and dried to afford the title compound (2.11 g) as a beige solid m.p. 88-90°. δH (CDCl3) 1.48 (3H, t, J 7.6 Hz), 3.02 (2H, q, J 7.6 Hz), 7.57 (1H, d, J 9.0 Hz), 8.27 (1H, dd, J 2.3, 9.0 Hz) and 8.55 (1H, d, J 2.3 Hz).
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[C:15](I)[CH:14]=[CH:13][C:12]=3[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.IC1C=C2C(C=CN2)=CC=1.[C:37]([C:39]1([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41][CH2:40]1)#[CH:38].C(C1C=CC(C2C=CC=CC=2C(F)(F)F)=CC=1)#C>>[C:1]12([C:11]3[CH:16]=[C:15]([C:38]#[C:37][C:39]4([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:44][O:43][C:42]([CH3:46])([CH3:45])[O:41][CH2:40]4)[CH:14]=[CH:13][C:12]=3[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCCCCCCCOc1ccc(I)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: C#Cc1ccc(-c2ccccc2C(F)(F)F)cc1
Agent: Ic1ccc2cc[nH]c2c1
Product: CCCCCCCCOc1ccc(C#CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
When the product of Step A was substituted for 6-iodoindole and tert-butyl 5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 4′-ethynyl-2-(trifluoromethyl) biphenyl in Example 59, Step B the identical process afforded the title compound in 48%, as creamy paste. 1H-NMR (CDCl3) 0.85 (tr, 3H, J=8.99 Hz); 1.27-1.47 (m, 23H); 1.73 (s, 6H); 1.8-1.87 (m, 2H); 2.06 (s, 9H); 3.94 (tr, 2H, J=6.34 Hz); 3.99 (d, 2H, J=11.44 Hz); 4.08 (d, 2H, J=11.52 Hz); 5.17 (s, 1H); 6.73 (d, 1H, J=8.41 Hz); 7.19-7.21 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[C:12]1([CH2:11][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1cccc2ccccc12
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1OCc1cccc2ccccc12
Temperature: 100 °C
Yield: 43.2 %

Procedure:
To a solution of 2-hydroxybenzaldehyde (2.30 g, 18.8 mmol) in DMF (20 mL) is added 1-(chloromethyl)-naphthalene (3.36 mL, 22.6 mmol) and K2CO3 (3.11 g, 22.6 mmol), and the reaction mixture is heated to 100° C. for 12 h. Once complete, the reaction mixture is cooled to room temperature and diluted with water (100 mL) prior to being poured into a separatory funnel containing ethyl acetate (250 mL). The organic layer is separated, washed with brine (2×) and dried over sodium sulfate prior to concentration. The crude product is purified by column chromatography (5% ethyl acetate in hexanes) to afford 2-(1-naphthylmethoxy)benzaldehyde (2.13 g, 43%) as a light yellow oil.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[C:10]([Br:13])[CH:11]=[CH:12][C:4]=2[C:3]1=O.[NH2:15][NH:16][C:17]([NH2:19])=[S:18]>>[Br:13][C:10]1[CH:11]=[CH:12][C:4]2[C:3]3[N:19]=[C:17]([NH:16][NH2:15])[S:18][C:2]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:9]=1
Reactant: O=C1c2ccc(Br)cc2OCCC1Br
Reactant: NNC(N)=S
Product: NNc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A solution of 4,8-dibromo-3,4-dihydro-2H-benzo[b]oxepin-5-one (1.5 g, 4.7 mmol) and thiosemicarbazide (455 mg, 5 mmol) in IMS (15 mL) was stirred at 85° C. for 2 h, allowed to cool down to RT and filtered to give the title compound as a beige solid (1.03 g, 70%). LCMS (Method B): RT=3.06 min, [M+H]+=312 and 314. 1H NMR (DMSO-d6): 10.10 (2 H, bs), 9.80 (1 H, bs), 8.27 (1 H, d, J=8.6 Hz), 7.34 (1 H, dd, J=8.6, 2.1 Hz), 7.22 (1 H, d, J=2.1 Hz), 4.31 (2 H, t, J=5.0 Hz), 3.19 (2 H, t, J=5.0 Hz).
Reaction SMILES: [C:1]1([C@H:7]([CH3:20])[CH2:8][O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@@H](C)CO)C=CC=CC=1>>[C:1]1([C@@H:7]([CH3:20])[CH2:8][O:9][S:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)c2ccccc2)cc1
Agent: C[C@@H](CO)c1ccccc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](C)c2ccccc2)cc1

Procedure:
Following the procedure analogous to that used for the synthesis of toluene-4-sulfonic acid (S)-2-phenyl-propyl ester, but using (R)-2-phenyl-1-propanol, the title compound was prepared
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>N1C=CC=CC=1>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([O:8][N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[O:1])(=[O:20])=[O:19])=[CH:16][CH:17]=1)([O-:11])=[O:10]
Reactant: [O-][n+]1ccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: O=c1ccccn1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 92 %

Procedure:
2-Hydroxypyridine-1-oxide (0.5 g, 4.5 mmol) was reacted with 4-nitrobenzenesulfonyl chloride (3.0 g, 13.5 mmol) in 40 mL of pyridine to afford PZBG-1c in 92% yield (1.23 g, 4.2 mmol). 1H NMR (500 MHz, CDCl3) δ=8.42 (d, J=8.6 Hz, 2H), 8.23 (d, J=9.2 Hz, 2H), 7.65 (dd, J1=7.5 Hz, J2=1.8 Hz, 1H), 7.34 (dt, J1=9.2 Hz, J2=1.7 Hz, 1H), 6.52 (d, J=9.2 Hz, 1H), 6.22 (t, J=7.7 Hz, 1H). 13C NMR (100 MHz, DMSO) δ=156.6, 152.3, 141.6, 139.4, 138.3, 131.8, 125.6, 122.8, 106.4. ESI-MS(+): m/z 297.28 [M+H]+, 319.02 [M+Na]+.
Reaction SMILES: Cl[C:2]1[C:6]2[N:7]([C:17](=[O:34])[CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:21][CH2:20]3)[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[N:4]([CH3:35])[CH:3]=1.C.[OH-].[Na+].C(#N)C>C(O)C.[Pd]>[CH2:32]([N:29]([CH2:30][CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:17]([N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]3[N:4]([CH3:35])[CH:3]=[CH:2][C:6]2=3)=[O:34])[CH2:20][CH2:21]1)[CH3:33]
Reactant: CCN(CC)CCCCC1CCN(CC(=O)N2c3ccccc3NC(=O)c3c2c(Cl)cn3C)CC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Product: CCN(CC)CCCCC1CCN(CC(=O)N2c3ccccc3NC(=O)c3c2ccn3C)CC1
Reaction time: 20 h

Procedure:
3.957 g (8.14 millimol) of 3-chloro-4-[[4-[4-(diethylamino)-butyl]-1-piperidinyl]acetyl ]-1-methyl-1,4,9,10-tetrahydropyr rolo[3,2-b][1,5]benzodiazepin- 10-one were dissolved in 350 ml of hot ethanol and after the addition of 3 g of palladium on animal charcoal (20%), hydrogenated for 20 hours under a hydrogen pressure of 50 bar and at a temperature of 40° C. The catalyst was filtered off, the filtrate was concentrated by evaporation in vacuo, the crystalline hydrochloride was taken up in 20 ml of water, the solution obtained was made alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. The combined extracts were dried over sodium sulphate and evaporated down and the residue remaining was recrystallised. 1 g (26.3% of theory) of colourless crystals were obtained, m.p. 198° C. (acetonitrile).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=N[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.BrC1C=CC=[C:28]([F:32])C=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:28]([F:32])[CH:19]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cccc(Br)c1
Reactant: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccnc2)ccn1
Product: Cc1cc(NC(=O)c2nc(C)ccc2Nc2cccc(F)c2)ccn1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide (example 5) in accordance with the general method of example 20 using 1-Bromo-3-fluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=337.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][C:13]3[CH:14]=[C:15]4[CH:22]=[N:21][NH:20][C:16]4=[CH:17][C:18]=3[N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:23]1[CH2:27]OC[CH2:24]1.[H-].[Na+].[CH2:30](Br)[CH:31]=[CH2:32]>O>[CH2:27]([N:20]1[C:16]2=[CH:17][C:18]3[N:19]=[C:10]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=4)[CH:11]=[N:12][C:13]=3[CH:14]=[C:15]2[CH:22]=[N:21]1)[CH:23]=[CH2:24].[CH2:32]([N:21]1[CH:22]=[C:15]2[C:16]([CH:17]=[C:18]3[C:13](=[CH:14]2)[N:12]=[CH:11][C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:19]3)=[N:20]1)[CH:31]=[CH2:30]
Reactant: COc1ccc(-c2cnc3cc4cn[nH]c4cc3n2)cc1F
Reactant: C=CCBr
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=CCn1cc2cc3ncc(-c4ccc(OC)c(F)c4)nc3cc2n1
Product: C=CCn1ncc2cc3ncc(-c4ccc(OC)c(F)c4)nc3cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 0.50 g of 7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline, 30 ml of anhydrous THF is added 0.061 g of 60% NaH. It is stirred at room temperature for 10 minutes, then allyl bromide 0.206 g is added dropwise into the red mixture. The resulting mixture is stirred at room temperature overnight then poured into water, extracted with methylene chloride and the organic layer is separated, dried (Na2SO4), concentrated in vacuo which gives yellow crude product. This is purified by silica-gel column chromatography using methylene chloride, then changed to 1%-4% acetone/methylene chloride as the solvent system to obtain 1-allyl-7-(3-fluoro-4-methoxyphenyl)-1H-pyrazolo[3,4-g]quinoxaline (m.p. 121°-124° C.) and 2-allyl-7-(3-fluoro-4-methoxy-phenyl)-2H-pyrazolo[3,4-g]quinoxaline (m.p. 196°-200° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:39][C@H:40]([CH2:49][O:50][CH3:51])[C:41]([N:43]1[CH2:46][CH:45]([C:47]#[N:48])[CH2:44]1)=[O:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[C:47]([CH:45]1[CH2:44][N:43]([C:41](=[O:42])[C@H:40]([NH:39][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=2)=[O:22])[CH2:49][O:50][CH3:51])[CH2:46]1)#[N:48]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: COC[C@@H](N)C(=O)N1CC(C#N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A 10 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (50 mg, 0.11 mmol), 1-((R)-2-amino-3-methoxy-propionyl)-azetidine-3-carbonitrile trifluoroacetate (42 mg, 0.14 mmol), and HATU (42 mg, 0.11 mmol). Then added acetonitrile (1 mL) followed by N,N-diisopropylethylamine (0.19 mL, 1.1 mmol). The light yellow reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with dichloromethane. The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 5-90% EtOAc) to afford 44 mg (63%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-amide as an off-white solid. MS: [M+H]+=623.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]1.C(N(CC)CC)C.CO>O1CCCC1>[Cl:11][C:4]1[N:3]=[C:2]([NH:19][CH2:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NCC1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)nc1NCC1CCOCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (1 g, 5.18 mmol)), (tetrahydro-2H-pyran-4-yl)methanamine (1.044 g, 9.07 mmol) and triethylamine (2.167 mL, 15.55 mmol) in tetrahydrofuran (22.83 mL) was stirred at 0° C. for 30 minutes and at ambient temperature for 2 hours. Methanol was added (10 mL) followed by silica gel and the mixture was concentrated and purified by silica gel flash chromatography (Isco®, Redi-Sep® column), eluting with a gradient of 2-30% ethyl acetate/hexane to afford the title compound. MS (ESI) m/z 272 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:3]([Br:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1C(=O)NC(=O)[C@]12Cc1ccc(N)cc1C2
Solvent: ClC(Cl)Cl
Product: CN1C(=O)NC(=O)[C@]12Cc1ccc(N)c(Br)c1C2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
(R)-5′-Amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (580 mg, 2.51 mmol, described in Intermediate 8) was suspended in CHCl3 (250 mL) and N-bromosuccinimide (335 mg, 1.88 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 40 min, then washed with dilute aqueous NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 0:100, to give (R)-5′-amino-4′-bromo-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, which eluted first, and the title compound, which eluted second. MS: m/z=353 (M+1+CH3CN).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20]>O1CCCC1>[CH3:16][O:17][CH:18]([CH3:22])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: COC(C)C(=O)Cl
Solvent: C1CCOC1
Product: COC(C)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 56.2 %

Procedure:
5.0 g (24.6 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone and 3.6 g (29.4 millimoles) of 2-methoxypropionyl chloride in 150 ml of absolute tetrahydrofuran were refluxed for 2 hours, while stirring. The mixture was evaporated down, the residue was stirred with water and the product was filtered off under suction, washed with water, dried, and recrystallized from propanol. 4.0 g (56%) of 6-[p-(2-methoxypropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained as colorless crystals. Mp.: 193°-194° C.
Reaction SMILES: C(OC([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)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][CH2:36][CH:37]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=1)[OH:38]>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][CH2:36][CH:37]([OH:38])[C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=2)=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: NCC(O)c1ccc2ccccc2c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NCC(O)c2ccc3ccccc3c2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and (1RS)-2-amino-1-(2-naphthyl)ethanol, the title compound was obtained in 77% purity by HPLC. MS(ESI+): m/z=544.