Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:4]=1[NH2:5].[C:12](C1NC=CN=1)(C1NC=CN=1)=[O:13]>C1COCC1>[CH3:11][O:10][C:7]1[CH:6]=[C:4]2[C:3]([CH2:2][NH:1][C:12](=[O:13])[NH:5]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(CN)c(N)c1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)NC(=O)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
2-aminomethyl-5-methoxyaniline (1.2 g. 7.9 mmol) and carbonyl diimidazole (1.53 g, 9.5 mmol) were added to THF (100 ml) and the mixture was stirred at room temperature overnight. The insoluble matter precipitated was obtained by filtration, washed with dichloromethane and water, dried to obtain 7-methoxy-3,4-dihydro-1H-quinazolin-2-one (1.11 g) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH2:23]Cl)[N:14]=2)[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]([CH3:12])[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]([CH2:23][N:29]3[C:25](=[O:35])[C:26]4[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:28]3=[O:30])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(N(C)c2nc(CN3C(=O)c4ccccc4C3=O)nc3ccccc23)cc1Cl
Temperature: 50 °C

Procedure:
A mixture of (3-chloro-4-ethoxy-phenyl)-(2-chloromethyl-quinazolin-4-yl)-methyl-amine (119 mg, 0.328 mmol) and potassium phthalimide (79 mg, 0.43 mmol) in DMF (2 mL) was heated at 50° C. for 3.5 h. EtOAc (25 mL) was added and this was washed with water (4×5 mL) then satd NaCl (2×5 mL). The organic layer was dried (MgSO4), filtered through a pad of silica with an EtOAc wash then concd. The title compound was obtained as an off-white solid (124 mg; 80%) after MPLC (SiO2/0-50% EtOAc in hexanes). 1H NMR (CDCl3) δ 7.96-7.90 (m, 2H), 7.78-7.73 (m, 2H), 7.72 (m, 1H), 7.53 (m, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.05-6.95 (m, 2H), 6.91 (dd, J=2.4, 8.8 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 5.14 (s, 2H), 4.10 (q, J=6.9 Hz, 2H), 3.24 (s, 3H), 1.48 (t, J=6.8 Hz, 3H); LC-MS (ESI+; 473 ([M+H]+)).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.Cl.[NH:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)[NH2:8]>O>[CH3:16][O:15][C:12]1[N:13]=[CH:14][C:9]([NH:7][NH:8][C:2]([NH2:3])=[O:1])=[CH:10][CH:11]=1
Reactant: N#C[O-]
Reactant: COc1ccc(NN)cn1
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc(NNC(N)=O)cn1
Reaction time: 2 h
Yield: 148 %

Procedure:
Potassium cyanate (8.41 g, 104 mmol) was added to a solution of 5-hydrazino-2-methoxypyridine dihydrochloride (20 g, 94.3 mmol) in water (200 mL). The mixture was stirred for 2 hour and adjusted pH to 7. The solvent was removed under reduced pressure and obtained crude powder to give 2-(6-methoxypyridin-3-yl)hydrazinecarboxamide. (25.4 g, 148% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH2:15])=[CH:13][C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:11]2)=[CH:6][CH:5]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([NH:15][C:22]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])=[CH:13][C:12]([C:16]([CH3:17])([CH3:19])[CH3:18])=[N:11]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-benzoic acid methyl ester (5.3 g, 19.4 mmol) in anhydrous THF (200 mL) was slowly added phenyl chloroformate (6.81 mL, 54.3 mmol), followed by sodium carbonate (2.1 g, 19.4 mmol). The mixture was stirred at room temperature overnight. Ethyl acetate (500 mL) was added, followed by saturated sodium carbonate (300 mL). The organic layer was washed with saturated sodium carbonate (3×) and brine (1×), dried over MgSO4, and concentrated at reduced pressure. The residue was washed with ether to give 4.3 g (56%) of the desired product. 1H-NMR (DMSO-d6) δ 10.19 (s, 1H), 8.10 (d, J=9.0 Hz, 2H), 7.73 (d, J=9.0 Hz, 2H), 7.38-7.11 (m, 5H), 6.41 (s, 1H), 3.87 (s, 3H), 1.27 (s, 1H); MS LC-MS [M+H]+=394.1, RT=3.53 min.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 4-fluoro-3-nitro aniline (1.00 g, 6.41 mmol) in anhydrous CH2Cl2 (25 ml) was added pyridine (1.52 g, 19.23 mmol) and the solution was cooled to 0° C. under argon. Benzoyl chloride (0.90 g, 6.41 mmol) was added slowly and the solution was then allowed to slowly warm to room temperature and stir for 24 h. The solution was poured into 1NHCl and the organic layer was separated. The aqueous layer was extracted 3× with ethyl acetate (50 ml). The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate (4:1) to give N-(4-fluoro-3-nitro-phenyl)-benzamide. (1.60 g, 96%)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:16]=1)[O:10][CH:11]([CH3:15])[C:12](Cl)=[O:13].[OH:28][CH:29]([P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])[CH3:30]>>[Cl:1][C:2]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:17]([O-:19])=[O:18])=[C:9]([CH:16]=1)[O:10][CH:11]([CH3:15])[C:12]([O:28][CH:29]([P:31](=[O:38])([O:32][CH2:33][CH3:34])[O:35][CH2:36][CH3:37])[CH3:30])=[O:13]
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Reactant: CCOP(=O)(OCC)C(C)O
Product: CCOP(=O)(OCC)C(C)OC(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
by using 2-[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenoxy]-propionyl chloride and diethyl 1-hydroxyethylphosphonate there is obtained diethyl 1-[2-[5-(o-chloro-p-trifluoromethyl-phenoxy)-2-nitrophenoxy]-propionyloxy]-ethylphosphonate, 1H-NMR (CDCl3, 400 MHz) 7.93 ppm and 7.92 ppm (2d, 1H), 7.79 ppm (d, 1H), 7.51-7.55 ppm (m, 1H), 7.23 ppm and 7.19 ppm (2d, 1H), 6.68 ppm and 6.58 ppm (2d, 1H), 6.53 ppm and 6.46 ppm (2q, 1H), 5.31 ppm and 5.29 ppm (2q, 1H), 4.88 and 4.85 ppm (2q, 1H), 4.21-4.05 ppm (m, 4H), 1.73 ppm and 1.72 ppm (2d, 3H), 1.45 ppm and 1.42 ppm (2q, 3H), 1.36-1.26 ppm (m, 6H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]1(I)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]1([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: C1=Cc2ccccc2C1
Reactant: Ic1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: C1=C(c2cccc3ccccc23)Cc2ccccc21
Temperature: 25 °C
Yield: 31 %

Procedure:
20 ml of triethylarine, 2.2 g (20 mmole) of indene, 5.08 g (20 mmole) of 1-naphtyl-iodide and 0.134 g (0.6 mmole) of Pd(OAc)2 were stirred under reflux for 10 h. After that the mixture was cooled to room temperature and evaporated. The residual oil was recrystallized from ethanol and dried under vacuum to obtain 1.5 g (31%) of the product.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:5]=2[N:6]=1.F[C:13]1[C:18]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([N:26]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[N:20]=2)=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:26]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[C:21]2[N:22]=[C:23]([CH3:25])[N:24]=[C:19]([C:18]3[C:13]([NH:11][C:8]4[CH:9]=[CH:10][C:4]5[O:3][C:2]([CH3:1])=[N:6][C:5]=5[CH:7]=4)=[N:14][CH:15]=[CH:16][CH:17]=3)[N:20]=2)=[CH:42][CH:41]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: Cc1nc2cc(N)ccc2o1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc4oc(C)nc4c3)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 2-methylbenzo[d]oxazol-5-amine (Bionet Research Intermediates) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine, and isolated as a brown oil (100%). 1H NMR (400 MHz, CDCl3) δ 11.94 (s, 1H); 8.31 (br. s., 1H); 8.04 (br. s., 1H); 7.31-7.42 (m, 1H); 7.27-7.30 (m, 2H); 7.14-7.24 (m, 3H); 6.79-6.96 (m, 5H); 4.84 (br. s., 4H); 3.80 (d, J=9.6 Hz, 6H); 2.62 (br. s., 3H); 2.59 (br. s., 4H). m/z (ESI, +ve ion) 574.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].CC1C=CC(S(O[CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)(=O)=O)=CC=1.Cl>CN(C=O)C>[CH3:22][O:21][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:37][CH2:36]1)[N:9]=[CH:8][N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C:6]2=[O:20]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6.12 g, 20 mmol) potassium carbonate (5.52 g, 40 mmol) in DMF (60 ml) was stirred at ambient temperature for 30 minutes. 4-(4-Methylphenylsulphonyloxymethyl)-1-tert-butyloxycarbonylpiperidine (8.86 g, 24 mmol), (prepared as described for the starting material in Example 10), was added and the mixture was stirred at 100° C. for 2 hours. After cooling, the mixture was poured onto water/ice (400 ml, 1/1) containing 2M hydrochloric acid (10 ml). The precipitate was collected by filtration, washed with water and dried under vacuum over phophorus pentoxide. The solid was triturated in a mixture of ether/pentane (1/1), collected by filtration and dried to give 6-methoxy-3-((pivaloyloxy)methyl)-7-((1-tert-butyloxycarbonylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (7.9 g, 78.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][CH:24]([CH2:26][OH:27])[O:23][C:22]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][CH:24]([CH2:26][O:27][S:37]([CH3:36])(=[O:39])=[O:38])[O:23][C:22]2=[O:28])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(CO)OC3=O)cc2F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(COS(C)(=O)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of 375 mg (0.95 mmol) of oxazolidinone 9 and 144 mg (0.20 mL, 1.42 mmol) triethylamine in 3.8 mL dichloromethane at 0° C. was treated dropwise with 130 mg (0.09 mL, 1.14 mmol) of methanesulfonyl chloride followed by stirring at 0° C. for 1 hour. The solution was diluted with 30 mL dichloromethane and was extracted with water (2×25 mL) and with saturated NaHCO3 (25 mL). Drying (Na2 SO4) and concentration in vacuo afforded 440 mg (98%) of mesylate 10 as a white solid, sufficiently pure for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)=O>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2=[N:8][C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=3)=[CH:10][N:6]2[N:7]=1
Reactant: Cc1ccc(C(=O)CBr)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)nn1
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-c2cn3nc(Cl)ccc3n2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A stirred solution of 6-chloropyridazin-3-amine (18.4 g, 0.14 mol) and 2-bromo-1-(4-methyl-3-nitro-phenyl)ethanone (36.13 g, 0.14 mol) in acetonitrile (219 mL) is heated at reflux for 18 hr. The mixture is diluted with water (500 mL), stirred at room temperature for 1 hour and solids are collected by filtration to give the title compound (35.65 g, 88% yield). LCMS m/z=289.4 [M+H]+, tR=2.65 min.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O>>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:20]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc[n+]1[O-]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1cccc(C(F)(F)F)c1

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 3-trifluoromethyl-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=265 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([CH3:23])[C:16]4[O:20][N:19]=[C:18]([CH3:21])[C:17]=4[CH:22]=3)[C:11](=[O:24])[C:10](=O)[CH:9]2[C:26](=O)[CH2:27][CH3:28])=[CH:4][CH:3]=1.[NH:30]([CH2:32][CH2:33][OH:34])[NH2:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:26]([CH2:27][CH3:28])=[N:31][N:30]([CH2:32][CH2:33][OH:34])[C:10]=3[C:11](=[O:24])[N:12]2[C:13]2[CH:14]=[C:15]([CH3:23])[C:16]3[O:20][N:19]=[C:18]([CH3:21])[C:17]=3[CH:22]=2)=[CH:6][CH:7]=1
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c3onc(C)c3c2)C1c1ccc(Cl)cc1
Reactant: NNCCO
Product: CCc1nn(CCO)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3onc(C)c3c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 78 using 5-(4-chlorophenyl)-1-(3,7-dimethylbenzo[d]isoxazol-5-yl)-4-propionylpyrrolidine-2,3-dione (Step 79.1) and 2-hydrazinylethanol. The crude material was purified by silica gel chromatography (hexane/EtOAc/MeOH 90:10:1 to 50:50:5 to 0:10:1). tR: 1.10 min (LC-MS 2); ESI-MS: 451 [M+H]+ (LC-MS 2).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:27]#[N:28])=[C:18](OS(C(F)(F)F)(=O)=O)[C:13]=3[C:12]3[CH:29]=[CH:30][CH:31]=[N:32][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC.[Cl-].[Li+]>O1CCOCC1.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>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:27]#[N:28])=[C:18]([CH:33]=[CH2:34])[C:13]=3[C:12]3[CH:29]=[CH:30][CH:31]=[N:32][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ncc2c(c1OS(=O)(=O)C(F)(F)F)c1cccnc1n2S(=O)(=O)c1ccccc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1c(C#N)ncc2c1c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A mixture of trifluoromethanesulfonic acid 9-benzenesulfonyl-6-cyano-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-5-yl ester (150 mg, 0.31 mmol), tributyl(vinyl)stannane (102 μL, 0.35 mmol), lithium chloride (40 mg, 0.93 mmol) and tetrakis(triphenylphosphine)palladium(0) (7.0 mg, 6.0 μmol) in dioxane (1.5 mL) was degassed with argon and heated under reflux for 18 h. The reaction mixture was allowed to cool to ambient temperature then diluted with DCM (9 mL) and methanol (1 mL). The resultant residue was purified by chromatography (silica, 2 g column, Si-SPE, 0-2% MeOH in DCM) and triturated with pentane (2×2 mL) to afford the title compound as a white solid (60 mg, 52%). LCMS (Method B): RT=3.73 min, M+H+=361.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[NH:5]2.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[N:5]2[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: CC1Nc2cc(Br)ccc2-n2cccc21
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)N2c3cc(Br)ccc3-n3cccc3C2C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
A solution of 7-bromo-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (225 mg, 0.86 mmol) in methylene chloride (4 mL), under nitrogen, was treated with m-anisoyl chloride (219 mg, 1.28 mmol) followed by triethyl amine (0.24 mL, 1.72 mmol). The reaction was stirred at 25° C. for 15 h, after which time the reaction was washed with a saturated aqueous solution of sodium bicarbonate, and the reaction mixture was concentrated in vacuo. The product was purified via Biotage Horizon® (25S, silica, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane) to yield 287 mg (84%) of 7-bromo-5-(3-methoxybenzoyl)-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline as a white foam. MS (ESI) m/z 397/399 ([M+H]+); HRMS: calcd for C20H17BrN2O2, 396.0473; found (ESI+), 397.05389.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(n4cccn4)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(n4cccn4)CC3)cnc12
Yield: 53.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(1H-pyrazol-1-yl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.102 g, 0.229 mmol) obtained in step 2 and methanesulfonamide (0.109 g, 1.14 mmol), the title compound (0.064 g, 53%) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.CC#N.O.CC#N>O>[CH:31]([N:14]([CH2:13][C@H:11]1[C@H:10]([CH2:34][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:9][NH:8][CH2:12]1)[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)([CH3:33])[CH3:32]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: O
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CN2CCCCC2)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described in Example 5 from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and piperidine. MS (LC-MS): 462.1 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 3.74 min.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]#[CH:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[C:12]([O:15][CH:16]([CH2:21][O:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:17][N:18]=[N+:19]=[N-:20])(=[O:14])[CH3:13].CCN(C(C)C)C(C)C>C1COCC1.[Cu]I>[C:12]([O:15][CH:16]([CH2:21][O:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:17][N:18]1[CH:11]=[C:10]([CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[N:20]=[N:19]1)(=[O:14])[CH3:13]
Reactant: C#CCn1ccnc1[N+](=O)[O-]
Reactant: CC(=O)OC(CN=[N+]=[N-])COS(=O)(=O)c1ccc(C)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC(COS(=O)(=O)c1ccc(C)cc1)Cn1cc(Cn2ccnc2[N+](=O)[O-])nn1
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 2-nitro-1-(prop-2-ynyl)-1H-imidazole (0.2 gm, 1.32 mmol) and 1-azido-3-(tosyloxy)propan-2-yl acetate (0.41 gm, 1.32 mmol) in THF (2.5 mL), was treated with CuI (0.025 gm, 0.132 mmol) and DIPEA (0.3 mL, 1.46 mmol) at room temperature. After stirring the reaction mixture for overnight, silica was added, solvent evaporated under reduced pressure and purified by chromatography on silica gel (MeOH/CH2Cl2, 1/10) to give the 1-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-3-(tosyloxy)propan-2-yl acetate (0.5 gm, 81%) as white solid. 1H NMR (CDCl3, 400 MHz) δ: 7.76-7.78 (m, 3H), 7.35-7.39 (m, 3H), 7.15 (br, 1H), 5.68 (d, J=5.6 Hz, 2H), 5.27-5.32 (m, 1H), 4.56-4.67 (m, 2H), 4.19 (dd, J=4.0, 11.2 Hz, 1H), 4.08 (dd, J=4.0, 11.2 Hz, 1H), 2.46 (s, 3H), 1.97 (s, 3H); Mass Spec (lo-res): Calc'd for C18H20N6O7S: 464.11. found: 465.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C(=O)O)c2[nH]ccc2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(C)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
To 5-methyl-1H-indole-7-carboxylic acid (1.1 g), potassium carbonate (1.3 g) was added DMF (22 mL), and then methyl iodide (1.3 mL) was added thereto under ice-cooling. After stirring at room temperature overnight, the reaction mixture was adjusted to pH 3 by adding a 10% aqueous citric acid solution. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate: 95/5-85/15) to obtain methyl 5-methyl-1H-indole-7-carboxylate (1.2 g).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][OH:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OC(=O)C)(=O)C>>[C:16]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: OCC1c2ccccc2-c2ccccc21
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 98 %

Procedure:
A 250 mL Erlenmeyer flask was charged with 9-fluorenemethanol (30.0 g, 153 mmol, Aldrich), sodium acetate (15.0 g, 183 mmol, Aldrich), and acetic anhydride (0.150 L, 1580 mmol, Aldrich). The reaction mixture was heated over a steam bath, under continuous stirring for 4 hours. The warm mixture was poured into ice (150 g). After reaching room temperature, the solid product was isolated by filtration and washed with cold water. The dried product was used without further purification (35.7 g, 150 mmol, 98% yield, >99% purity by GC).