Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Cl:19][C:20]1[N:24]=[CH:23][NH:22][N:21]=1>>[Cl:19][C:20]1[N:24]=[CH:23][N:22]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[N:3]=2)[N:21]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Clc1nc[nH]n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Cl)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.12) (0.4 g, 1.47 mmol) and commercially available 3-chloro-1H-[1,2,4]triazole (0.22 g, 2.17 mmol) according to the general procedure IVa. Obtained as a yellow solid (0.36 g, 72%). MS (ISP) 340.0 [(M+H)+]; mp 137.5° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9].[NH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1>>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2)=[O:9]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CBr)ccc1Cl
Reactant: O=C1CCNCC1
Product: O=C1CCN(Cc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1

Procedure:
Prepared according to the method described in Example 8c from 5-bromomethyl-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 8b) and 4-piperidinone.
Reaction SMILES: C(OC(N1CC(OC2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)C=CN=2)CC1C(O)=O)=O)(C)(C)C.C1([B:35]([OH:37])[OH:36])C=CC=CC=1.CC(C)([O-])C.[Na+]>C1COCC1>[CH3:25][O:24][C:20]1[CH:21]=[CH:22][C:23]([B:35]([OH:37])[OH:36])=[CH:18][CH:19]=1
Reactant: COc1ccc2c(OC3CC(C(=O)O)N(C(=O)OC(C)(C)C)C3)nccc2c1
Reactant: OB(O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1
Yield: 236.9 %

Procedure:
A mixture of 4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (39 mg, 0.10 mmol), phenylboronic acid (14.6 mg, 0.12 mmol), sodium tert-butoxide (38 mg, 0.40 mmol) and ((t-Bu)2POH)2PdCl2 (POPd) (5 mg, 0.01 mmol) in THF (2 mL) was heated to reflux for 4 h. After cooling down, the formed mixture was quenched with 5% citric acid (aq) and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over MgSO4, filtered, evaporated. The residue was purified by prep-HPLC to yield 36 mg (83%) of the desired product as an off-white foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:12])([Cl:13])[Cl:14])[O:8][CH:7]([C:15]([Cl:18])([Cl:17])[Cl:16])[C:6]=2[CH:19]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-hydroxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin (1.0 g.) and acetic anhydride (10 ml.) was warmed on the steam bath for 15 minutes, and then cooled to ambient temperature. Water (40 ml.) was added, and the mixture stirred for 1 hour. The product was removed by filtration, washed with water, dried and crystallised from ethanol to give 6-acetoxy-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 142°-144° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1)C1C=CC=CC=1>CCO.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1
Reactant: O=C1CN(c2ccc(-c3cn[nH]c3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CN(c2ccc(-c3cn[nH]c3)cc2O)S(=O)(=O)N1
Reaction time: 18 h

Procedure:
A mixture of 5-[2-benzyloxy-4-(1H-pyrazol-4-yl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg) and Pd(OH)2 (5 mg) in 3 mL of EtOH/EtOAc (1:1) is hydrogenated at 1 atm for 18 h. The catalyst is filtered and the filtrate evaporated. The residue is purified by preparative HPLC to give the title compound: (M−1)−=293; HPLC retention time=0.88 min (method A).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([Br:25])[CH:23]=3)[NH:18][CH:17]=2)[OH:15])[CH:7]=[C:8]([O:10][CH:11]([F:13])[F:12])[CH:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[F:13][CH:11]([F:12])[O:10][C:8]1[CH:7]=[C:6]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([Br:25])[CH:23]=3)[NH:18][CH:17]=2)=[O:15])[CH:5]=[C:4]([O:3][CH:2]([F:26])[F:1])[CH:9]=1
Reactant: OC(c1cc(OC(F)F)cc(OC(F)F)c1)c1c[nH]c2ncc(Br)cc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: O=C(c1cc(OC(F)F)cc(OC(F)F)c1)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
To (3,5-Bis-difluoromethoxy-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (530, 70.0 mg, 0.16 mmol) in tetrahydrofuran (6.0 mL) was added Dess-Martin periodinane (75.0 mg, 0.18 mmol). The reaction was stirred at room temperature for 10 minutes. The reaction mixture was concentrated with silica gel and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound as a white solid (P-1519, 65.0 mg, 93%.). MS (ESI) [M−H+]−=431.0. 433.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11](Cl)(=[O:13])=[O:12].[NH3:15]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([NH2:15])(=[O:13])=[O:12]
Reactant: N
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.75 h

Procedure:
To a stirred solution of 15.0 g (0.063 mole) of 2,5-dimethoxybenzenesulfonyl chloride in 150 mL of tetrahydrofuran was added dropwise 80 mL of ammonia (28% aqueous solution). After complete addition the mixture was allowed to stir for 1.75 hours at room temperature. Upon standing the mixture separated into two phases. The organic phase was removed from the aqueous phase and was evaporated under reduced pressure to leave a solid residue. This residue was recrystallized from hot water (125 mL) and ethanol (40 mL) to yield 13.1 g of 2,5-dimethoxyphenylsulfonamide (mp 146.5-148.5).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]=2[O:5][CH:4]=[CH:3][CH2:2]1.[Cl:13][C:14]([Cl:22])([Cl:21])[S:15][N:16]([CH3:20])[C:17](Cl)=[O:18]>C1C=CC=CC=1>[O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][C:17](=[O:18])[N:16]([S:15][C:14]([Cl:22])([Cl:21])[Cl:13])[CH3:20])[C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(SC(Cl)(Cl)Cl)C(=O)Cl
Reactant: Oc1cccc2c1OC=CCO2
Solvent: c1ccccc1
Product: CN(SC(Cl)(Cl)Cl)C(=O)Oc1cccc2c1OCCCO2

Procedure:
1.3 G. of sodium hydride (50% dispersion in oil) are washed twice with petroleum ether (40°-45° C.) and then suspended in 30 ml. of absolute benzene in a flask. 4.15 G. 1,5-benzodioxepin-6-ol (0.025 mol) are added stepwise with stirring and under a nitrogen atmosphere. This mixture is stirred for 30 minutes at room temperature and then a solution of 6.7 g. of N-trichloromethylthio-N-methyl carbamyl chloride (freshly prepared) in 30 ml. of absolute benzene is added over a 30 minute period. The resulting mixture is stirred at room temperature for four hours, then poured into 50 ml. of ice water and extracted three times with 30 ml. of benzene. The benzene extracts are washed with water, dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel and eluted with dichloromethylene. On evaporation, 3,4-dihydro-2H-1,5-benzodioxepin-6-yl-[(trichloromethyl)thio]-methylcarbamate is obtained as a yellow oil; MD24 :1.5658.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[C:33](B(O)O)=[CH:32][CH:31]=[N:30]1>C(O)C.C1(C)C=CC=CC=1.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>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: OB(O)c1ccn[nH]1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccn[nH]3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
1-Methylethyl((cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol) was dissolved in ethanol (1 mL) and Toluene (1 mL), mixed with potassium carbonate (74.9 mg, 0.542 mmol), 1H-pyrazol-5-ylboronic acid (36.4 mg, 0.325 mmol, available from Frontier Scientific) followed by tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) and refluxed under nitrogen at 90° C. After 21 hours a sample of tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) was added to the reaction which was left to stir under nitrogen at the same temperature. Another sample of 1H-pyrazol-5-ylboronic acid (36.4 mg, 0.325 mmol) was added after 171 hours total reaction time and heating and stirring continued. Another sample of 1H-pyrazol-5-ylboronic acid (36.4 mg, 0.325 mmol) was added to the mixture after 345 hours. After 391 hours total reaction time the reaction was partitioned between distilled water (40 mL) and EtOAc (40 mL). The organic and aqueous layers were run off and the latter was extracted twice more using EtOAc (2×40 mL). Organic fractions were combined, washed (brine (80 mL), dried (sodium sulfate), filtered and evaporated to dryness to give a clear, colourless solid (110 mg). This was purified on a 12+M Biotage silica column, eluting with 0 to 100% EtOAc in cyclohexane. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (6 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH2:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:16][C:8]12[CH2:14][CH:12]3[CH2:11][CH:10]([CH2:15][C:6]([C:4]([O:3][CH3:2])=[O:5])([CH2:13]3)[CH2:7]1)[CH2:9]2)=[O:22]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C12CC3CC(CC(NC(=O)c4cccc(Cl)c4)(C3)C1)C2
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 3-amino-adamantane-1-carboxylic acid methyl ester HCl salt (Hermogenes N. J. et al.; U.S. Pat. No. 7,947,680 B2) (160 mg, 0.65 mmol) and 3-chlorobenzoic acid (130 mg, 0.78 mmol) in DMF (5 mL) was added DIEA (340 mg, 2.6 mmol) and HATU (300 mg, 0.78 mmol) under N2. After stirring at room temperature for an hour, the reaction was quenched with brine, the aqueous layer was extracted with ethyl acetate (3×20 mL), and the combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1) to afford 220 mg (97%) of the title compound, methyl 3[(3-chlorobenzoyl)amino]adamantane-1-carboxylate, as a white solid. ESI-MS m/z: 348 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)Cc1cccc(O)c1
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(CC(=O)O)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A stirred suspension of 3-hydroxyphenylacetic acid (10.2 g, 67 mmol) in acetic anhydride (100 mL, 1.06 mol) under anhydrous conditions was treated with pyridine (0.5 mL). In the mildly exothermic reaction, the solids dissolved within several minutes and the mixture was maintained at 40° C. for 5 h. The reaction was concentrated in vacuo to about half volume, then water (30 g) in the form of ice chips was added at such a rate that the temperature remained <45° C. When the exotherm had subsided, a second portion of water (200 mL) was added slowly and the mixture was stirred for another 30 min. The precipitated solid was filtered, washed with water and dried to constant weight in vacuo over P2O5 to give 3-acetoxyphenylacetic acid (11.7 g, 90%) which was used without further purification. In an inert atmosphere, a solution of the above 3-acetoxyphenylacetic acid (1.942 g, 10 mmol), diphenyl-phosphoryl azide (2.8 g, 10.17 mmol) and diisopropylethylamine (1.92 mL, 11 mmol) in benzene (25 mL) was stirred at room temperature for 1 h, then the reaction temperature was slowly raised to 70° C. Evolution of gas began to be evident as the reaction temperature reached approximately 55° C. and became much more vigorous as the reaction temperature approached 70° C. Within 30 minutes at that temperature gas evolution had stopped and the reaction solution containing 3-acetoxybenzylisocyanate was cooled to 40° C. Another portion of DIPEA (3.84 mL, 22 mmol) was added, followed by 4-amino-2-chlorobenzoic acid methyl ester hydrochloride salt (2.95 g, 13.3 mmol) and the brownish purple solution was stirred and heated at reflux under argon overnight. The reaction mixture was cooled, diluted with benzene (50 mL) and washed in turn with 1N HCl (50 mL) and dilute brine. The aqueous layers were re-extracted with benzene, and the combined extracts were dried (MgSO4), evaporated, and purified by HPLC (silica gel; 40% ethyl acetate/hexane). Evaporation of the appropriate fractions provided 3.24 g of the solid urea which was then crystallized from dichloromethane-ethyl acetate to give 4-[[[[(3-acetoxy)phenyl]methyl]amino]-carbonyl]amino-2-chlorobenzoic acid, methyl ester (2.71 g, 72%) as a colorless solid, mp 113–114° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:50][CH3:51])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH:48]=O)[CH:43]=5)[C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:50][CH3:51])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:52]6[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]6)[CH:43]=5)[C:37]([O:40][CH3:41])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(-c3cccc(C=O)c3)c2)c1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(OC)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-6-(methyloxy)-3-biphenylyl]methyl}-5-methyl-1,3-benzenedicarboxamide (40.1 mg. 0.06 mmol) was diluted in DMSO (1.5 mL) and dispensed into a 1 dram vial, with fitted magnetic stir bar, containing piperazine (0.18 mmol), and acetic acid (3.6 mg, 0.6 mmol). The resulting solution was stirred at room temperature for 4 h. MP-B(OAc)3H (0.6 mmol, 140 mg) was added and the solution was stirred for another 12 h. The polymer reagent was filtered and purification was completed via Gilson HPLC (with 0.1% TFA in the solvents). The product was dissolved in 3 mL of MeOH and passed through 0.5 g amine columns (washed with 8 mL MeOH) to afford 29.8 mg (65.3%) of the title compound. LC-MS m/z 760 (M+H)+, 1.224 min (ret time).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](Cl)=[O:5].[CH2:13]([O:20][N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][CH:24]=[N:25][C:26]=2[NH2:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:13]([O:20][N:21]1[CH:29]=[N:28][C:27]2[C:22]1=[N:23][CH:24]=[N:25][C:26]=2[N:30]1[C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]2[C:1]1=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Reactant: Nc1ncnc2c1ncn2OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1c1ncnc2c1ncn2OCc1ccccc1
Yield: 49 %

Procedure:
Phthaloyl dichloride (13.35 g; 92.2 mmol) was added to a cooled solution of 9-benzyloxyadenine (14.9 g, 61.5 mmol), 4-dimethylaminopyridine (1.5 g, 12.3 mmol) and triethylamine (25.7 ml, 184.4 mmol) in tetrahydrofuran (200 ml). After 1 hour at room temperature the solvent was removed under reduced pressure and the residue partitioned between chloroform (500 ml) and saturated potassium bicarbonate (300 ml). The organic phase was separated, washed with water (200 ml), brine (200 ml), dried (MgSO4) and evaporated to dryness. Column chromatography on silica gel eluting with chloroformmethanol (100:1) afforded the title compound (11.20 g, 49%). IR: νmax (KBr) 3070, 1800, 1740, 1730, 1605, 1585, 1450 and 1410 cm-1 ; 1H NMR δH [(CD3)2SO] 5.70(2H, s, CH2Ph), 7.55(5H, s, CH2Ph), 8.20(4H, s, Ar), 8.95(1H, s, H-2), 9.25(1H, s, H-8). Found: C, 64.71; H, 3.78; N, 18.85%; m/z 371.1025. C20H13N5O3 requires: C, 64.68; H, 3.54; N, 18.86%; m/e 371.1018.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[I:11]N1C(=O)CCC1=O.O>C(O)(=O)C>[I:11][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Solvent: O
Product: O=C1Cc2cc(I)ccc2N1
Temperature: 0 °C
Yield: 69.9 %

Procedure:
A solution of 2-indolinone (2.66 g, 20 mmol) in acetic acid (20 ml) was stirred at room temperature in the presence of N-iodosuccinimide (5.4 g, 24 mmol) for 2 hours. H2O (150 ml) was then added. The precipitate was filtered, washed with H2O, and dried. The resulting solid was refluxed in ethyl acetate (50 ml), cooled to 0° C., filtered, washed with ethylacetate and ether and dried to provide 5-iodo-1,3-dihydro-indol-2-one (3.62 g. 70%) as a beige solid, m.p. 190-192° C. and MS: m/e=259 (M+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1
Reactant: Nc1cncc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cncc(N)n1
Temperature: 130 °C
Yield: 79.7 %

Procedure:
A mixture of 6-chloro-2-pyrazinamine (200 mg, 1.544 mmol) and sodium methoxide (250 mg, 4.63 mmol) in methanol (3.9 ml) was heated to 130° C. via a microwave reactor for 60 min. The crude product mixture was purified by RP-HPLC to give 6-(methyloxy)-2-pyrazinamine (154 mg, 1.231 mmol, 80% yield). MS (ES+) m/z 125.8 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1>>[CH2:26]([N:22]([CH2:23][CH2:24][OH:25])[C:3]1[C:2]([C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1)[CH3:27]
Reactant: OB(O)c1cncnc1
Reactant: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Product: CCN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncnc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-(ethyl(2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 156.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (Condition 3) tR=0.97 min, m/z=448.3 [M+H]+, m/z=446.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=6.96 Hz, 3H) 3.11-3.16 (m, 2H) 3.34-3.41 (m, 2H) 3.49 (q, J=5.65 Hz, 2H) 4.62 (t, J=5.27 Hz, 1H) 7.36 (d, J=8.41 Hz, 2H) 7.80-7.90 (m, 2H) 8.11 (d, J=2.38 Hz, 1H) 8.78 (d, J=2.26 Hz, 1H) 9.03 (s, 2H) 9.21 (s, 1H) 10.26 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:14][C@@H:13]([O:25][Si](C(C)(C)C)(C)C)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@H:13]([OH:25])[CH2:14][C@@H:15]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 16.7 %

Procedure:
To a solution of 8.7 g (18 mmol) (3R,5R)-3,5-bis-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid benzyl ester in 200 ml THF were added 18 ml (18 mmol) of a 1M solution of tetrabutyl ammoniumfluoride in THF at 0° C. After completed addition, the mixture was allowed to warm to room temperature over night. Addition of water was followed by extraction with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulfate. Flash chromatography gave 1.1 g (16%) of the title compound as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[CH:12]4[CH:17]([N:5]([C:6]=23)[CH:4]=[C:3]1[C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]4.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[N+:21]([C:8]1[C:7]2[C:2](=[O:1])[C:3]([C:18]([OH:20])=[O:19])=[CH:4][N:5]3[C:6]=2[C:11]([CH:12]2[CH:17]3[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:9]=1)([O-:23])=[O:22]
Reactant: O=C(O)c1cn2c3c(cccc3c1=O)C1CCCCC12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cn2c3c(ccc([N+](=O)[O-])c3c1=O)C1CCCCC12
Temperature: 0 °C

Procedure:
6 g of 7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxylic acid was dissolved in 35 ml of concentrated sulfuric acid and stirred while cooling with ice, followed by dropwise addition of a mixture of 4.3 ml of concentrated nitric acid having a specific gravity of 1.42 and 15 ml of the concentrated sulfuric acid. After completion of the addition, the resulting mixture was stirred for 1 hour at room temperature and poured into 200 g of ice to precipitate yellow crystals. Recrystallization from dimethylformamide-water gave 7 g of 3-nitro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazole-5-carboxylic acid having a melting point of 251°-253° C.