Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:15][C@H:16]([NH2:18])[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32]([C@@H:35]([O:38][Si:39]([CH2:44][CH3:45])([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:36]I)=[CH:31][C:30]=1[NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:15][C@H:16]([NH:18][CH2:36][C@@H:35]([C:32]3[CH:33]=[CH:34][C:29]([O:28][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[C:30]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:31]=3)[O:38][Si:39]([CH2:40][CH3:41])([CH2:42][CH3:43])[CH2:44][CH3:45])[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:20]
Reactant: CCN(CC)C(=O)c1ccc2c(C[C@@H](C)N)c[nH]c2c1
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc2c(C[C@@H](C)NC[C@H](O[Si](CC)(CC)CC)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)c[nH]c2c1
Temperature: 110 °C
Reaction time: 21 h
Yield: 36.7 %

Procedure:
To a solution of (R)-3-(2-aminopropyl)-1H-indole-6-carboxylic acid diethylamide (20.0 mg, 0.0742 mmol) in acetonitrile (1.0 ml) is added (R)—N-[2-benzyloxy-5-(2-iodo-1-triethylsilyloxyethyl)phenyl]-methanesulfonamide (41.1 mg, 0.0742 mmol), and the mixture is stirred at 110° C. for 21 hours in a sealed vessel. The reaction solution is concentrated under reduced pressure, and the residue is purified by preparative TLC (a saturated ammonia solution in chloroform/methanol=50/1) to give 3-{(2R)-2-[2-(4-benzyloxy-3-methanesulfonylamino-phenyl)-(2R)-2-(triethylsilyloxy) ethylamino]propyl}-1H-indole-6-carboxylic acid diethylamide (19.2 mg, 0.0272 mmol, 37%).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Br:44].C([O-])([O-])=O.[Na+].[Na+].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.O1CCCC1>[Br:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:33]1[C:32]([C:19]2[CH:20]=[CH:21][C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:17][CH:18]=2)=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Brc1ccccc1-c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)cc2)OC1(C)C
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: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccccc1-c1ccccc1-c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 61.6 %

Procedure:
A mixture of Compound 2 (3.00 g, 7.57 mmol), 2,2′-dibromo-1,1′-biphenyl (4.72 g, 15.1 mmol), tetrakis(triphenylphosphine)palladium(0) (0.350 g, 0.303 mmol), Na2CO3 (3.18 g, 30.0 mmol), H2O (30 mL) and tetrahydrofuran (THF) (50 mL) was degassed with argon for about 44 min while stirring. The reaction mixture was then maintained under argon at about 80° C. while stirring. Upon confirming consumption of the starting material by TLC (SiO2, 19:1-CH2Cl2:acetone), the reaction was cooled to RT and poured over CH2Cl2 (ca. 250 mL). The organics were then washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified via flash chromatography (SiO2, 100% CH2Cl2 to 39:1-CH2Cl2:acetone) to yield Compound 3 (2.34 g, 62%) as an off-white foam: confirmed by LCMS (APCI): calculated for C31H21BrN2 (M+): 501; Found: 501.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([Cl:15])[C:4]=2[CH:3]=1
Reactant: O=c1[nH]cnc2ncc(Br)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ncc(Br)cc12
Temperature: 25 °C

Procedure:
6-Bromopyrido[2,3-d]pyrimidin-4(3H)-one (3.0 g) and POCl3 (15 mL) were heated at 130° C. under nitrogen for 3 h. The homogeneous dark solution was concentrated under reduced pressure and diluted with EtOAc (150 mL). The heterogeneous brown slurry was poured onto mixture of ice/aq. NaHCO3 and allowed the mixture warm to room temperature. The heterogeneous brown mixture was further diluted with EtOAc (75 mL) and separated the organic layer. The organic layer was partitioned with aq. NaCl, separated, stirred with MgSO4 and filtered through a pad of Celite® and silica gel. The pale yellow filtrate was concentrated and the crude solid was stirred in 50% EA/hexanes. 6-Bromo-4-chloropyrido[2,3-d]pyrimidine was obtained as a pale yellow crystalline solid (1.8 g, purity: 95%) upon filtration.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[CH:11][C:10]=2[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:4][C:3]=1[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].[O:33]=[C:34]1[NH:38][C:37](=[O:39])[CH:36]([CH2:40][C:41]2[CH:51]=[CH:50][C:44]([O:45][CH2:46][C:47](O)=[O:48])=[CH:43][CH:42]=2)[S:35]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:33]=[C:34]1[NH:38][C:37](=[O:39])[CH:36]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:45][CH2:46][C:47]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[C:13]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:12]([OH:19])=[CH:11][C:10]=4[C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:4][C:3]=3[N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:48])=[CH:50][CH:51]=2)[S:35]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)cc2C(C)(C)C)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cc(C(C)(C)C)c(O)cc2C(C)(C)C)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 99.8 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2,5-di-t-butyl-4-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.71 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.68 g), diethyl cyanophosphonate (0.39 g), triethylamine (0.24 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.13 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:10][C:11]=1[O:12][CH3:13])C(O)=O.C([N:25](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:10][C:11]=1[O:12][CH3:13])[NH2:25]
Reactant: COc1cc(C(=O)O)c(C(=O)c2ccnc(Cl)c2)cc1OC
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N)c(C(=O)c2ccnc(Cl)c2)cc1OC
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,4-dimethoxy-6-(2-chloroisonicotinoyl)benzoic acid (70 g) in tetrahydrofuran (1800 ml) is added triethylamine (45.5 ml) at room temperature under nitrogen atmosphere, and thereto is added dropwise ethyl chloroformate (25 ml) at a temperature below -20° C., and the mixture is stirred at -20° C. for 10 minutes. To the reaction mixture is added a 1.38 M aqueous sodium azide solution (500 ml), and the mixture is stirred at room temperature for 1.5 hour, and extracted with ethyl acetate. The extract is washed, dried, and concentrated. The residue is dissolved in toluene (1300 ml), and the mixture is heated under reflux for one hour. To the reaction mixture is added conc. hydrochloric acid (450 ml) under ice-cooling, and the mixture is heated with stirring at 80° C. for one hour. To the reaction mixture is added ice-water, and the mixture is extracted with chloroform. The extract s washed, dried and concentrated. The residue is crystallized from ether to give 3,4-dimethoxy-6-(2-chloroisonicotinoyl)aniline (50.3 g).
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[CH2:23]([C:30]1[N:31]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)[N:32]=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[C:35](=[O:41])[N:34]2CC1C=CC(OC)=CC=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O.C1COCC1>[CH2:23]([C:30]1[N:31]([CH2:51][C:52]2[CH:53]=[CH:54][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:56][CH:57]=2)[N:32]=[C:33]2[C:38]=1[C:37](=[O:39])[N:36]([CH3:40])[C:35](=[O:41])[NH:34]2)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Cc4ccccc4)n(Cc4ccc(-c5ccccc5)cc4)nc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)c(Cc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of ammonium cerium (IV) nitrate (204 mg, 0.371 mmol) in water (0.6 mL) is added to a solution of 3-benzyl-2-(biphenyl-4-ylmethyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (40.3 mg, 0.0743 mmol) in THF (2 mL). The resulting orange solution is stirred at room temperature overnight. Another batch of CAN (204 mg, 0.371 mmol) is added and the mixture is stirred for 3 hours, and then the third batch of CAN (204 mg) is added, and the mixture is stirred at r.t. overnight. The reaction mixture is evaporated to dryness. The residue is treated with brine, and extracted with methylene chloride five times. The organic phase is combined and concentrated. The residue is purified by chromatography to give 11.6 mg product as white solids (Yield: 36.9%). 1H NMR (400 MHz, acetone-d6) δ 3.27 (s, 3H), 4.51 (s, 2H), 5.33 (s, 2H), 7.13-7.62 (m, 14H), 10.26 (s, 1H). MS (FAB) m/z 423.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:29][O:30][CH3:31].[Cl-].[NH4+]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[O:18][CH2:29][O:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(O)c1
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(C(C)=O)ccc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of 3′,4′-dihydroxyacetophenone (2.00 g) in N,N-dimethylformamide (40 ml) were added lithium carbonate (2.44 g) and benzyl bromide (4.0 ml), and the mixture was stirred for 14.5 hours at 50° C. To the reaction mixture was added 1N hydrochloric acid, and the resulting mixture was extracted with a mixed solution of diethyl ether and ethyl acetate (3/1). The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) gave 4′-benzyloxy-3′-hydroxyacetophenone (2.00 g). To a stirred solution of the obtained 4′-benzyloxy-3′-hydroxyacetophenone (2.00 g) in dichloromethane (25 ml) was added N,N-diisopropylethylamine (2.2 ml) under ice-cooling, and the mixture was stirred for 10 minutes. Chloromethylmethyl ether (1.2 ml) was added to the mixture, and the resulting mixture was stirred for 5.5 hours at room temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) gave 4′-benzyloxy-3′-methoxymethoxyacetophenone (2.28 g).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)=[N:3]1.O.[NH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.Cl.[OH-].[K+]>C(O)C>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[C:20]2[CH2:21][CH2:22][NH:17][CH2:18][CH:19]=2)=[N:3]1
Reactant: O=C1CCNCC1
Reactant: Cn1nnc(-c2ccc3[nH]ccc3c2)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nnc(-c2ccc3[nH]cc(C4=CCNCC4)c3c2)n1
Temperature: 25 °C

Procedure:
A solution of 5-(2-methyltetrazol-5-yl)-1H-indole (2b) (40 g), piperidin-4-one, hydrate, hydrochloride (80 g) and potassium hydroxide (48 g) in ethanol (1000 mL) was boiled at reflux for 16 hours. After cooling to room temperature, precipitated material was filtered off and carefully washed with water. The remaining crystalline product was dried in vacuo at 80° C. leaving 41 g of crude title compound 3a which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH2:16][O:15][C:14](=[O:18])[NH:13][C:12]=3[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[C:9]=2[CH:22]=[O:23])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O>[CH2:26]([N:13]1[C:12]2[N:11]=[C:10]([CH:19]([CH3:21])[CH3:20])[C:9]([CH:22]=[O:23])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:17]=2[CH2:16][O:15][C:14]1=[O:18])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=O)COC(=O)N2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C=O)COC(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.36 g (7.5 mmol) of the compound from Example VII are dissolved in 20 ml of anhydrous dimethylformamide, and the mixture is treated with 0.28 g (9.4 mmol) of 80% strength sodium hydride under a gentle stream of argon. The mixture is stirred at room temperature for 15 min and treated with 1.54 g (9 mmol) of benzyl bromide. After 60 min, 30 ml of water are cautiously added and the mixture is extracted twice with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to dryness in vacuo. The residue which remains is chromatographed in a column (φ 3 cm) on 50 g of silica gel 230-400 mesh using petroleum ether/ethyl acetate 4:1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][N:7]=1.[CH2:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1)[CH2:21][CH3:22].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:3]([C:16]([NH:18][CH3:19])=[O:17])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:28][CH2:27][C:26]3[CH:29]=[CH:30][C:23]([CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CCCc1ccc(CN)cc1
Reactant: CNC(=O)c1nc(-c2cccc(C=O)c2)cnc1N
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCc1ccc(CNCc2cccc(-c3cnc(N)c(C(=O)NC)n3)c2)cc1
Yield: 32.4 %

Procedure:
To a stirred solution of 3-amino-6-(3-formylphenyl)-N-methylpyrazine-2-carboxamide (50 mg, 0.19 mmol) and 4-propylbenzylamine (35.7 mg, 0.24 mmol) in TBF (5 mL) was added sodium cyanoborohydride (ca. 5 eq.) and the solution was stirred until refluxed for 1 h. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (50 mL) and saturated aqueous solution of Na2CO3 (10 mL). The phases were separated. The organic layer was washed with saturated aqueous sodium chloride then dried (Na2SO4). Filtration and concentration followed by HPLC purification gave (24 mg, 32% yield) of 3-amino-N-methyl-6-[3-({[(4-propylphenyl)methyl]amino}methyl)phenyl]pyrazine-2-carboxamide: 1H NMR (400 MHz; DMSO-d6): 9.7 (br s, 1H); 9.0 (m, 1H); 8.87 (s, 1H); 8.5 (s, 1H); 8.4 (d, 1H); 7.5 (m, 6H); 7.43 (m, 2H); 4.2 (d, 2H); 2.82 (d, 3H); 2.56 (m, 2H); 1.6 (m, 2H); 0.9 (m, 3H); MS (EI) for C23H27N5O: 390 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:49])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33]([C:39]3[CH:44]=[CH:43][N:42]=[C:41]([C:45]([O:47]C)=O)[CH:40]=3)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:50][NH2:51]>CO>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([C:45](=[O:47])[NH:51][CH3:50])[CH:40]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:49])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:13]1)=[O:17]
Reactant: CN
Reactant: COC(=O)c1cc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)ccn1
Solvent: CO
Product: CNC(=O)c1cc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)ccn1
Reaction time: 1 h

Procedure:
A stirred solution of methyl ester 148 (30 mg, 0.05 mmol) in MeOH (2 mL) is treated with methylamine (1 mL, 40% solution in water) at RT. After 1 h, the reaction mixture is reduced in vacuo and the residue purified by column chromatography (75% EtOAc in heptane) to give the title compound.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)=[NH:4].[NH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[C:13]=1[C:14]([OH:16])=O.C(O)(=O)C>CO>[Br:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:12]2[C:13]=1[C:14]([OH:16])=[N:4][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[N:9][CH:10]=1)=[N:11]2
Reactant: Nc1cccc(Br)c1C(=O)O
Reactant: COC(=N)c1cncnc1
Solvent: CO
Solvent: CC(=O)O
Product: Oc1nc(-c2cncnc2)nc2cccc(Br)c12
Reaction time: 16 h
Yield: 27.3 %

Procedure:
To a stirred suspension of methylpyrimidine-5-carbimidate (2.00 g, 14.5 mmol) in methanol (20 mL) was added 2-amino-6-bromobenzoic acid (3.1 g, 14.5 mmol). The mixture was heated to reflux where it stirred for 16 h under the nitrogen atmosphere. At the conclusion of this period, acetic acid (2.72 ml, 47 mmol) was added drop wise. Upon completion of addition, methanol was evaporated under reduced pressure to yield a residue. The residue was triturated with ether (100 mL), ethyl acetate (50 mL) and the resulting solid was dried to yield 5-bromo-2-(pyrimidin-5-yl)quinazolin-4-ol (1.2 g, 27%) as an off-white solid. The crude product was used without further purification. 1H NMR (400 MHz, DMSO-d6, δ): 7.64 (dd, J=7.2 Hz, 8.4 Hz, 1H); 7.73-7.75 (m, 2H); 9.35 (s, 1H); 9.46 (s, 2H); 12.9 (br s, 1H). ES-MS: [M++1]=303 and [M++3]=305.
Reaction SMILES: Cl.[C:2]12([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.N1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)Cl>[C:2]12([C:12]3[CH:13]=[CH:14][C:15]([NH:18][C:26](=[O:27])[O:28][CH2:29][CH3:30])=[CH:16][CH:17]=3)[CH2:9][CH:8]3[CH2:10][CH:4]([CH2:5][CH:6]([CH2:7]3)[CH2:11]1)[CH2:3]2
Reactant: Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
5.28 g (20 mmol) of 4-adamantan-1-yl-phenylamine hydrochloride were placed in 100 ml of methylene chloride and treated with 3.22 g (42.0 mmol) of pyridine. A solution of 2.39 g (22.0 mmol) of ethyl chloroformate in 15 ml of methylene chloride was added dropwise to this suspension at room temperature while stirring during 15 minutes. The reaction mixture was stirred at room temperature for 2 hours. Subsequently, the mixture was washed with water and the organic phase was dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from methylene chloride/n-hexane. 5.6 g of ethyl 4-adamantan-1-yl-phenyl-carbamate were obtained as a white crystallizate. M.p.: 132°-134°.
Reaction SMILES: C[O-].[Na+].C([O:7][C@@H:8]1[C@@H:22]([O:23]C(=O)C)[C@H:21]([O:27]C(=O)C)[CH2:20][S:19][C@H:9]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)(=O)C>CO>[O:10]([C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=1)[C@@H:9]1[S:19][CH2:20][C@@H:21]([OH:27])[C@H:22]([OH:23])[C@H:8]1[OH:7]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 129.5 %

Procedure:
1.5 ml of a solution of sodium methylate in methanol (8% w/v of Na) are added under an inert atmosphere to a suspension of 10 g (25.4.10-3 ) of 4-cyanophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside in 200 ml of methanol. The reaction mixture is stirred at room temperature for 30 min, neutralized by the addition of Amberlite® IR 120 H+ resin and filtered. After evaporation to dryness, the residue is crystallized from methanol to give 8.8 g (yield: 73%) of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([Br:14])[CH:12]=2)[N:7]([S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1c[nH]c2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (15.0 mmol), benzenesulfonyl chloride (11.9 g, 8.61 mL, 67.5 mmol) and triethylamine (9.61 g, 13.2 mmol) in dry THF (100 mL) was heated under reflux for 19 h. The resultant suspension was allowed to cool to ambient temperature and diluted with saturated aqueous sodium carbonate solution (50 mL) and extracted with DCM (2×50 mL) and THF (1×50 mL). The combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica, 50 g cartridge, Si-SPE, 0-100% DCM in pentane). The relevant fractions were concentrated in vacuo and the residue was triturated with pentane (10 mL) to afford the title compound as a white solid (5.25 g, 88%). LCMS (Method B): RT=4.11 min, M+H+=395/397.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([CH3:18])([N+:15]([O-])=O)[CH3:14].O.NN>[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([CH3:18])([CH3:14])[NH2:15]
Reactant: COc1ccc2[nH]cc(CC(C)(C)[N+](=O)[O-])c2c1
Agent: [Ni]
Agent: NN
Solvent: O
Product: COc1ccc2[nH]cc(CC(C)(C)N)c2c1

Procedure:
The nitro compound produced in Procedure 11C was reduced with Raney nickel and hydrazine hydrate according to the method of Procedure 10D. The structure of the product was confirmed by examination of the NMR spectrum, m.p. 114°-116°, yield 25.8 g. from 31.3 g. of nitro compound.