Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].O1CCCC1.[F:8][C:9]1[C:14]([N:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26](=[O:30])[C:25]([CH3:35])([O:31]C(C)=O)[CH2:24]4)[N:17]=[N:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1>C(OCC)(=O)C>[F:8][C:9]1[C:14]([N:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26](=[O:30])[C:25]([OH:31])([CH3:35])[CH2:24]4)[N:17]=[N:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(=O)OC1(C)Cc2cc(-c3nnn(-c4cccnc4F)c3C)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(-c2ccc3c(c2)CC(C)(O)C3=O)nnn1-c1cccnc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
At room temperature, 100 μl of 2M sodium hydride aqueous solution was added to 1 ml solution of tetrahydrofuran with 30 mg of 1-(2-fluoropyridine-3-yl)-4-(2-methyl-2-methylcarbonyloxy-1-oxoindane-5-yl)-5-methyl-1H-[1,2,3]triazole obtained in Example 51. The mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate, washed with water and saturated saline solution, and dried with anhydrous sodium sulfate. The residues obtained by distilling out the solvents under reduced pressure were purified by silicagel column chromatography (hexane:ethyl acetate=80:20) to obtain 10 mg of the above compound as a white solid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9](=[O:13])/[CH:10]=[CH:11]/[CH3:12].[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:1]1([CH:9]([OH:13])[CH:10]=[CH:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: C/C=C/C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC=CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.9 %

Procedure:
To a cooled (0-55° C.) 927 mL of 1 M solution of phenyl magnesium bromide in tetrahydofuran was added dropwise a solution of crotonaldehyde (65.0 g) in 130 mL of anhydrous ether over a period of 2 hours and 45 minutes. The reaction was stirred for an additional 45 minutes and then warmed to room temperature. After four more hours of stirring, saturated ammonium chloride aqueous solution (750 mL) was added to the reaction. The mixture was extracted with 750 mL of ether twice. The combined extract was dried over anhydrous potassium carbonate and filtered. The solvent was evaporated to give 135.88 g (99.9%) of the desired 1-phenyl-2-buten-1-ol as an oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=3[Cl:21])[C:6]=2[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][C:12]=3[Cl:21])[C:6]=2[CH:5]=[CH:4][N+:3]=1[O-:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1ccc(-n2ccc3c(Cl)nccc32)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: [O-][n+]1ccc2c(ccn2-c2ccc(C(F)(F)F)cc2Cl)c1Cl
Reaction time: 2 h
Yield: 29.8 %

Procedure:
4-chloro-1-(2'-chloro-4'-trifluoromethylphenyl)-pyrrolo[3,2-c]pyridine (1.10 g, 33 mmol) and meta-chloroperbenzoic acid (approximately 80-85%, 1.15 g) were stirred together in chloroform (20 ml) at room temperature overnight. A further quantity of meta-chloroperbenzoic acid (1.15 g) was added, and stirring continued for 2 hours. The mixture was diluted with dichloromethane and washed with saturated aqueous sodium carbonate solution. The organic portion was dried over magnesium sulfate, filtered, and the filtrate evaporated in vacuo. The residue was triturated with hexane to give 4-chloro-1-(2'-chloro-4'-trifluoromethylphenyl)-pyrrolo[3,2-c]-pyridine 5-oxide (0.69 g) as a tan solid, m.p. 119°-123° C. (with dec.)
Reaction SMILES: [N+](C1C=CC(CNC(N)=O)=CC=1)([O-])=[O:2].[NH2:15][C:16]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)[C:20](=[O:32])[N:19]([CH3:33])[C:18](=[O:34])[CH:17]=1.[Cl-].[Ca+2].[Cl-]>O.C(O)(=O)C.[Zn]>[C:18]([OH:34])(=[O:2])[CH3:17].[NH2:15][C:16]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[C:20](=[O:32])[N:19]([CH3:33])[C:18](=[O:34])[CH:17]=1
Reactant: Cn1c(=O)cc(N)n(Cc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: NC(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)cc(N)n(Cc2ccc(N)cc2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Using the general procedure for Intermediate 1, (4-nitro-benzyl)-urea [J. Med. Chem. 1996, 39, 1924] is converted into 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidin-2,4-dione, [MH]+ 277. A solution of calcium chloride (4.94 g, 45 mmol) in water (100 ml) is added to a solution of 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidine-2,4-dione (19.08 g, 69.0 mmol) in acetic acid (300 ml). Zinc dust (58.8 g, 900 mmol) is then added portionwise with external cooling. The reaction is stirred at room temperature for 1.5 hours, filtered through a celite plug and washed successively with ethanol and acetic acid. Evaporation of the combined filtrate and washings affords 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidin-2,4-dione acetic acid salt, [M-3H]− 243. Acetic anhydride (7.2 ml, 76.0 mmol) is added to a cooled (0° C.) suspension of 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt (17.0 g, 69.0mmol) in pyridine (260 ml). The reaction mixture is warmed to room temperature, stirred for 6 hours and the solvent evaporated. The residue is triturated with water and the solid collected by filtration and dried to afford N-[4-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 289. Using the general procedure for Intermediate 1, this compound is converted into N-[4-(5,6-diamino-3-methyl-2,4-dioxo-3,4dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 304.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].C(=O)(O)[O-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: c1c[nH]cn1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(OCC)n1ccnc1
Yield: 63 %

Procedure:
A mixture of imidazole (15 g, 0.220 mol, 1 eq), triethyl orthoformate (130 g, 146.6 mL, 0.880 mol, 4, eq) and p-toluenesulfonic acid (1.17 g, 0.00616 mol, 0.028 eq) was heated at 145°-175° C. until no more ethanol was distillable from the reaction mixture. The excess orthoformate was removed in vacuo. Solid sodium bicarbonate (1.17 g, 0.011 mol) was added and the residue was vacuum distilled to give the title compound (23.6 g, 68%). b.p. 89°-91° C./0.3 mm Hg.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[CH:17][C:18]4[C:24](=[O:25])[C:23]([C:26]#[N:27])=[CH:22][N:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:19]=4[N:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-:34].[K+].O>C(O)(C)(C)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:16]=[CH:17][C:18]4[C:24](=[O:25])[C:23]([C:26]([NH2:27])=[O:34])=[CH:22][N:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:19]=4[N:20]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: [OH-]
Reactant: CN1CCN(c2ccc(Nc3ncc4c(=O)c(C#N)cn(-c5ccccc5)c4n3)cc2)CC1
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CN1CCN(c2ccc(Nc3ncc4c(=O)c(C(N)=O)cn(-c5ccccc5)c4n3)cc2)CC1
Temperature: 85 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a solution of 2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carbonitrile (Example 13F, 9 mg) in 1 mL of t-butanol was added potassium hydroxide (ground, 5 mg). The mixture was stirred at 85° C. for 1 hour. After cooling to rt, water was added and the precipitates were extracted into EtOAc. The organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated under vacuum to leave 2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-5-oxo-8-phenyl-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide as a yellow solid (7.2 mg, 79%). 1H NMR (300 MHz, CDCl3) δ (ppm): 10.64 (br, 1H), 10.30 (s, 1H), 9.17 (s, 1H), 7.71 (m, 3H), 7.53 (br, 1H), 7.43 (m, 2H), 6.94 (br, 2H), 6.35 (br, 2H), 5.06 (br, 1H), 3.12 (m, 4H), 2.59 (m, 4H), 2.37 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H25N7O2: 456.51 (M+H), Found: 456.6.
Reaction SMILES: [N+](C1C=CC(O[C:11](=O)[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[OH:22])=CC=1)([O-])=O.[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)=[O:27].CO>C1(C)C(C)=CC=CC=1>[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([NH:33][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[OH:22])[S:31][CH:32]=1)=[O:27]
Reactant: COc1cc(O)c(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Reactant: COC(=O)c1csc(N)n1
Solvent: CO
Solvent: Cc1ccccc1C
Product: COC(=O)c1csc(NCc2cc(OC)c(OC)cc2O)n1
Temperature: 130 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
In 1 mL of xylene were suspended 200 mg of 2-hydroxy-4,5-dimethoxybenzoic acid 4-nitrophenyl ester and 119 mg of 2-amino-1,3-thiazole-4-carboxylic acid methyl ester in a stream of argon, which was then stirred at 130° C. for 12 hours. The reaction mixture was allowed to stand to cool, to which 1 mL of methanol was then added, followed by heating to reflux for one hour. The resultant reaction mixture was allowed to stand to cool, followed by collecting the precipitated crystal by filtration at 30° C. or lower before drying under reduced pressure to provide 180 mg of the title compound (5a) at a yield of 80%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[N:8]=1.CN(C=O)C.C(Cl)(=O)C([Cl:43])=O>C(Cl)Cl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[N:8][C:7]([O:6][CH2:5][C:4]3[CH:31]=[CH:32][C:33]([F:34])=[C:2]([F:1])[CH:3]=3)=[C:12]([CH:11]=2)[C:13]([Cl:43])=[O:15])=[CH:17][CH:18]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3,4-difluorobenzyloxy)-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylic acid (120 mg, 0.20 mmol) from Example 77 in methylene chloride (3 mL) was added a drop of DMF (cat.) and oxalyl chloride (0.100 mL, 1.1 mmol). The reaction was stirred at rt for 1 h and was then evaporated to dryness. The acid chloride was dissolved in methylene chloride and used directly in the subsequent amide formation.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([OH:19])[CH:3]=1.Br[CH2:21][CH2:22][O:23][C:24](=[O:26])[CH3:25]>C(#N)C>[C:24]([O:23][CH2:22][CH2:21][O:19][C:4]1[CH:3]=[C:2]([NH2:1])[C:17]([Cl:18])=[CH:16][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])(=[O:26])[CH3:25]
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CC(=O)OCCBr
Solvent: CC#N
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCOC(C)=O
Yield: 85.5 %

Procedure:
A solution of the tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (5.27 g, 10 mmoles) (prepared in Preparation No. 3) in acetonitrile (100 ml) and 2-bromoethylacetate (2 g, 12 mmoles) was stirred for 48 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic layer was washed with ice-cold 0.4N sodium hydroxide solution, water, dried and the solvent evaporated. The residue was chromatographed over deactivated silica using methylene chloride (100), methanol (2), ammonia (0.5) solvent system. The appropriate fractions were combined and the solvent evaporated to leave a residue of 3.18 g (85%) of the title compound. Crystallization from toluene gave a sample, mp. 101°-102° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)(=[O:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1.[ClH:29].C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(O)C>[ClH:29].[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)(=[O:12])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[NH:34])[NH2:28])[CH:22]=1
Reactant: Cn1c(COc2cccc(C#N)c2)nc2cc(S(=O)(=O)N3CCCC3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(COc2cccc(C(=N)N)c2)nc2cc(S(=O)(=O)N3CCCC3)ccc21
Yield: 71 %

Procedure:
Prepared analogously to Example 32 from 1-methyl-2-[(3-cyanophenyl)oxymethyl]-benzimidazol-5-yl-sulphonic acid-pyrrolidide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 71% of theory, C20H23N5O3S (413.5) EKA mass spectrum: (M+H)+ =414
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[S:26]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[CH:28]=[CH:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:31]1[CH2:32][CH2:33][C:34]2[S:26][CH:27]=[CH:28][C:29]=2[CH2:30]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: c1cc2c(s1)CCNC2
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCc3sccc3C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.81 minutes; C24H20Cl2N4O2S (499.42); mass spectrum: (M−H)−=498/500/502 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([NH2:15])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:12]1[CH:11]=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][C:8]=2[NH2:15]
Reactant: COCCOc1nc(N)c2[nH]cnc2n1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1nc(N)c2ncn(Cc3cccc(Br)c3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2-methoxyethoxy)-9H-purin-6-amine (15) (1.0 g, 4.78 mmol), 3-bromobenzyl bromide (1.5 g, 6.00 mmol) and anhydrous potassium carbonate (0.85 g, 6.15 mmol) were combined in DMF (15 mL) and stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried with sodium sulfate and the solvent was removed under vacuum. The resulting residue was triturated with a mixture of diethylether and ethyl acetate (4:1) and filtered. 9-(3-bromobenzyl)-2-(2-methoxyethoxy)-9H-purin-6-amine, Compound (39) (0.77 g, 43%) was obtained as a yellowish solid. 1H-NMR (DMSO) δ: 8.07 (s, 1H), 7.57 (s, 1H), 7.52-7.46 (m, 1H), 7.34-7.22 (m, 4H), 5.26 (s, 2H), 4.32 (t, J=4.5 Hz, 2H), 3.60 (t, J=4.5 Hz, 2H), 3.27 (s, 3H). MS: 378/380 (MH+)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[C@@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]3[C@@H:11]([CH2:19][OH:20])[CH2:10]2)[CH:3]=1.[NH2:21][C@@H:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>C(Cl)Cl>[C@@H:22]1([NH:21][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]3[C@@H:13]4[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]4[C@@H:11]([CH2:19][OH:20])[CH2:10]3)[CH:3]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(Cl)ncn3)[C@@H]2O1
Reactant: N[C@H]1CCc2ccccc21
Solvent: ClCCl
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(N[C@H]4CCc5ccccc54)ncn3)[C@@H]2O1
Temperature: 180 °C
Yield: 82.4 %

Procedure:
A mixture of {(3aR,4R,6R,6aS)-6-[(6-chloropyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol (200 mg, 0.667 mmol) and (S)-(+)-1-aminoindan (0.188 mL, 1.47 mmol) were heated to 180° C. for 3 h in a sealed tube using MWI. The mixture was dissolved in DCM and the resulting suspension was washed with H2O followed by saturated ammonium chloride solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in EtOAc to afford the title compound as an amorphous solid (218 mg, 82.4%). LC/MS: Rt=1.44 min, ES+ 397 (AA standard).
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][O:10][C:7]2=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][O:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCO3)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Reaction time: 14 h
Yield: 102.8 %

Procedure:
10% Pd on carbon (108.7 mg, 0.1021 mmol) was added under a nitrogen atmosphere to a solution of tert-butyl [(3S)-1-(5-nitro-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (411.2 mg, 1.128 mmol) in MeOH (5.00 mL). The reaction mixture was purged with hydrogen gas and was stirred under hydrogen (1 atm.) for 14 h. The reaction mixture was then filtered through a pad of diatomaceous earth. The pad was eluted with further MeOH. The filtrate was concentrated under reduced pressure to give the sub-title compound as an off-white solid (387.9 mg), which was used directly in the next step without further purification. LCMS calc. for C17H22N4O3 (M+H)+: m/z=335.2. found 335.2.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13](O)=O)=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:16].[Na+]>>[C:11]1(=[O:16])[C:12]2[C:7]([C:1]3[C:6]([CH:13]=2)=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=[N:10]1
Reactant: [OH-]
Reactant: O=C(O)c1cnccc1-c1ccccc1
Agent: [Na+]
Product: O=C1N=CC=C2C1=Cc1ccccc12
Temperature: 200 °C
Reaction time: 5 h

Procedure:
4-Phenylnicotinic acid (4.7 g, 23.8 mmol) from the previous step was suspended in polyphosphoric acid (160.3 g) and slowly heated to 200° C. with stirring. After 5 hours, the mixture was cooled to 140° C. and slowly poured over crushed ice and stirred for 24 hours. The mixture was then neutralized to pH=4 with 50% sodium hydroxide solution and extracted 3 times with dichloromethane. The dichloromethane extracts were combined and the solvent was removed under reduced pressure to yield the yellow solid of 2-azafluorenone (3.1 g, HPLC RT=2.16 min, method A; LC-MS m/z=182), 1H NMR, 400 MHz, CHCl3, 8.72 ppm (s, 1H), 8.75 ppm (d, 1H), 7.75 ppm (d, 1H), 7.65 ppm (d, 1H), 7.62-7.55 ppm (m, 1H), 7.51-7.46 ppm (m, 2H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:12][C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C:23]#[N:24])[CH:17]=[CH:16]4)=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[C:32]([O:34][CH3:35])=[O:33].O>O1CCOCC1>[C:23]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:12]=[CH:11][C:7]1[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=1)[CH2:1][N:2]([C:32]([O:34][CH3:35])=[O:33])[CH2:3][CH2:4]3)[CH:22]=[CH:21]2)#[N:24]
Reactant: N#Cc1ccc2cc(C=Cc3ccc4c(c3)CCNC4)ccc2c1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N1CCc2cc(C=Cc3ccc4cc(C#N)ccc4c3)ccc2C1
Reaction time: 16 h

Procedure:
A solution of Example 42J (650 mg, 1.53 mmol) in dioxane (30 mL) at room temperature was treated with 10% K2CO3 (10 mL) and methyl chloroformate (700 mg) and stirred for 16 hours. The mixture was treated with water and extracted with dichloromethane. The combined extracts were washed sequentially with 5% HCl, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with dichloromethane to provide the desired product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH3:16])[CH:9]=1)[NH2:6].ClCCl.C(=O)([O-])[O-].[K+].[K+].[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([NH:6][C:29](=[O:30])[CH2:28][Cl:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH3:16])[CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@H](N)Cc1ccc(C)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@H](Cc1ccc(C)c(OC)c1)NC(=O)CCl
Reaction time: 0.5 h

Procedure:
To a mixture of 3-methoxy-4-methyl-D-phenylalanine methyl ester hydrochloride (1.60 g) in a mixed solvent of dichloromethane (7 ml) and water (9 ml) was added potassium carbonate (1.70 g) in small portions under ice cooling. Chloroacetyl chloride (0.66 ml) was added to the mixture at 5° C. or below over 15 minutes and then the total mixture was stirred for 30 minutes. The organic layer was separated, washed with an aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give (2R)-2-[N-(chloroacetyl)amino]-3-(3-methoxy-4-methylphenyl)propionic acid methyl ester in the form of an oily substance.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=12.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([CH2:10][N:26]3[CH2:27][CH2:28][CH:23]([C:19]4[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=4)[CH2:24][CH2:25]3)[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc2nsnc2c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4nsnc4c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 2,1,3-benzothiadiazole-5-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 395.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>CCOC(C)=O>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([CH2:12][OH:13])=[CH:10]2
Reactant: C1CCNC1
Reactant: Cc1cccc2cc(CO)c(Cl)nc12
Solvent: CCOC(C)=O
Product: Cc1cccc2cc(CO)c(N3CCCC3)nc12
Yield: 88 %

Procedure:
(2-Chloro-8-methylquinolin-3-yl)methanol (200 mg, 0.97 mmol) and pyrrolidine (2 mL) were stirred in a sealed tube at 100° C. for 4 h. After cooling, the solution was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgSO4), filtered and the solvent was removed in vacuo. Purification by column chromatography on silica, eluting with 20% EtOAc in isohexane, gave the title compound (206 mg, 88%). δH (CDCl3) 7.86 (1H, s), 7.46 (1H, d, J=8.01 Hz), 7.40 (1H, d, J=7.04 Hz), 7.13 (1H, t, J=7.50 Hz), 4.85 (2H, s), 3.72 (4H, t, J=6.36 Hz), 2.65 (3H, s), 2.12 (1H, s), 2.03-1.96 (4H, m).