Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([C:9]1[C:33]([F:34])=[C:32]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C:12]2[C:13](=[O:31])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([F:30])[CH:18]=3)[O:16][C:11]=2[C:10]=1[F:42])[CH2:5][CH2:6][CH2:7]Cl)(=[O:3])[CH3:2].[I-].[Na+].Cl.[CH3:46][NH:47][CH3:48].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:1]([N:4]([C:9]1[C:33]([F:34])=[C:32]([NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C:12]2[C:13](=[O:31])[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([F:30])[CH:18]=3)[O:16][C:11]=2[C:10]=1[F:42])[CH2:5][CH2:6][CH2:7][N:47]([CH3:48])[CH3:46])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCCl)c1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(CCCN(C)C)c1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 70 °C
Reaction time: 23 h
Yield: 63.5 %

Procedure:
932 mg (1.54 mmol) of the above 7-[N-acetyl-N-(3-chloropropyl)amino]-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one was dissolved in 10 mL of dimethylformamide under argon atmosphere, 320 mg (7.68 mmol) of sodium iodide, 1.25 g (15.4 mmol) of dimethylamine hydrochloride and 2.12 g (15.4 mmol) of potassium carbonate were added and the mixture was stirred at 70° C. for 23 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform-chloroform:methanol:aqueous ammonia=40:1:1) to give 603 mg of 7-[N-acetyl-N-(3-dimethylaminopropyl)amino]-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-4H-1-benzopyran-4-one (yield: 64%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1.[C:19]([NH:26][CH2:27][CH2:28][NH2:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CS(C)=O>[C:22]([O:21][C:19](=[O:20])[NH:26][CH2:27][CH2:28][NH:29][C:11]1[CH:10]=[C:9]([O:8][CH3:7])[CH:14]=[CH:13][C:12]=1[N+:15]([O-:17])=[O:16])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 104 %

Procedure:
A 2 L flask equipped with a stir bar was charged with DMSO (800 mL), K2CO3 (161 g, 1.6 mol) and 4-methoxy-2-fluoro-1-nitrobenzene (100 g, 0.58 mol). Mono-N-Boc-1,2-diaminoethane (94 g, 0.55 mol) was added to the reaction mixture and stirred for 12 h at 60° C. The reaction mixture was triturated with ice cold water (1.2 L) and the resulting yellow precipitate was collected by vacuum filtration. The precipitate was washed several times with water (5×1 L) and dried on a high vacuum for 48 h to give the desired product as a bright yellow solid (178 g, 98%.)
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:15]1[C:20](=[O:21])[N:19]([CH3:22])[CH:18]=[C:17]([C:23]2[C:24]([CH3:42])=[C:25]([NH:29][C:30](=[O:41])[C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=3)[CH:26]=[CH:27][CH:28]=2)[CH:16]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:17]3[CH:16]=[C:15]([NH:13][C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:12][N:11]=4)[C:20](=[O:21])[N:19]([CH3:22])[CH:18]=3)[C:24]=2[CH3:42])=[O:41])=[CH:32][CH:33]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: Nc1ccc(N2CCOCC2)cn1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Br)c(=O)n(C)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cc(Nc2ccc(N3CCOCC3)cn2)c(=O)n(C)c1
Temperature: 95 °C
Yield: 41.4 %

Procedure:
A 48-mL sealed tube equipped with a magnetic stirring bar was charged with 5-morpholin-4-yl-pyridin-2-ylamine (0.065 g, 0.36 mmol), N-[3-(5-bromo-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-methyl-phenyl]-4-tert-butyl-benzamide (13) (0.16 g, 0.35 mmol), Pd2(dba)3 (0.030 g, 0.030 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.030 g, 0.050 mmol), and Cs2CO3 (0.22 g, 0.66 mmol) in dioxane (10 mL). After the mixture was degassed for 15 min., it was heated at 95° C. for 16 h. Then, the reaction mixture was cooled to room temperature and poured into H2O (10 mL). To this was added dichloromethane (10 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (3×10 mL), and the combined organic extracts were washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. The crude mixture was purified by column chromatography, gradient 0-10% MeOH in dichloromethane/ether (1/1), to afford 0.080 g (41%) of 4-tert-butyl-N-{2-methyl-3-[1-methyl-5-(5-morpholin-4-yl-pyridin-2-ylamino)-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl}-benzamide (8) as a solid; LCMS m/z 552.2342 (M+).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1CCCCC1>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([OH:11])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: C1CCCCC1
Product: CC(C)(C)C1CCC(O)CC1
Yield: 93.8 %

Procedure:
A mixture composed of 100 g (0.649 mole) of 4-tert-butyl-cyclohexanone, 1.35 g of the catalyst prepared as indicated in Example 1 and 150 g of cyclohexane were put into an autoclave under nitrogen and then hydrogen was introduced until the pressure settled at about 106Pa. The mixture was then heated to 70° and the reaction was followed by gas chromatography. The reaction was stopped by cooling and the autoclave was flushed with nitrogen. After filtering, the catalyst was recovered under argon flow, washed with cyclohexane and recycled for the following hydrogenation operations. The clear filtrate was evaporated to give a residue that, once distilled, provided 95.15 g of an isomeric mixture containing 87.7% of cis isomer.
Reaction SMILES: ClC1C=CC=CC=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[N:15][CH:16]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=NC=1.[Cl:61][C:62]1[CH:67]=[CH:66][C:65](N=C=O)=[C:64]([O:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH:63]=1>>[Cl:61][C:62]1[CH:67]=[CH:66][C:65]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[C:64]([O:71][C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)[CH:63]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccccc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Cl)cc4Oc4ccccc4)cn3)cc2C1=O

Procedure:
The compound of example 395 was prepared analogous to the compound of example 393 by reaction of the compound of example 392 with 4-chloro-2-phenoxy phenyl isocyanate. The compound of example 395 was used directly for the preparation of compound of example 396 without purification.
Reaction SMILES: [CH2:1]([N:4]([C:15]1[C:20](=[O:21])[N:19]2[C@H:22]([C:28](=[O:50])[NH:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([NH:39][C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[NH:38])=[CH:33][CH:32]=3)[CH2:23][C@@H:24]([CH2:25][CH:26]=[CH2:27])[C:18]2=[N:17][CH:16]=1)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[CH2:51]([C:54]1(CC=C)C2=NC=C(N(CC=C)C(OCC3C=CC=CC=3)=O)C(=O)N2[C@H](C(O)=O)C1)[CH:52]=C.Cl.C(OC(=O)NC(C1C=CC(CN)=CC=1)=N)C1C=CC=CC=1>>[CH2:1]([N:4]([C:15]1[C:20](=[O:21])[N:19]2[C@H:22]([C:28](=[O:50])[NH:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([NH:39][C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])=[NH:38])=[CH:35][CH:36]=3)[CH2:23][C:24]([CH2:54][CH:51]=[CH2:52])([CH2:25][CH:26]=[CH2:27])[C:18]2=[N:17][CH:16]=1)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)O)CC2(CC=C)CC=C
Reactant: C=CC[C@@H]1C[C@@H](C(=O)NCc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)n2c1ncc(N(CC=C)C(=O)OCc1ccccc1)c2=O
Agent: Cl
Agent: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)CC2(CC=C)CC=C
Yield: 41 %

Procedure:
According to the procedure for the preparation of 28e, 29d (162 mg, 0.360 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester hydrochloride to afford after flash chromatography (66% EtOAc/hexanes) 105 mg (41%) of 29e. MS (ESI) 715.5 (M+H+), 737.5 (M+Na+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH2:23].C(O)(C)C>CN(C=O)C>[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Reactant: Cc1ccc(N)cc1O
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COCCOc1cc2nncc(Nc3ccc(C)c(O)c3)c2cc1OC

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.4 g, 1.5 mmol) and 3-hydroxy-4-methylaniline (0.2 g, 1.6 mmol) in DMF (5 ml) was heated at 150° C. for 20 minutes. After cooling, isopropanol (15 ml) was added and the resulting solid filtered off, washed with isopropanol and dried under vacuum to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (yellow solid, 537 mg 91%).
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][C@@H:17]([OH:27])[C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[S:30](Cl)([CH3:33])(=[O:32])=[O:31].OS(O)(=O)=O.CC(=O)OCC>N1C=CC=CC=1.O.C(O)(=O)C>[OH:27][CH:17]1[CH:16]2[CH:15]([CH2:14][CH:13]([OH:28])[C:12]3([CH3:29])[CH:11]2[CH2:10][CH2:9][CH:8]3[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([O:25][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:22][CH2:21]2)[CH2:18]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: CC(CCC(=O)O)C1CCC2C3C(O)CC4CC(OS(C)(=O)=O)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 g of cholic acid are dissolved in 500 ml of pyridine and 23.1 ml of mesyl chloride are added dropwise at 0° C. over a period of 30 minutes. The mixture is stirred at RT for 3 hours, then poured onto a solution of 400 ml of H2SO4 in 3 l of water at 0° C. and extracted 4 times with 750 ml of EA each time. The organic phase is dried over Na2SO4 and the solvent is removed in vacuo. The residue is crystallized using diisopropyl ether and 117.1 g are obtained; m.p. 121° C. (with decomposition). Rf (EA/HEP/acetic acid 5:5:1)=0.31 MS (FAB): 487 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=2)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[BH3-]C#N.[Na+].CC(O)=O>CO.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C@@H:8]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:21][CH:22]=2)[CH:16]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc(C=O)cc2)c1)Cc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2ccc(CNc3ccccc3)cc2)c1)Cc1c[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A solution of Example 116A (0.03 g, 0.06 mmol) in 2 mL of MeOH was cooled to 0° C. then treated with aniline (0.018 g 0.2 mmol), NaBH3CN (0.004 g, 0.06 mmol) and AcOH (1 ml). The mixture was allowed to warm to room temperature overnight. The mixture was diluted with ethyl acetate (20 ml), washed with water (10 ml) and brine (10 ml). The ethyl acetate was evaporated off and the residue was used without further purification.
Reaction SMILES: [H-].[Na+].[N:3]1([C:9](=[O:13])[C@H:10]([OH:12])[CH3:11])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>O1CCCC1.C(OCC)C>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][C@H:10]([CH3:11])[C:9]([N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[O:13])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](O)C(=O)N1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)O[C@H](C)C(=O)N2CCOCC2)cc1
Yield: 57 %

Procedure:
To a suspension of sodium hydride (60% in paraffin liquid) (8.41 g, 210 mmol) in tetrahydrofuran (120 ml was dropped (2R)-1-morpholin-4-yl-1-oxopropane-2-ol (32.1 g) in tetrahydrofuran (150 ml) under stirring, ice cooling and an atmosphere of nitrogen. The mixture was then stirred for 30 minutes at 50° C. After being ice-cooled, thereto was dropped a solution of p-toluenesulfonyl chloride (45.8 g, 234 mmol) in tetrahydrofuran (180 ml), and the mixture was stirred for 4 hours at room temperature. Thereto was added 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the oily residue. Thereto was added diethyl ether and the resulting precipitate was taken by filtration, washed with diethyl ether and dried under reduced pressure to give the subject compound as a white solid (36.1 g, 115 mmol, 58%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[CH:21][C:20]([CH2:23][N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[CH:19][C:18]=2[C:37]2[N:45]=[C:44]([CH3:46])[N:43]=[C:42]3[C:38]=2[N:39]=[CH:40][N:41]3C2CCCCO2)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[N:15]=[CH:14][C:13]([NH:16][C:17]2[C:18]([C:37]3[N:45]=[C:44]([CH3:46])[N:43]=[C:42]4[C:38]=3[N:39]=[CH:40][NH:41]4)=[CH:19][C:20]([CH2:23][N:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)=[CH:21][N:22]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(Nc2ncc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(CN3CCNCC3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
TFA (2.00 mL) was added to a stirred mixture of tert-butyl 4-((6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)methyl)piperazine-1-carboxylate (112 mg, 0.182 mmol) in DCM (2.00 mL) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated and re-diluted with DCM, NaHCO3(aq) and water (10 mL each). The separated aqueous layer was extracted with DCM (4×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by flash column chromatography (DCM to 10% MeOH in DCM) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-(piperazin-1-ylmethyl)pyridin-2-amine (15 mg, 0.035 mmol, 19.11% yield) as a yellow solid. LCMS (API-ES) m/z 432 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 12.63 (br. s., 1H) 9.69 (br. s., 1H) 8.60 (br. s., 1H) 8.54 (br. s., 1H) 7.86-8.30 (m, 3H) 6.85 (d, J=9.19 Hz, 1H) 3.85 (s, 3H) 3.52 (br. s., 2H) 2.90 (br. s., 4H) 2.85 (br. s., 3H) 2.37-2.49 (m, 4H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[I:12][C:13]1[CH:14]=[CH:15][C:16]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:17]([CH:20]=1)[CH2:18]Br>>[CH3:2][O:3][C:4](=[O:11])[CH:5]([CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)[CH2:18][C:17]1[CH:20]=[C:13]([I:12])[CH:14]=[CH:15][C:16]=1[O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27]
Reactant: COCCOCOc1ccc(I)cc1CBr
Reactant: COC(=O)C[C@H]1CCCN1
Agent: Cl
Product: COCCOCOc1ccc(I)cc1CC(C(=O)OC)C1CCCN1

Procedure:
(R)-Pyrrolidin-2-yl-acetic acid methyl ester hydrochloride (0.78 g, 4.4 mmol) is alkylated with 5-Iodo-2-(2-methoxyethoxymethoxy)benzyl bromide (1.5 g, 3.7 mmol) as described in EXAMPLE 12B to yield 3-[5-Iodo-2-(2-methoxyethoxymethoxy)phenyl]-2-pyrrolidin-2-yl propionic acid methyl ester. This material is treated with triethylamine (0.52 mL, 3.74 mmol) and Boc anhydride (0.82 g, 3.74 mmol) in methylene chloride (25 mL) at 0° C. The reaction mixture is warmed to ambient temperature over 3 h. The solvent is removed under vacuo and the residue is partitioned between ethyl acetate and bicarbonate solution. The organic layer is separated, washed with water and brine, dried over MgSO4 and concentrated to a tan oil. This material is chromatographed (25% ethyl acetate/hexane) to give the title compound as an oil (1.66 g, 3.6 mmol). 1H NMR (CDCl3, 300 MHz) □ 7.43-7.38(m, 2H), 6.88(d, 1H), 5.23(s, 2H), 4.23-4.06(m, 1H), 3.83-3.76(m, 2H), 3.57(s, 3H), 3.56-3.48(m, 2H), 3.37(s, 3H), 3.36-3.26(m, 3H), 2.94-2.78(m, 1H), 2.76-2.61(m, 1H), 2.03-1.75(m, 4H), 1.45(s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:17]1([C:23](Cl)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([NH:1][C:23](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(Cl)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-4-chlorobenzonitrile (7.25 g, 47.5 mmol ), in anh. pyridine (38 mL, 475 mmol) and DCM (300 mL) cooled in an ice-H2O bath under Ar was added PhCOCl (5.8 mL, 50 mmol) dropwise. The reaction was allowed to slowly warm to rt within the cooling bath and then was stirred at rt overnight. The reaction mixture was washed (H2O, 2 M aq HCl (2×), H2O, brine), dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a white solid; MS (ES+): m/z 257.1 (100) [MH+]; HPLC: tR=3.27 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[F:18][C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:28]=[N:29][C:30]([F:33])=[CH:31][CH:32]=2)=[O:25])[CH2:20]1.ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=[C:2]([N:22]2[CH2:23][C@H:19]([F:18])[CH2:20][C@H:21]2[C:24]([NH:26][C:27]2[CH:28]=[N:29][C:30]([F:33])=[CH:31][CH:32]=2)=[O:25])[N:7]=1
Reactant: O=C(Nc1ccc(F)nc1)[C@@H]1C[C@@H](F)CN1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: O=C(Nc1ccc(F)nc1)[C@@H]1C[C@@H](F)CN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1

Procedure:
79B was prepared from 1A and 79A as described for 1C: MS: 462/464(M+H)+, HPLC (Method F) Ret time: 2.61 min.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[C:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(OC(=O)c2ccccc2)cc1
Yield: 91.9 %

Procedure:
A mixture of 65.0 g (0.60 mol) of p-cresol, 92.7 g (0.66 mol) of benzoyl chloride, and 6 mL of anhydrous pyridine was refluxed for 1.5 hr and then added to 600 mL of 2% hydrochloric acid. The product was extracted with 2×100 mL of ether, the combined extract was washed by 2% NaOH, then dried over Na2SO4, and evaporated to dryness. Drying the residue in vacuum gave 117 g (92%) of p-tolyl benzoate (bp 127-135° C./25 mm Hg). A mixture of 117 g (0.552 mol) of p-tolyl benzoate and 92.0 (0.689 mol) of AlCl3 was slowly (for ca. 0.5 hr) heated to 120-125° C. This mixture was stirred at this temperature for 1 hr, and then 1000 mL of 2M HCl was added at 0° C. The product was extracted with 3×200 mL of diethyl ether, the combined extract was dried over Na2SO4 and then evaporated to dryness. This procedure gave 116 g (99%) of the title product which was further used without an additional purification.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.Cl.[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH3:29])[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:28]([CH3:29])[C:2]2[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=2)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: FC(F)(F)c1nnc(Cl)s1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nnc(C(F)(F)F)s1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A mixture of 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (0.70 g, 3.72 mmol) (prepared by a procedure similar to that described in DE 82/3218482), 4-methylamino-piperidine-1-carboxylic acid benzyl ester hydrochloride (1.06 g, 3.72 mmol) and diisopropylethylamine (1.60 ml, 9.30 mmol) in acetonitrile (10 ml) was stirred at 120° C. for 30 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by short open column chromatography (silica gel; 0-0.5% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo to yield D1 (0.91 g, 62%) as a solid. C17H19F3N4O2S requires 400. Found 401 (MH+).
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][C:15]([C:17]([CH3:19])=[O:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]>C(Cl)(Cl)(Cl)Cl>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:16][C:15]([C:17]([CH2:19][Br:1])=[O:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: BrBr
Reactant: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CBr)c1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A solution of 38 g (0.24 mole) of bromine in 100 ml of CCl4 was added dropwise over 50 min to a stirred, refluxing mixture of 55 g (0.24 mole) of methyl 5-(p-nitrophenyl)-2-furyl ketone and 1200 ml of CCl4. After the addition was complete, the reaction mixture was heated under reflux for 3/4 hr and allowed to stand at room temperature overnight. The yellow solid was collected by filtration to give 69 g (93%) of bromomethyl 5-(p-nitrophenyl)-2-furyl ketone, m.p. 153°-162°.