Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[CH:19][C:20]4[CH:25]=[C:24]([CH:26]=O)[N:23]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:21]=4[N:22]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[O:34]([NH2:36])[CH3:35].Cl.[CH3:38]CO>>[CH2:31]([CH:28]([N:23]1[C:21]2[N:22]=[C:17]([NH:16][C:13]3[CH:12]=[CH:11][C:10]([N:7]4[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]4)=[CH:15][CH:14]=3)[N:18]=[CH:19][C:20]=2[CH:25]=[C:24]1[C:26](=[N:36][O:34][CH3:35])[CH3:38])[CH2:29][CH3:30])[CH3:32]
Reactant: CCC(CC)n1c(C=O)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Reactant: CCO
Reactant: CON
Agent: Cl
Product: CCC(CC)n1c(C(C)=NOC)cc2cnc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-[4-(4-acetyl-piperazin-1-yl)-phenylamino]-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (25 mg, 0.057 mmol), methoxylamine hydrochloride (20 mg, 0.22 mmol) and 6N HCl (0.03 mL) in EtOH (1 mL) is stirred at ambient temperature for 6 h. The mixture was quenched with saturated NaHCO3 aqueous solution, extracted with CH2Cl2. The extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product is purified by preparative HPLC to give 12 mg of 1-{4-[4-(7-(1-ethyl-propyl)-6-{1-methoxyimino-ethyl}-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-phenyl]-piperazin-1-yl}-ethanone as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:16]([OH:17])[C:15]4[S:18][CH2:19][CH2:20][S:21][C:14]=4[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:26]([N:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27].C(#N)C>O1CCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:13]([O:22][C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[O:27])[C:14]4[S:21][CH2:20][CH2:19][S:18][C:15]=4[C:16]3=[O:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: O=C1C2=C(SCCS2)C(O)N1c1ccc2ccc(Cl)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC#N
Product: CN1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc3ccc(Cl)cc3n2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
6-(7-Chloroquinol-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (9.0 g.) is added over the course of half an hour, at 15°-20° C, to a suspension of sodium hydride (1.35 g.) in anhydrous tetrahydrofuran (250 cc.). The reaction mixture is diluted with anhydrous dimethylformamide (50 cc.). 6-(7-Chloroquinol-2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (a further 9.0 g.) is added over the course of half an hour, at 15° C, and then 1-chlorocarbonyl-4-methylpiperazine (25.0 g.) dissolved in anhydrous tetrahydrofuran (150 cc.) is added at 5° C. The reaction mixture is stirred for 4 hours at 5° C. After evaporating the tetrahydrofuran under reduced pressure (20 mm. Hg), the reaction mixture is treated with water (500 cc.). The gummy precipitate which has appeared is filtered off and taken up in an ice-cold 2N aqueous solution of methanesulphonic acid (350 cc.). The ice-cold aqueous acid solution is filtered and then rendered alkaline by adding 10N sodium hydroxide solution. The oil which separates out is extracted three times with methylene chloride (total 600 cc.). The organic solution is washed three times with distilled water (total 450 cc.), dried over anhydrous sodium sulphate, treated with decolourising charcoal (1.0 g.) and evaporated. The partially crystalline residue obtained (13.3 g.) is dissolved in boiling acetonitrile (170 cc.). After cooling for 2 hours at 2° C, the crystals which have appeared are filtered off, washed twice with ice-cold acetonitrile (total 40 cc.) and dried under reduced pressure (20 mm. Hg). 6-(7-Chloroquinol-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-2,3,6,7-tetrahydro-1,4-dithiino[2,3-c]pyrrole (6.9 g.), melting at 192° C, is thus obtained.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[NH:25][CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]([OH:29])=[O:28].C1C=CC2N(O)N=NC=2C=1.[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[NH:25][CH:26]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:27]([O:29][C@@H:48]1[CH:49]2[CH2:52][CH2:53][N:46]([CH2:51][CH2:50]2)[CH2:47]1)=[O:28]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1cc(F)ccc1F)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cc(F)ccc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
PS-DCC (914 mg, 1.301 mmol, loading: 1.33 mmol/g) was suspended in dry THF (15 ml). 2-(2,5-Difluorophenylamino)-2-phenylacetic acid hydrochloride (I20) (195 mg, 0.65 mmol), HOBT (199 mg, 1.30 mmol), and (R)-quinuclidin-3-ol (248 mg, 1.95 mmol) were added, and the suspension was shaken at RT for 16 hours (Conversion complete by UPLC-MS). PS-DCC was removed by filtration under suction, and the filtrate was evaporated. The resulting residue was dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer was separated, dried over Na2SO4, filtered and evaporated. The crude was purified by filtration through a silica-pad using DCM/MeOH=95/5 as the eluent. The title compound is collected (195 mg, 80% yield, mixture of diastereomers).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.I[CH3:15]>>[CH3:15][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([NH2:11])[CH:8]=2)[CH:4]=[N:5]1.[CH3:15][N:5]1[CH:4]=[C:3]2[C:7]([CH:8]=[C:9]([NH2:11])[CH:10]=[C:2]2[CH3:1])=[N:6]1
Reactant: Cc1cc([N+](=O)[O-])cc2[nH]ncc12
Reactant: CI
Product: Cc1cc(N)cc2c1cnn2C
Product: Cc1cc(N)cc2nn(C)cc12

Procedure:
In accordance with Example 24 (Steps 1 and 2), 4-methyl-6-nitro-1H-indazole was used instead of 6-nitro-1H-indazole, and iodomethane was used instead of sodium chlorodifluoroacetate to obtain 1,4-dimethyl-1H-indazol-6-amine and 2,4-dimethyl-2H-indazol-6-amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:27][C:26]4[C:25](=[O:35])[CH:24]([C:36]([O:38][CH3:39])=[O:37])[CH2:23][CH2:22][C:21]=4[N:20]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:40]C(C)([O-])C.[K+].CI>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:28]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:27][C:26]4[C:25](=[O:35])[C:24]([CH3:40])([C:36]([O:38][CH3:39])=[O:37])[CH2:23][CH2:22][C:21]=4[N:20]=3)=[CH:17][CH:18]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
A solution of methyl 2-(4-(1-((tert-butoxycarbonyl)amino)cyclobutyl)phenyl)-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinoline-6-carboxylate (65 mg, 0.12 mmol) in anhydrous THF (1.0 mL) was cooled to 0° C. under a nitrogen atmosphere, followed by the dropwise addition of potassium tert-butoxide solution (1M in THF, 150 μL, 0.15 mmol). The mixture was stirred at 0° C. for 15 minutes followed by the addition of methyl iodide (10 μL, 0.16 mmol). The reaction mixture was allowed to warm to room temperature and stirred for a further 4 hours. The mixture was diluted with ethyl acetate (2.0 mL), washed with 1M HCl solution (2.0 mL), brine (2×2.0 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give the desired product as a brown solid (54 mg, 83% yield). LCMS (Method A) RT=7.92 min, M+H+=541.18.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:46][C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[C:54]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH:55]=2)[CH:50]=[CH:49][CH:48]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:58]([O:57][C:54]1[CH:55]=[C:56]2[C:51]([CH:50]=[CH:49][CH:48]=[C:47]2[NH:46][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:52][CH:53]=1)[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1cccc2ccc(OCc3ccccc3)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cccc2ccc(OCc3ccccc3)cc12
Reaction time: 18 h

Procedure:
To N-(tert-butoxycarbonyl)glycine (527 mg, 3.01 mmol) in dry CH2Cl2 (5 mL) under argon were added PYBOP (1.65 g, 3.16 mmol), 1-amino-7-benzyloxynaphthalene, as described above in Step J, (750 mg, 3.01 mmol), and N,N-diisopropylethylamine (0.55 mL, 3.16 mmol). The reaction mixture was stirred for 18 hrs, then partitioned between CH2Cl2 (200 mL) and 10% aqueous citric acid (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was sufficiently pure for use in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([O:14]C)=[O:13].[CH2:16](N(CC)CC)C.[C:23]([O:26][C:27]1[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:29](Cl)=[O:30])(=[O:25])[CH3:24].C(OCC)(=O)C>O1CCCC1>[C:23]([O:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](=[O:30])[CH2:16][NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([OH:14])=[O:13])(=[O:25])[CH3:24]
Reactant: CCN(CC)CC
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccccc1C(=O)CNc1c(C(=O)O)[nH]c2cc(Cl)ccc12
Yield: 76.4 %

Procedure:
Dissolve 3-amino-2-carbmethoxy-6-chloroindole (1 g, 4.4 mmol) in anhydrous tetrahydrofuran (50 mL). Add triethylamine (4.8 mmol) and acetylsalicoyl chloride (4.8 mmol) and stir for 5 minutes. Dilute into ethyl acetate (500 mL), separate the organic phase, wash with water, saturated sodium hydrogen carbonate and saturated sodium chloride. Dry and evaporate the solvent in vacuo. Recrystallize to give the title compound (1.3 g, 79%); mp 184°-86° C.
Reaction SMILES: [CH2:1]1[N:6]([C:7]2[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4]OC1.Cl.[CH3:16][NH:17][OH:18].[C:19](=[O:22])([O-])[O-].[Na+].[Na+]>O.C(O)C>[OH:18][N:17]([CH3:16])[C:13](=[NH:14])[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]1[CH2:1][CH2:19][O:22][CH2:4][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccccc1N1CCOCC1
Reactant: CNO
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(O)C(=N)c1ccccc1N1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a stirred solution of 2-(4-morpholino)benzonitrile (3.76 g, 20 mmol) and N-methylhydroxylamine hydrochloride (3.34 g, 40.0 mmol) in 1:1 water/ethanol (100 mL) was added sodium carbonate (2.12 g, 20 mmol) and the resulting mixture stirred at 90° C. overnight. After cooling and concentrating, the resulting residue was suspended in MeOH/CHCl3 (1:9). The insoluble solids were removed by filtration and concentration of the mother liquor gave the title product as an amber oil (3.8 g) that was carried on without further purification. LCMS calcd for C12H18N3O2 (M+H): 236.13; found: 236.31.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH2:22][C:23]([NH:25][CH:26]2[C:38](=[O:39])[N:28]3[CH:29]([C:35]([OH:37])=[O:36])[CH:30]([CH2:33][OH:34])[CH2:31][S:32][C@H:27]23)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(OCC)(=O)C.O1CCCC1>[C:16]1([CH2:22][C:23]([NH:25][CH:26]2[C:38](=[O:39])[N:28]3[CH:29]([C:35]([O:37][CH:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:36])[CH:30]([CH2:33][OH:34])[CH2:31][S:32][C@H:27]23)=[O:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(CO)CS[C@H]12
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)CS[C@H]12
Temperature: 25 °C
Yield: 24.2 %

Procedure:
A solution of diphenyldiazomethane (4 g.) in ethyl acetate was added to a stirred solution of 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylic acid (7.0 g.) in ethyl acetate (100 ml.) and tetrahydrofuran (20 ml.), and stirred at room temperature for an hour. After adding acetic acid to the resultant solution, the solution was concentrated in vacuo. The residue was subjected to column chromatography on silica gel, and then eluted with a mixed solvent of ethyl acetate and diisopropyl ether. The eluate was evaporated in vacuo to give diphenylmethyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (2.5 g.).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:13]=[C:12]([S:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[N:11]=[C:10]([OH:23])[CH:9]=1.[C:24]([S-:26])#[N:25].[K+].BrBr>CN(C=O)C.O>[NH2:25][C:24]1[S:26][C:9]2[C:10]([OH:23])=[N:11][C:12]([S:14][C@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])=[N:13][C:8]=2[N:7]=1
Reactant: C[C@H](Sc1nc(N)cc(O)n1)c1ccccc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H](Sc1nc(O)c2sc(N)nc2n1)c1ccccc1
Temperature: 0 °C
Reaction time: 30 h
Yield: 65.7 %

Procedure:
Pyridine (0.6 g, 7.6 mmol) was added to 6-amino-2-{[(1S)-1-phenylethyl]thio}pyrimidin-4-ol (1 g, 4 mmol) and KSCN (1.7 g, 16 mmol) in DMF (20 mL). The reaction mixture was cooled to 0° C. and bromine (0.65 g, 4.0 mmol) was then added in one portion. The reaction mixture was poured into water after 2 h and the orange precipitate was filtered off and washed with water. The solid was suspended in a mixture of DMF (6 mL) and water (2 mL) and heated to 110° C. After 30 h, the reaction mixture was poured into water, the yellowish precipitate was filtered off and washed with water and ether. The solid was dried in vacuum at 40° C. to give the title compound (0.8 g, 65% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([C:11]2(O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:12]2=[O:29])=[CH:6][C:3]=1[C:4]#[N:5].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:12]2=[O:29])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(CN2C(=O)C(O)(c3cc(C#N)c(O)cc3O)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=O)C(c3cc(C#N)c(O)cc3O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
To a stirred suspension of 2,4-dihydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (10.3 g, 25.5 mmol) and triethylsilane (12.3 mL, 77.0 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (10.0 mL, 129 mmol). The reaction mixture was stirred at ambient temperature for 18 h and concentrated in vacuo. The residue was triturated in hexanes to afford 2,4-dihydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (9.70 g, 98%): mp 162-163° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ 10.84 (s, 1H), 10.47 (s, 1H), 7.39 (s, 1H), 7.28 (d, J=9.0 Hz, 2H), 7.13-7.08 (m, 1H), 6.93-6.78 (m, 5H), 6.43 (s, 1H), 5.72 (s, 1H), 4.92-4.73 (m, 3H), 3.69 (s, 3H); MS (ES+) m/z 386.9 (M+1).
Reaction SMILES: O=C1N(CC(O)=O)C2C=CC=CC=2N(C(=O)C)C[C@@H]1N[C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:29]([O:36][C:37](=[O:63])[CH2:38][N:39]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]([C:50](=[O:52])[CH3:51])[CH2:42][C@H:41]([NH:53][C:54](=[O:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:40]1=[O:62])C1C=CC=CC=1>CO.[Pd]>[CH3:29][O:36][C:37](=[O:63])[CH2:38][N:39]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]([C:50](=[O:52])[CH2:51][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:42][C@H:41]([NH:53][C:54](=[O:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:40]1=[O:62]
Reactant: CC(=O)N1C[C@H](NC(=O)c2ccccc2)C(=O)N(CC(=O)O)c2ccccc21
Reactant: CC(=O)N1C[C@H](NC(=O)c2ccccc2)C(=O)N(CC(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
Method B. (3S)2-Oxo-3-benzoylamino-5-acetyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid (603d). A mixture of (3S)-2-oxo-3-(benzoylamino)-5-acetyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid benzyl ester (602d; 510 mg, 1.08 mmol) and 5% Pd/C (250 mg) in MeOH (10 ml) stirred under H2 (1 atm) for 0.5 h. The reaction was filtered and concentrated in vacuo 410 mg of 603d as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]#[N:14])[C@H:10]([O:15]C(=O)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([OH:15])[C@H:11]([C:13]#[N:14])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C#N
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](C#N)C1

Procedure:
80.1 A solution of (3S,4S)-3-acetoxy-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, prepared according to example 79.2) in 10 ml of a 2M NH3 solution in MeOH was stirred at 22° C. for 1 h and evaporated. The residue was chromatographed on silica (heptane/AcOEt, 2.5:1) to give (3S,4S)-3-cyano-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester. Colorless solid. MS 213.3 ([M+H]+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:17]=[CH:16][C:15]2[N:14]([CH3:18])[C:13](=[O:19])[C@@H:12]([CH2:20][CH3:21])[N:11]([CH:22]([CH3:24])[CH3:23])[C:10]=2[N:9]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(O)(C(F)(F)F)=O>>[CH2:20]([C@H:12]1[N:11]([CH:22]([CH3:23])[CH3:24])[C:10]2[N:9]=[C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[N:17]=[CH:16][C:15]=2[N:14]([CH3:18])[C:13]1=[O:19])[CH3:21]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3N)nc2N1C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3NS(C)(=O)=O)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 114, with (R)-2-(3-aminopyridin-4-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 93) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91) and with methane sulfonylchloride instead of chloromethylcarbonate. LCMS (0.05% TFA): 405.2 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 12.77 (bs, 1H), 8.89 (bs, 1H), 8.50 (bs, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 4.55 (m, 1H), 4.49 (m, 1H), 3.34 (s, 3H), 3.26 (s, 3H), 1.87 (m, 1H), 1.77 (m, 1H), 1.44 (bs, 6H), 0.75 (bs, 3H).
Reaction SMILES: O[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([CH3:13])=[N:4][C:3]=1[CH2:14][CH2:15][CH2:16][OH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:13][C:5]1[N:4]=[C:3]2[CH2:14][CH2:15][CH2:16][O:17][C:2]2=[N:7][C:6]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1nc(O)c(CCCO)nc1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2c(nc1C)CCCO2
Reaction time: 0.83 h

Procedure:
To a solution of ethyl 6-hydroxy-5-(3-hydroxypropyl)-3-methylpyrazine-2-carboxylate (1.03 g, 4.29 mmol) and triphenylphosphine (1.69 g, 6.43 mmol) in tetrahydrofuran (86 mL) was added diethyl azodicarboxylate solution (40% wt. % in toluene, 2.92 mL, 6.43 mmol) at room temperature. After being stirred for 50 min, the reaction mixture was concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3), triturated with diisopropyl ether, and silica gel column chromatography (chloroform to chloroform:methanol=19:1) to give ethyl 2-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazine-3-carboxylate. MS (APCI): m/z 223 (M+H).
Reaction SMILES: [CH3:1][CH:2]([NH:6][CH2:7][C:8]1[S:12][C:11](B(O)O)=[CH:10][CH:9]=1)[CH2:3][O:4][CH3:5].Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>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.CO.O.O1CCOCC1>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:11]4[S:12][C:8]([CH2:7][NH:6][CH:2]([CH3:1])[CH2:3][O:4][CH3:5])=[CH:9][CH:10]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: COCC(C)NCc1ccc(B(O)O)s1
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: CO
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(C)COC)s4)cc23)CC1
Yield: 35.2 %

Procedure:
[5-({[1-methyl-2-(methyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid (60 mg, 0.262 mmol) was transferred to a CEM microwave tube with methanol. The methanol was evaporated under a stream of N2. To this was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.19 mmol), potassium carbonate (160 mg, 1.16 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol), dioxane (1.5 mL), and water (0.5 mL). The vial was capped and reacted in a CEM microwave at 150° C. for 30 min. This solution was loaded onto a 2 g SCX SPE cartridge primed with 3 mL of methanol. The cartridge was then sequentially eluted with water (3 mL), methanol (9 mL), and 2M NH3 in MeOH (6 mL). The NH3 in MeOH fractions were dried under a stream of N2 at 40° C. The crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP with UV (230 nm) and MS detection. The desired fractions were passed thru two sequential 500 mg Pharmasil CHQAX cartridge primed with 1 mL of methanol and 1 mL of water. The solvents were evaporated under a stream of N2 at 60° C. to give 34.7 mg of the title compound (34%).