Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[O:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:38]1([CH2:41][N:42]2[C:50]3[N:49]=[C:48]([CH2:51][C:52]4[CH:57]=[CH:56][C:55]([NH:58][CH3:59])=[CH:54][CH:53]=4)[NH:47][C:46]=3[C:45](=[O:60])[N:44]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[F:68])[C:43]2=[O:69])[CH2:40][CH2:39]1>ClCCl>[CH:38]1([CH2:41][N:42]2[C:50]3[N:49]=[C:48]([CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N:58]([CH3:59])[C:7]([C:6]5[C:2]([CH3:1])=[N:3][O:4][C:5]=5[CH3:10])=[O:9])=[CH:56][CH:57]=4)[NH:47][C:46]=3[C:45](=[O:60])[N:44]([CH2:61][C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=3[F:68])[C:43]2=[O:69])[CH2:40][CH2:39]1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1noc(C)c1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
A mixture of 3,5-dimethyl-isoxazole-4-carboxylic acid (8.1 mg, 0.057 mmol) in dichloromethane (1.5 mL) cooled to 0° C. was treated with triphenylphosphine (17 mg, 0.063 mmol), and N-chlorosuccinimide (10 mg, 0.074 mmol). This mixture was stirred at 0° C. for 15 min and at 25° C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (50 mg, 0.11 mmol). The reaction was then stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2:98 methanol/dichloromethane) afforded 3,5-dimethyl-isoxazole-4-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (7.4 mg, 23.2%) as an off-white solid: EI-HRMS m/e calcd for C30H29N6O4F (M+) 556.2234, found 556.2229.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([O:18][CH3:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc2nc(-c3c(F)cccc3F)[nH]c12
Product: COc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1ccccc1
Yield: 90.7 %

Procedure:
2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole (5005, Example 46) (2.02 g, 7.77 mmol) was reacted with benzyl bromide (1.20 mL, 10.1 mmol, 130 M%). The crude product was purified by flash chromatography eluting with 2% MeOH/CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-benzyl-2-(2.6-difluorophenyl)-4-methoxylbenzimidazole (2.47 g, 7.05 mmol, 90% yield). M.p. 139-141° C. 1H-NMR (200 MHz, CD2Cl2) δ7.48 (m, 1H, H4′), 7.25-6.96 (m, 8H), 6.86 (dd, J=0.8, 8.3 Hz, 1H, H5), 6.72 (dd, J=8.0, 0.8 Hz, 1H, H7), 5.24 (s, 2H, CH2Ph), 4.01 (s, 3H, OCH3).
Reaction SMILES: CC1[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:7][C:6]2=[O:15].S(=O)(=O)(O)O.[Cr](O)(O)(=O)=O.[C:26]([OH:29])(=[O:28])[CH3:27]>O>[C:27]1([C:26]([OH:29])=[O:28])[CH:3]=[N:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:7][C:6]2=[O:15]
Reactant: CC(=O)O
Reactant: Cc1cnn2c(=O)[nH]c3ccccc3c12
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cnn2c(=O)[nH]c3ccccc3c12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To 40 g (0.19 mole) of 1-methyl-pyrazolo[1,5-c]quinazolin-5(6H)-one in a rapidly stirring mixture of 350 g of concentrated sulfuric acid and 100 g of acetic acid is added, dropwise a solution of 100 g of chromic acid in 175 g water and 50 g acetic acid. After 12 hours, the reaction is poured into 2 1. of ice water. The reaction mixture is concentrated, cooled and the title compound filtered off and dried.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[CH3:6].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:30]=[N:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])[CH:18]=[CH:19][CH:20]=1.[OH-].[NH4+]>C(OCC)(=O)C.ClCCl>[CH3:6][C:5]1[N:14]([C:15]2[CH:16]=[C:17]([C:21]3[CH:30]=[N:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH2:2][CH2:3][N:4]=1
Reactant: CC(=O)NCCCl
Reactant: COC(=O)c1ccncc1-c1cccc(N)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccncc1-c1cccc(N2CCN=C2C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.3 %

Procedure:
N-(2-chloroethyl)acetamide (0.32 g) in ethyl acetate (5 ml) was added over 10 min. to a stirred suspension of phosphorus pentachloride (0.55 g) in ethyl acetate (2 ml) at 0° C. under nitrogen to give a clear pale straw solution. After 45 min. at 0° C. a solution of methyl 3-(3-aminophenyl)isonicotinate (0.4 g) in dichloromethane (10 ml) was added over 15 min. at 0-5° C. The mixture was stirred at 0° C. for 10 min. and then allowed to warm up to 20° C. After 3 h the mixture was treated with ammonium hydroxide solution (28%, 5 ml) over 10 min. and stirring continued for ca. 1 h. The layers were allowed to separate, the organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane:methanol:ammonia=100:10:1, v/v/v) to give 0.25 g (48%) of yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](Br)([F:15])[F:14])[CH3:10].C(OCC)(=O)C>CN(C=O)C>[CH2:9]([O:11][C:12](=[O:17])[C:13]([F:15])([F:14])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Fc1ccc(I)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)(F)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1-Fluoro-4-iodobenzene (30 g, 135 mmol) and 2-bromo2,2-difluoroacetic acid ethyl ester (29 g, 142.9 mmol) were dissolved in DMF (100 ml) and Cu (21.5 g, 71.2 mmol) was added. The reaction mixture was heated at 90° C. for 18 h. Ethyl acetate (100 ml) was added and the reaction mixture was quenched with a solution of potassium dihydrogen phosphate (20 g) in water (200 ml). The resultant solution was stirred for 30 min, filtered and was washed with ethyl acetate. The organic layer was separated, washed with water and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give 2,2-difluoro-2-(4-fluorophenyl)acetic acid ethyl ester (26.5 g) as a yellow liquid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:40][CH2:39][C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)=[O:18])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: NCc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4ccncc4)cc3)oc2C)cc1
Yield: 72.8 %

Procedure:
Method E. Reaction of oxalyl chloride (178 λL, 2.0 mmol) and benzoic acid 4 (379 mg, 1.0 mmol) with subsequent coupling to 4-pyridinylmethylamine (114 λL, 1.1 mmol) gave benzamide 10 (336 mg, 71%) as a white powder: mp (EtOAc) 169-172° C.; 1H NMR δ 9.24 (t, J=5.9Hz, 1 H, CONH), 8.50 (dd, J=4.4, 1.6Hz, 2 H, H-2′, H-6′), 8.03 (dd, J=8.6, 1.8Hz, 2 H, H-2, H-6), 7.92 (dd, J=8.6, 1.8Hz, 2 H, H-3, H-5), 7.67 (d, J=8.3Hz, 2 H, H-2″, H-6″), 7.42 (d, J=8.3Hz, 2 H, H-3″, H-5″), 7.32 (dd, J=4.4, 1.6Hz, 2 H, H-3′, H-5′), 4.63 (s, 2 H, CH2SO2), 4.51 (d, J=5.9Hz, 2 H, CH2N), 2.41 (s, 3 H, CH3), 2.14 (s, 3 H, CH3); 13C NMR δ 165.7, 158.0, 150.0, 148.9 (2), 148.4, 144.5, 135.6, 135.3, 129.7 (2), 128.9, 128.3 (2), 128.1 (2), 126.0, 125.5 (2), 122.2 (2), 53.0, 41.8, 21.1, 9.7; MS m/z 462.8 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 65.10; H, 4.96; N, 9.10%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1.CN(C)C(=O)C>C(=O)([O-])O.[Na+]>[Cl:28][C:29]1[N:34]=[C:33]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18]([C:20]5[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=5)=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:6][N:5]3[CH:27]=2)[CH:32]=[CH:31][N:30]=1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(N)cn3c2)c1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc3nc(Nc4ccnc(Cl)n4)cn3c2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.7 %

Procedure:
A mixture of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (150 mg, 0.417 mmol), 2,4-dichloropyrimidine (63.8 mg, 0.428 mmol) and N,N-dimethylacetamide (5 mL) was stirred at room temperature for 20 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→100% ethyl acetate-hexane→2% methanol-ethyl acetate) to give the title compound (38.8 mg, 20%) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:49]=[CH:48][C:11]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24]3[CH:47]=[CH:46][C:27]([C:28]([NH:30][C:31]5[CH:32]=[C:33]6[C:37](=[CH:38][CH:39]=5)[N:36]([CH2:40][C:41](OCC)=[O:42])[CH:35]=[CH:34]6)=[O:29])=[CH:26][CH:25]=3)[CH:19]=[CH:18]4)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:50][CH2:51][C:52]([O:54][CH3:55])=[O:53]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24]3[CH:47]=[CH:46][C:27]([C:28]([NH:30][C:31]5[CH:32]=[C:33]6[C:37](=[CH:38][CH:39]=5)[N:36]([CH2:40][C:41]([NH:50][CH2:51][C:52]([O:54][CH3:55])=[O:53])=[O:42])[CH:35]=[CH:34]6)=[O:29])=[CH:26][CH:25]=3)[CH:19]=[CH:18]4)=[O:13])=[CH:48][CH:49]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)CN
Reactant: CCOC(=O)Cn1ccc2cc(NC(=O)c3ccc(-n4ccc5cc(NC(=O)c6ccc(N7CCC(O)CC7)cc6)ccc54)cc3)ccc21
Product: COC(=O)CNC(=O)Cn1ccc2cc(NC(=O)c3ccc(-n4ccc5cc(NC(=O)c6ccc(N7CCC(O)CC7)cc6)ccc54)cc3)ccc21

Procedure:
Compound 971 was prepared by treatment of Compound 962 with methyl aminoacetate. [M+H]+ calcd for C40H38N6O6: 699.29; found 699.25.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([CH:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[CH:33][CH:34]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN1CCC(c2ccc(N)cc2)CC1
Reactant: CN(Cc1ccccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2ccc(Nc3nc4c(Nc5ccccc5CN(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
N-Methyl-N-(2-{2-[4-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-benzyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(1-methyl-piperidin-4-yl)-phenylamine (44.0 mg, 0.231 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.068 g, 64%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.5 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.46-7.38 (m, 2H), 7.35 (t, J=7.5 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.13 (t, J=7.5 Hz, 1H), 7.00 (s, 1H), 6.83 (d, J=7.8 Hz, 1H), 6.76 (s, 1H), 6.70 (t, J=7.0 Hz, 1H), 4.36 (s, 2H), 2.95 (d, J=11.2 Hz, 2H), 2.91 (s, 3H), 2.78 (s, 3H), 2.50-2.40 (m, 1H), 2.33 (s, 3H), 2.10-2.00 (m, 2H), 1.87-1.73 (m, 4H). MS=520 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:18]>>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c1C
Yield: 33.6 %

Procedure:
6-Pyridin-3-yl-1,3-dihydroindol-2-one (40 mg, 0.19 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (50 mg) give, 29 mg (33%) of the title compound as a light orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CN4CCCCC4)n3)c2[C@@H]2CCN12
Yield: 96.5 %

Procedure:
3.76 g (10 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 5 g (58 mmol) of piperidine and 25 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 9/1 there were obtained 4.1 g (96%) of (S)-8-chloro-1-[5-(piperidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 177°-179°, which was converted into the hydrochloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[N:1]1([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:18])[CH2:6][CH2:5][NH:4][C:3]2[N:7]=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: c1cnc2c(c1)NCCN2
Reactant: O=C(Cl)c1ccccc1
Product: O=C(c1ccccc1)N1CCNc2ncccc21
Yield: 10 %

Procedure:
1,2,3,4-tetrahydropyrido[2,3-b]pyrazine was reacted with benzoyl chloride as in General Procedure 2 to give the title compound as a beige solid (<10% yield). M.p. 166-168° C., LCMS: m/z=240.12 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 3.45-3.49 (m, 2H), 3.84-3.87 (m, 2H), 6.40 (s, 1H), 6.77 (dd, J=4.8 Hz, 4.5 Hz, 1H), 6.92 (dd, J=1.5 Hz, 7.8 Hz, 1H), 7.10 (dd, J=1.5 Hz, 4.6 Hz, 1H), 7.25-7.34 (m, 5H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2].[C:41]([OH:46])(=[O:45])[CH2:42][CH:43]=[CH2:44].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:44]=[CH:43]/[CH2:42][C:41]([OH:46])=[O:45])=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: C=CCC(=O)O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 57.5 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole (3.0 g) and 3-butenoic acid (1.0 g) in acetonitrile (15 mL) were added triethylamine (2.4 g), palladium acetate(II) (0.11 g) and tris(2-methylphenyl)phosphine (0.29 g), and the mixture was refluxed overnight under shading the light. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-dichloromethane/methanol=10/1) to give the title compound (1.74 g).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([CH2:19][N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH:15]=[N:16]3)=[CH:11][C:10]=2[F:25])=[O:7])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[C:14]([CH2:19][N:20]5[CH2:21][CH2:22][CH2:23][CH2:24]5)[CH:15]=[N:16]4)=[CH:11][C:10]=3[F:25])=[O:7])=[CH:26][CH:27]=2)=[CH:31][CH:30]=1
Reactant: O=C(Nc1cc2ncc(CN3CCCC3)cc2cc1F)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ncc(CN3CCCC3)cc2cc1F)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 16 h
Yield: 53.4 %

Procedure:
To a solution of 4-bromo-N-[6-fluoro-3-(1-pyrrolidinylmethyl)-7-quinolinyl]benzamide (100 mg, 0.233 mmol) obtained in Example 49, 4-fluorophenylboronic acid (65.3 mg, 0.467 mmol) and 2N sodium carbonate (0.233 ml) in 1,2-dimethoxyethane (3 ml) was added tetrakistriphenylphosphine palladium (8.1 mg, 0.007 mmol) at 90° C., and the mixture was stirred under a nitrogen atmosphere for 16 hrs. The reaction solution was diluted with ethyl acetate and dried over anhydrous sodium sulfate. The obtained crude product was purified by NH-silica gel chromatography (eluting solvent; ethyl acetate) and treated with ethyl acetate-isopropyl ether (1:5) to give the title compound (55.2 mg) as a powder.
Reaction SMILES: [Br:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[C:6]([CH3:11])[CH2:7][S:8](=[O:10])(=[O:9])[C@H:3]12.Cl.[CH3:31]NC.C=O.C(O)(C)(C)C>C(Cl)Cl>[Br:1][C@H:2]1[C:28](=[O:29])[N:4]2[C:5]([C:12]([O:14][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:13])=[C:6]([CH3:11])[C:7](=[CH2:31])[S:8](=[O:9])(=[O:10])[C@H:3]12
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Br)[C@H]2S(=O)(=O)C1
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: C=C1C(C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](Br)[C@H]2S1(=O)=O
Temperature: 95 °C
Yield: 69.4 %

Procedure:
To a stirred solution of benzhydryl 7α-bromo-3-methyl-3-cephem-4-carboxylate-1,1-dioxide (2.8 g, 0.0059 mol) in methylene chloride (12 ml) were added dimethylamine hydrochloride (1.44 g, 0.0176 mol), formaldehyde (0.61 g, 0.020 mol) and t-butyl alcohol (100 ml), the mixture was heated to reflux at 95° C. for 3 hours. Solvent was removed under reduced pressure and the residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate and concentrated to dryness. The residue was purified by column chromatography with a solvent gradient of 10 to 25% ethyl acetate/hexane to afford benzhydryl 7α-bromo-2-methylene-3-methyl-3-cephem-4-carboxylate-1, 1-dioxide (2.0 g, 69.5%) as a white foam. IR (Nujol) ν max 1720, 1800 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:17][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]#[N:15])([CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyano-piperidine-1-carboxylic acid tert-butyl ester (4.52 g, 20 mmol) in THF (50 mL) was added LHMDS in THF (24 mL, 24 mmol) at 0° C. After stirring at 0° C. for 1 hour, MeI (5.7 g) was added. The reaction mixture was kept at 0° C. for 2 hours, then partitioned between EtOAc and H2O. After concentration in vacuo, the residue was purified by silica column chromatography with EtOAc/hexanes to give the desired product.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=2)[C:42]#[N:43])O1>>[C:42]([C:41]1[CH:44]=[C:37]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:19])([F:18])[F:20])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:38]=[N:39][CH:40]=1)#[N:43]
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2cc(C(=O)Nc3ccc(SC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 189.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow solid. UPLC-MS (Condition 3) tR=1.09 min, m/z=500.3 [M+H]+, m/z=498.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.69 (m, 1H) 1.77-1.96 (m, 1H) 2.16-2.30 (m, 1H) 2.97 (dd, J=11.00, 7.09 Hz, 1H) 3.10-3.22 (m, 2H) 3.22-3.27 (m, 1H) 3.34-3.45 (m, 2H) 4.60 (br. s, 1H) 7.70 (d, J=8.80 Hz, 2H) 7.87-7.99 (m, 2H) 8.09 (d, J=2.45 Hz, 1H) 8.41 (t, J=2.08 Hz, 1H) 8.80 (d, J=2.45 Hz, 1H) 8.91 (d, J=2.20 Hz, 1H) 9.02 (d, J=1.96 Hz, 1H) 10.27 (s, 1H).