Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:48][C@H:49]1[CH2:55][CH:54]=[CH:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[C:50]1=[O:63]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:11])[NH:48][C@H:49]1[CH2:55][CH:54]=[CH:53][CH2:52][N:51]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[CH3:62])[C:50]1=[O:63])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccccc1N1CC=CC[C@H](N)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CC=CCN(c4ccccc4C)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S,Z)-2-oxo-1-o-tolyl-2,3,4,7-tetrahydro-1H-azepin-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (29 mg, 0.051 mmol) and Intermediate 68 (17 mg, 0.051 mmol) to give a white solid (24 mg, 61% yield). Anal. Calcd. for C44H52N4O6S m/z 764.7. found: 765.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.45-6.98 (m, 12H), 6.98-6.84 (m, 2H), 5.89-5.70 (m, 2H), 5.39-5.21 (m, 2H), 5.11 (d, J=5.4 Hz, 1H), 5.04-4.91 (m, 1H), 4.81 (t, J=19.2 Hz, 1H), 4.45 (s, 2H), 3.98 (s, 1H), 3.67 (d, J=3.2 Hz, 3H), 3.63-3.43 (m, 1H), 3.09 (dd, J=25.8, 13.3 Hz, 1H), 2.95-2.62 (m, 5H), 2.54-2.21 (m, 4H), 2.16 and 2.12 (2s, 3H), 2.07-1.89 (m, 3H), 1.87-1.40 (m, 8H).
Reaction SMILES: [PH2]([O-])=O.[Na+].[OH2:5].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@@:14]2([CH3:39])[C:18](=[O:19])[N:17]([CH2:20][C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[C:16](=[O:31])[N:15]2[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:10][CH:9]=1)#N>[Ni].N1C=CC=CC=1.C(O)(=O)C.O>[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C@@:14]2([CH3:39])[C:18](=[O:19])[N:17]([CH2:20][C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[C:16](=[O:31])[N:15]2[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:10][CH:9]=1)=[O:5]
Reactant: C[C@]1(c2ccc(C#N)cc2)C(=O)N(CC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: O
Agent: [Ni]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: C[C@]1(c2ccc(C=O)cc2)C(=O)N(CC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 60 °C
Yield: 79 %

Procedure:
24.3 g of sodium hypophosphite×H2O and 4.02 g of Raney nickel were added to a solution of 6.08 g (13.42 mmol) of 8.1 in 200 ml of pyridine/acetic acid/water (2:1:1) at 0° C. and the reaction mixture was heated at 60° C. for 8 h. After cooling to room temperature and filtration, the reaction mixture was concentrated in vacuo, the residue was taken up in ethyl acetate and the ethyl acetate phase was extracted 2× with water, 2×with 10% strength citric acid solution, 2× with saturated NaHCO3 solution and with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and, after filtration, the solvent was removed in vacuo. 4.82 g (79%) of 8.2 were obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[NH:8][CH2:7][C@@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:24][C:25]1[CH:30]=[C:29](Cl)[N:28]=[C:27]([S:32][CH3:33])[N:26]=1>C1COCC1>[Cl:24][C:25]1[N:26]=[C:27]([S:32][CH3:33])[N:28]=[C:29]([N:8]2[C@H:3]([C:2]([F:12])([F:1])[F:13])[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7]2)[CH:30]=1
Reactant: O=C(O)[C@H]1CC[C@@H](C(F)(F)F)NC1
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(N2C[C@@H](C(=O)O)CC[C@H]2C(F)(F)F)n1
Reaction time: 0.08 h

Procedure:
To cis-6-(trifluoromethyl)-3-piperidinecarboxylic acid (3.393 g, 14.52 mmol) in THF (1.5 mL) were added molecular sieves, and the resulting mixture was stirred for 5 minutes into a 250 mL RB flask. The mixture was cooled in an ice bath, and then LiHMDS (43.6 mL, 43.6 mmol) was added slowly. After the addition was completed, 4,6-dichloro-2-(methylthio)pyrimidine (3.40 g, 17.43 mmol) was added. After 0.5 hours, the reaction was quenched with 30 mL of water and by the dropwise addition of 6N HCl until pH was acidic. The resulting mixture was extracted with EtOAc (3×30 mL). The organics were combined, washed with brine, dried (MgSO4), filtered and concentrated to afford the crude title compound as an oil. LC-MS (ES) m/z=356 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[C:6]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([NH2:22])[CH:3]=1.[CH3:23][O-:24].[Na+]>CO.O>[CH3:23][O:24][C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[C:6]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([NH2:22])[CH:3]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)c(-c2cncnc2)c(C#Cc2ccccc2)n1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N)nc(C#Cc2ccccc2)c1-c1cncnc1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-chloro-6-(2-phenylethynyl)-5-pyrimidin-5-ylpyridin-2-amine C3c (400 mg, 1.3 mmol), sodium methoxide (a solution of 2.61 mmol in 0.29 ml MeOH) and MeOH (2 ml) is stirred for 20 minutes at 100° C. and 10 minutes at 110° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over Na2SO4, concentrated in vacuo and the product purified by NP chromatography. Yield: 228 mg (58%). HPLC-MS: M+H=303.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([CH2:17][NH2:18])[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[NH:31][N:30]=[C:29]([CH:32]3[CH2:34][CH2:33]3)[CH:28]=2)[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:32]1([C:29]2[NH:30][N:31]=[C:27]([NH:26][C:24]3[CH:23]=[CH:22][N:21]=[C:20]([NH:18][CH2:17][C:4]4[CH:3]=[C:2]([F:1])[C:7]5[N:8]([CH:11]6[CH2:16][CH2:15][CH2:14][CH2:13][O:12]6)[CH:9]=[N:10][C:6]=5[CH:5]=4)[N:25]=3)[CH:28]=2)[CH2:34][CH2:33]1
Reactant: NCc1cc(F)c2c(c1)ncn2C1CCCCO1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(CNc2nccc(Nc3cc(C4CC4)[nH]n3)n2)cc2ncn(C3CCCCO3)c12
Temperature: 120 °C
Yield: 62.6 %

Procedure:
A tube was charged with 270 (260 mg, 1.04 mmol), 53 (100 mg, 0.57 mmol), DIPEA (0.5 ml) in IPA (3 mL), degassed, sealed and heated at 120° C. overnight. The solvent was evaporated under reduced pressure to afford 160 mg (34%) N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methyl)pyrimidine-2,4-diamine (272) as yellow solid: MS (ESI) m/z=449.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([NH2:20])[CH2:13][S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:21]1[CH:26]=[C:25]([CH:27]=[O:28])[C:24]([CH:29]=O)=[CH:23][CH:22]=1>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:20]2[CH2:29][C:24]3[C:25](=[CH:26][CH:21]=[CH:22][CH:23]=3)[C:27]2=[O:28])[CH2:13][S:14]([N:17]([CH3:18])[CH3:19])(=[O:15])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: O=Cc1ccccc1C=O
Reactant: CCOc1cc(C(N)CS(=O)(=O)N(C)C)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CS(=O)(=O)N(C)C)N2Cc3ccccc3C2=O)ccc1OC

Procedure:
2-[1-(3-Ethoxy-4-methoxyphenyl)-2-(N,N-dimethylaminosulfonyl)ethyl]isoindolin-1-one was prepared by the procedure of Example 3 from 1-(3-ethoxy-4-methoxyphenyl)-2-(N,N-dimethylaminosulfonyl)ethylamine (150 mg, 0.49 mmol) and 1,2-phthalic dicarboxaldehyde (67 mg, 0.49 mmol) in acetic acid (2 mL). The product was obtained as a solid (142 mg, 69% yield): mp, 165.0-167.0° C.; 1H NMR (CDCl3) δ 1.45 (t, J=7 Hz, 3H, CH3), 2.86 (s, 6H, N(CH3)2), 3.58 (dd, J=4.7, 14.4 Hz, 1H, CHH), 3.86 (s, 3H CH3), 4.08 (q, J=7 Hz, 2H, CH2), 4.30 (d, J=16.5 Hz, 1H, NCHH), 4.33 (dd, J=9, 14.4 Hz, 1H, CHH), 4.49 (d, J=16.5 Hz, 1H, NCHH), 5.60 (dd, J=4.7, 9.5 Hz, 1H, NCH), 6.83 (d, J=8.3 Hz, 1H, Ar), 6.98 (dd, J=2, 8.3 Hz, 1H, Ar), 7.06 (d, J=2 Hz, 1H, Ar), 7.37-7.56 (m, 3H, Ar), 7.84 (d, J=7 Hz, 1H, Ar), 13C NMR (CDCl3) δ 14.69, 37.31, 48.64, 49.73, 52.91, 52.95, 64.54, 111.31, 112.46, 119.29, 122.76, 123.72, 128.03, 130.67, 131.55, 132.75, 141.26, 148.73, 149.39, 168.63; Anal Calcd for C21H26NO5S: C, 60.27; H, 6.26; N, 6.69. Found: C, 60.04; H, 6,10: N, 6.62.
Reaction SMILES: [N+:1](/[C:3](/[C:19](/[N+:35]#[C-:36])=[CH:20]/[C:21]1[CH:26]=[CH:25][C:24]([O:27][Si](C(C)(C)C)(C)C)=[CH:23][CH:22]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si](C(C)(C)C)(C)C)=[CH:7][CH:6]=1)#[C-:2].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[N+:1](/[C:3](/[C:19](/[N+:35]#[C-:36])=[CH:20]/[C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[CH:4]\[C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)#[C-:2]
Reactant: [C-]#[N+]C(=C\c1ccc(O[Si](C)(C)C(C)(C)C)cc1)/C(=C/c1ccc(O[Si](C)(C)C(C)(C)C)cc1)[N+]#[C-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: [C-]#[N+]C(=C\c1ccc(O)cc1)/C(=C/c1ccc(O)cc1)[N+]#[C-]
Reaction time: 3 h
Yield: 119.4 %

Procedure:
(1Z,3Z)-2,3-diisocyano-1,4-bis(4-tert-butyldimethylsilyloxyphenyl)buta-1,3-diene (74.0 mg, 0.14 mmol) prepared in Reference Synthetic Example 10 was dissolved in tetrahydrofuran in nitrogen atmosphere, and acetic acid (21 ml, 0.36 mmol) was added under cooing with ice. Then, a 1.0 mol/l tetra-n-butylammonium fluoride/tetrahydrofuran solution (280 ml, 0.28 mmol) was slowly added dropwise. The reaction solution was returned to room temperature, followed by stirring for 3 hours, and the reaction solution was purified as it was by silica gel column chromatography (hexane:ethyl acetate=2:1) to give (1Z, 3Z)-2,3-diisocyano-1,4-bis(4-hydroxyphenyl)buta-1,3-diene (48.2 mg, 85%) as a yellow powder.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[C:44]([N+:48]([O-:50])=[O:49])[CH:45]=3)[C:40]2=[O:51])[C:36](O)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:52][C:53]1[S:54][CH:55]=[CH:56][N:57]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[CH:28]1([CH2:34][CH:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[C:44]([N+:48]([O-:50])=[O:49])[CH:45]=3)[C:40]2=[O:51])[C:36]([NH:52][C:53]2[S:54][CH:55]=[CH:56][N:57]=2)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2cc([N+](=O)[O-])ccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nccs1)C(CC1CCCCC1)N1Cc2cc([N+](=O)[O-])ccc2C1=O
Yield: 34.7 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (ca. 1:1 mixture of regioisomers, prepared in Step C; 301 mg; 0.91 mmol) and 2-aminothiazole (116 mg; 1.12 mol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (as outlined in Example 1, Step B) provided after chromatography (Biotage 40M, eluent: 30% ethyl acetate/hexanes) 131 mg of 3-Cyclohexyl-2-(5-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide: EI-HRMS m/e calcd for C20H22N4O4S (M+) 414.1362, found 414.1362 and 121 mg of regioisomeric 3-Cyclohexyl-2-(6-nitro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide: EI-HRMS m/e calcd for C20H22N4O4S (M+) 414.1362, found 414.1368.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[CH3:18][C:19]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])([CH3:21])[CH3:20]>C(O)C>[C:19]([O:22][C:23](=[O:24])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:28][CH2:27]1)([CH3:21])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 80 °C
Yield: 37.4 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (74 mg, 0.48 mmol) in ethanol (1 ml) was added triethylamine (200 μl, 1.43 mmol) and 4-N-Boc-aminopiperidine (106 mg, 0.53 mmol). The solution was heated at 80° C. for 4 hours, and then cooled to room temperature. The precipitate was collected by filtration and washed with ethanol (2 ml), then dried under vacuum to yield the product (57 mg, 36%). LC/MS (LCT) Rt 4.57 [M+H]+ 318
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25].C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:18][CH2:19][CH2:20][O:21][CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCCNc1nc2ccc(C#CC(C)(C)O)cc2n1-c1ccnc(N)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
A mixture of 1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine (120 mg, 0.33 mmol), 2-methylbut-3-yn-2-ol (277.2 mg, 3.30 mmol), bis(triphenylphosphine)palladium(II) dichloride (231.67 mg) and triethylamine (2.4 mL) in dimethylsulfoxide (1 mL) was stirred under nitrogen for 1 hr at 70° C. The reaction mixture was cooled to room temperature and the solid material was removed by filtration. The filtrate was diluted with 5 mL of water then extracted with 3×30 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC to give 5.0 mg (4%) of 4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-methylbut-3-yn-2-ol as a white solid: 1H NMR (300 MHz, DMSO) delta 8.43 (d, J=5.4 Hz, 1H), 8.21 (d, J=5.4 Hz, 1H), 7.47 (s, 1H), 7.25 (s, 1H), 7.16-7.12 (m, 3H), 6.91 (d, 1H), 5.40 (s, 1H), 3.63-3.57 (m, 4H), 3.35 (s, 3H), 1.47 (s, 6H); LC-MS: m/z=+367 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])=O.Cl.[CH3:25][O:26][NH2:27]>O1CCCC1.O>[CH3:25][O:26][N:27]=[CH:1][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[C:12](=[O:23])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CON
Reactant: O=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CON=CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 24 h

Procedure:
To a solution of 3-formyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylic acid (35 mg) in tetrahydrofuran (3 ml) is added a solution of O-methylhydroxylamine hydrochloride (13 mg) in water (1.5 ml), and the mixture is left standing for 24 hours. After evaporation of the tetrahydrofuran at room temperature, the separated yellow oil is extracted with ethyl acetate. The extract solution is washed with water, dried and evaporated to leave pale yellow foam which gives crystals of 3-methoxyiminomethyl-7β-(2-thienylacetamido)-3-cephem-4-carboxylic acid (37 mg; nearly quantitative yield) by recrystallization from ether and ethyl acetate. m.p. 186°-189° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2O.P(Cl)(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[Cl:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
1-(6-Bromo-4-hydroxyquinolin-3-yl)propan-1-one (21 g, 67.7 mmol) was added to phosphoryl chloride (80 mL). The resultant suspension was then heated to 85° C. and stirred for 1.5 h. The reaction mixture was cooled to room temperature and poured carefully into a mixture of saturated sodium bicarbonate (250 mL) and 2N aqueous sodium hydroxide (250 mL). The solution was then extracted with ethyl acetate, the combined organics were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the desired product (16 g, 96%) as a tan solid: APCI MS m/z 298 [C12H9BrClNO+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[N:19](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.[OH-].[Na+]>Cl.C(O)C.CO>[NH2:19][C:10]1[C:9]2=[N:8][N:7]([CH2:34][CH2:35][CH3:36])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:18]2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCn1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3ccccc3c2c1CCCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCCCO
Temperature: 25 °C
Yield: 27.6 %

Procedure:
A solution of di(tert-butyl) 1-(4-hydroxybutyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (prepared as described in Parts A-C of Example 57, 0.507 g, 1.02 mmol) in 6 M HCl in ethanol (5 mL) was heated at 60° C. for 1.5 hours. The solution was allowed to cool to room temperature, and then was concentrated under reduced pressure to yield an oil. The oil was triturated with ether to obtain a solid that was isolated by filtration. The solid was dissolved in methanol and the solution was adjusted to approximately pH 14 with 50% aqueous sodium hydroxide. The solution was concentrated under reduced pressure and the crude product was purified by chromatography (silica gel, elution with 5% CMA in chloroform) followed by crystallization from hexanes/ethyl acetate to provide 0.084 g of 4-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butan-1-ol as white needles, mp 135.0-136.0° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12](Cl)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18]([OH:24])[C:19]1[O:23][CH:22]=[CH:21][CH:20]=1.O>C(OCC)C>[CH2:3]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12]([O:24][CH2:18][C:19]2[O:23][CH:22]=[CH:21][CH:20]=2)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ncc(Br)c(Cc2ccccc2)n1
Reactant: OCc1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Brc1cnc(OCc2ccco2)nc1Cc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
14.1 mg of 60% oily sodium hydride was added to a mixture of 73.3 mg of 4-benzyl-5-bromo-2-chloropyrimidine (Production Example 15), 1 ml of furfuryl alcohol and 14.8 mg of cuprous iodide at room temperature, followed by stirring at 90° C. for 2 hours. Water and diethyl ether were added to the reaction solution, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 10% ethyl acetate/hexane, to give 50.9 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CO[C:61](=O)[NH:62]C(C(N1CCCC1C1NC(C2C=CC3C(=CC=C(B4OC(C)(C)C(C)(C)O4)C=3)C=2)=CN=1)=O)C(C)C>>[CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([C:61]#[N:62])[CH2:44][N:43]6[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AZ), substituting (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for [2-methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester. 1H-NMR: 400 MHz, (DMSO-d6) δ 11.98 (s, 1H), 11.82 (s, 1H), 8.22 (m, 2H), 7.92-7.77 (m, 6H), 7.62 (m, 2H), 7.44 (d, J=7.6 Hz, 1H), 7.31 (d, J=8.0, 1H), 5.24 (t, J=5.2 Hz, 1H), 5.12 (d, J=4.0, 1H), 4.22-4.19 (m, 1H), 4.09-4.0 (m, 4H), 3.89-3.83 (m, 4H), 3.56 (d, J=5.6 Hz, 6H), 2.17 (brs, 2H), 2.06-1.90 (m, 4H), 0.95-0.84 (m, 14H); MS (ESI) m/z 814 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:24][NH2:25].C(N(CC)CC)C>C(O)C(C)C>[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:24][NH:25][C:2]1[N:6]([C@@H:7]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1
Reactant: NCc1ccc(-c2ccccc2)c(O)c1
Reactant: OC[C@H]1O[C@@H](n2c(Cl)nc3ccccc32)[C@H](O)[C@@H]1O
Solvent: CC(C)CO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)c(O)c3)nc3ccccc32)[C@H](O)[C@@H]1O
Yield: 30.3 %

Procedure:
2-Chloro-1-(β-D-ribofuranosyl)-1H-benzimidazole (0.21 g) and 3-hydroxy-4-phenylbenzylamine (0.19 g) were suspended in isobutanol (5 mL). To the mixture was added triethylamine (0.36 mL), and the mixture was stirred for reflux for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: methanol/ethyl acetate=1/20) to give the title compound (0.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: Cc1ccncc1I
Reactant: COc1cc2c(cc1Cl)C(=O)NCC2
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc2c(cc1Cl)C(=O)N(c1cnccc1C)CC2
Yield: 52.4 %

Procedure:
7-Chloro-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one (I-86d: 200 mg, 0.946 mmol) was reacted with 3-iodo-4-methylpyridine (228.2 mg, 1.042 mmol), 1,4-dioxane (5 mL), copper iodide (18 mg, 0.094 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (13.4 mg, 0.095 mmol) and potassium phosphate (603.3 mg, 2.84 mmol) for 48 hours at 120° C. to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 150 mg of the product (52.4% yield).