Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]([O:11]/[N:12]=[C:13](/[C:46]1[N:47]=[C:48]([NH:51]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:49][CH:50]=1)\[C:14]([NH:16][CH:17]1[C:44](=[O:45])[N:19]2[C:20]([C:28]([O:30]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:29])=[C:21]([CH:24]=[CH:25][CH2:26]I)[CH2:22][S:23][C@H:18]12)=[O:15])([CH3:10])[CH3:9])=[O:7])(C)(C)C.[N:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>ClCCl.C(OC(C)C)(C)C>[NH2:51][C:48]1[S:49][CH:50]=[C:46](/[C:13](=[N:12]/[O:11][C:8]([C:6]([OH:7])=[O:5])([CH3:10])[CH3:9])/[C:14]([NH:16][CH:17]2[C:44](=[O:45])[N:19]3[C:20]([C:28]([O-:30])=[O:29])=[C:21](/[CH:24]=[CH:25]/[CH2:26][N+:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[CH2:22][S:23][C@H:18]23)=[O:15])[N:47]=1
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)[O-])=C(/C=C/C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1)C(=O)O
Reaction time: 3.5 h
Yield: 7 %

Procedure:
A mixture of diphenylmethyl 7-[(Z)-2-(2-t-butoxycarbonyl-2-propoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(3-iodo-1-propen-1-yl)-3-cephem-4-carboxylate (X-4', 497 mg, 0.5 mmole) and pyridine (0.08 ml, 1 mmole) in dichloromethane (5 ml) was allowed to stand at room temperature for 3.5 hours, and was then diluted with diisopropyl ether. The resulting precipitate was collected by filtration and treated with trifluoroacetic acid (5 ml) and anisole (1 ml) at room temperature for 1 hour, and the resulting mixture was concentrated and triturated with ether to give crude product I-4B which was purified by HP-20 column chromatography, eluted with water (300 ml), 10% methanol (500 ml) and 30% methanol (300 ml). The eluate of 30% methanol was concentrated to a small volume, adjusted to pH 7 with sodium bicarbonate and lyophilized to afford 23 mg (7%) of the title compound I-4B. M.p. >150° C.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2([CH2:11][OH:12])[CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:15](Cl)(Cl)=[O:16].Cl.Cl.[NH2:21][C@@H:22]([CH2:35][CH2:36][CH2:37][CH2:38][NH:39][S:40]([N:43]([CH3:45])[CH3:44])(=[O:42])=[O:41])[CH:23]([OH:34])[C:24]([NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:25].C(N(CC)CC)C>O1CCCC1.C1(C)C=CC=CC=1>[CH3:45][N:43]([CH3:44])[S:40]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][C@H:22]([NH:21][C:15](=[O:16])[O:12][CH2:11][C:7]1([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1)[CH:23]([OH:34])[C:24](=[O:25])[NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)(=[O:41])=[O:42]
Reactant: O=C(Cl)Cl
Reactant: OCC1(Cc2ccc(F)cc2)CCC1
Reactant: CN(C)S(=O)(=O)NCCCC[C@H](N)C(O)C(=O)NCc1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)NCCCC[C@H](NC(=O)OCC1(Cc2ccc(F)cc2)CCC1)C(O)C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
To 110 mg (0.57 mmol) of [1-(4-fluorobenzyl)cyclobutyl]methanol in 2 mL of tetrahydrofuran was added 0.59 mL (1.1 mmol) of 1.93 M phosgene in toluene and the reaction stirred at room temperature overnight. The mixture was concentrated under reduced pressure and added to a solution of 250 mg (0.57 mmol) of (3S)-3-amino-7-{[(dimethylamino)sulfonyl]amino}-2-hydroxy-N-(3-pyridinylmethyl)heptanamide dihydrochloride and 0.28 mL of triethylamine in 4 mL of tetrahydrofuran. The mixture was filtered through a frit and the wash concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 7:3 acetone:hexanes to leave 200 mg (59%) of [1-(4-fluorobenzyl)cyclobutyl]methyl(1S)-5-{[(dimethylamino)sulfonyl]amino}-1-{1-hydroxy-2-oxo-2-[(3-pyridinylmethyl)amino]ethyl}pentylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 8.38-8.55 (m, 2H), 7.65 (m, 1H), 6.7.00-7.40 (m, 7H), 6.55 (d, J=9 Hz, 1H), (5.83 (d, J=6 Hz) and 5.72 (J=6 Hz), 1H), 4.31 (m, 2H), 4.00 (m, 1H), 3.71-3.88 (m, 2H), 3.42 under water peak (m, 2H), 2.74-2.90 (m, 3H), 2.66 (s, 6H), 1.70-1.95 (m, 6H), 1.25-1.59 (m, 6H). ES-LCMS m/z 594 (M+H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:10][CH2:11][CH2:12][CH2:13]Br>[OH-].[Na+]>[Br:10][CH2:11][CH2:12][CH2:13][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: BrCCCBr
Reactant: C1=Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Product: BrCCCC1=CCc2ccccc21
Reaction time: 6 h

Procedure:
The compound is prepared as described by Makoska in Tetrahedron Letters 38, 4261-4624 (1966) by adding a mixture of 580 g (5M) indene and 1010 g (5M) 1,3-dibromopropane to 1500 ml 50% aqueous NaOH containing 50 ml 40% methanolic Triton B. The temperature is held below 55° C by cooling in an ice bath. After stirring 6 hours the reaction mixture is diluted to 4 l. The layers are separated and the aqueous layer is extracted two times with ether. The combined organic layers are extracted two times with water, dried over MgSO4, filtered and the solvent is removed. The oily product is distilled and redistilled at reduced pressure collecting 432 g (36.6%) boiling 126°-140°/0.1 mm.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][CH:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:26](N1C=CN=C1)(N1C=CN=C1)=[O:27].[NH:38]([C:42]1[S:43][CH:44]=[C:45]([CH2:47][S:48][CH2:49][CH2:50][NH2:51])[N:46]=1)[C:39]([NH2:41])=[NH:40]>C(Cl)Cl>[NH:38]([C:42]1[S:43][CH:44]=[C:45]([CH2:47][S:48][CH2:49][CH2:50][NH:51][C:26]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH2:11][CH2:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH3:1])=[O:27])[N:46]=1)[C:39]([NH2:41])=[NH:40]
Reactant: CN(CCCCCCCN)CCC(c1ccccc1)c1ccccn1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CN(CCCCCCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.85 g (2.5 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,7-heptanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.65 g (2.8 mmol) of 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography (eluant: methylene chloride) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%])=597 ([M+H]+, 7), 196 (100); IR (KBr): 1655 cm-1 (C=O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[C:9]1([CH3:24])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1C1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][C:9]([CH3:24])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1-c1ccc(B(O)O)cc1
Reactant: Clc1cc(I)ccn1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccnc(Cl)c2)cc1
Yield: 44 %

Procedure:
A mixture of 2-chloro-4-iodopyridine (10.0 g, 41.8 mmol), p-tolylphenylboronic acid (5.68 g, 41.8 mmol), Pd(Ph3P)4 (1.45 g 1.25 mmol), sodium carbonate (13.3 g, 125 mmol), DME (300 mL) and water (75 mL) was degassed with nitrogen and then refluxed overnight. The mixture was concentrated and the extracted with ethyl acetate. The the ethyl acetate layer was dried on Na2SO4, vacuum distilled and recrystalized to give 2-chloro-4-(p-tolyl)pyridine (3.75 g, 18.4 mmol, 44% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([O:24]CC)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A mixture of intermediate 26, ethyl 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4] oxazine-2-carboxylate, (2.93 g, 8.2 mmol) and LiOH.H2O (0.84 g, 20 mmol) in 4:1 ethanol/tetrahydrofuran (50 mL) was stirred for 2 h at ambient temperature then concentrated under vacuum. The resulting yellow residue was treated with 1N HCl (25 mL) providing a precipitate that was filtered and dried under vacuum to yield the title compound as a white powder (2.68 g, 99% yield). 1H NMR (500 MHz, CDCl3) δ ppm: 7.54-7.48 (2H, m), 7.37-7.27 (3H, m), 5.44 (2H, s), 4.05-3.93 (4H, m), 1.60 (6H, s).). HRMS (M+H) calcd for C17H19N2O5: 331.1294; found: 331.1308. Anal calcd for C17H18N2O5: C, 61.81; H, 5.49; N, 8.48; found: C, 61.84; H, 5.36; N, 8.25.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[C:13]([O:24][CH2:25][C@@H:26]([C:35]([OH:37])=O)[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1.CN(C=O)C>CCOC(C)=O>[O:37]=[C:35]1[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:13]=2[O:24][CH2:25][C@@H:26]1[NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1c(N)cccc1-c1ccccc1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1COc2c(cccc2-c2ccccc2)NC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
0.136 ml of diethyl cyanophosphonate (147.8 mg, 0.906 mmol) is introduced, at 0° C., into a 25 mL three-necked flask containing 284 mg of 36 (0.763 mmol) and 6.2 mL of DMF, followed 10 minutes later by 0.102 ml of TEA (0.731 mmol). The reaction medium is stirred at 0° C. for 2 h. 20 ml of AcOEt are added and then the mixture is washed with twice 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 160 mg of expected product 37 are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.018 ml propionyl chloride (0.2 mmol). After 1.5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 79 mg of a light brown solid (96%). MS (ISP) 507.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:10][C:11]([O:13][CH:14]([O:16][C:17](=[O:33])[CH2:18][CH:19]([CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:15])=[O:12])[CH3:9]>C(Cl)Cl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[CH2:8]([O:10][C:11]([O:13][CH:14]([O:16][C:17](=[O:33])[CH2:18][CH:19]([CH2:24][NH2:25])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH3:15])=[O:12])[CH3:9]
Reactant: CCOC(=O)OC(C)OC(=O)CC(CNC(=O)OC(C)(C)C)CC(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)OC(C)OC(=O)CC(CN)CC(C)C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99 %

Procedure:
Trifluoroacetic acid (6.5 mL) was added to a solution of compound 4 (0.407 g, 1.08 mmol) and CH2Cl2 (2.85 mL) in an ice water bath, and the solution was maintained in the ice water bath for 30 minutes. The solution was warmed to room temperature and stirred for another 4.5 hours. The reaction solution was then concentrated and dried to give 0.50 g of 3-Aminomethyl-5-methyl-hexanoic acid 1-ethyloxycarbonyloxy-ethyl ester TFA salt 5 (Yield: 99%). 1HNMR (CDCl3, 500 MHz) δ 0.87˜0.91 (m, 6H), 1.23˜1.39 (m, 6H), 1.51 (6rs, 3H), 1.61 (S, 1H), 2.20˜2.38 (m, 1H), 2.40˜2.61 (m, 2H), 2.98˜3.21 (m, 2H), 4.2 (br s, 2H), 6.75 (br s 1H), 7.51˜7.80 (br s, 2H), 9.35˜9.80 (br s, 1H); 13C NMR (CDCl3, 125 MHz) δ13.86, 13.87, 19.16, 19.19, 21.70, 21.74, 22.38, 22.40, 24.83, 30.95, 31.02, 36.48, 36.69, 41.07, 41.32, 44.25, 44.36, 64.82, 91.41, 91.45, 153.38, 153.40, 171.87, 172.08.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:40]2[CH:39]=[CH:38][C:37]([O:36][CH2:35][C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)=[CH:42][CH:41]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: OB(O)c1ccc(OCc2ccncc2)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
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: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccncc3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 9 h
Yield: 52.3 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.02 g, 0.044 mmol), (4-(pyridin-4-ylmethoxy)phenyl)boronic acid (0.020 g, 0.088 mmol) and 2M Na2CO3 (0.055 ml, 0.110 mmol) in DMF (1 mL) was degassed for 3 min. Then, Pd(Ph3P)4 (5.07 mg, 4.39 μmol) was degassed for 1 min and placed in a pre-heated oil bath at 90° C. After 9 h, cooled and purified by prep-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(pyridin-4-ylmethoxy)phenyl)pyridin-3-yl)acetate (0.013 g, 0.023 mmol, 52.9% yield) as brown paste. LCMS (M+H)=560.4.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[F:33][C:34]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44](O)=O)=[N:41][NH:42][CH:43]=1)=[O:37].[CH3:52][C:53]1[C:54]([NH2:61])=[C:55]([NH2:60])[CH:56]=[CH:57][C:58]=1[CH3:59]>>[CH3:52][C:53]1[C:54]2[N:61]=[C:44]([C:40]3[C:39]([NH:38][C:36](=[O:37])[C:35]4[C:34]([F:33])=[CH:50][CH:49]=[CH:48][C:47]=4[F:51])=[CH:43][NH:42][N:41]=3)[NH:60][C:55]=2[CH:56]=[CH:57][C:58]=1[CH3:59]
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: Cc1ccc(N)c(N)c1C
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1C

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), but using 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D) and 3,4-dimethyl-1,2-phenylene diamine to give N-[3-(4,5-dimethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2,6-difluoro-benzamide (89 mg) as a pale orange solid. (LC/MS: Rt 2.98, [M+H]+ 368.15).
Reaction SMILES: N1CCC(C2OC(C3C=CN=CC=3)=[C:9]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23](=[N:27][OH:28])[CH2:22][CH2:21]4)C=2)CC1.[CH3:29][O-].[Na+].[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48](=[O:50])[CH3:49])[CH2:44][CH2:43]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CO>[CH2:32]([O:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([C:48](=[O:50])/[CH:49]=[CH:9]/[C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[C:23](=[N:27][O:28][CH3:29])[CH2:22][CH2:21]3)[CH2:44][CH2:43]1)=[O:41])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: ON=C1CCc2cc(-c3cc(C4CCNCC4)oc3-c3ccncc3)ccc21
Reactant: CC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CON=C1CCc2cc(/C=C/C(=O)C3CCN(C(=O)OCc4ccccc4)CC3)ccc21
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of the product of Step 1 (4.8 g, 25 mmol), sodium methoxide (1.35 g, 25 mmol) and 4-acetyl-piperidine-1-carboxylic acid benzyl ester (6.4 g, 25 mmol) (WO97/05877) in methanol (100 ml) was heated at reflux for 8 hours. After cooling to room temperature the solution was concentrated in vacuo and the residue diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried and concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound (6.92 g, 64%); MS(ES+) m/e 433 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[C:7](=[O:12])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C([O-])(=O)C.[K+].Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>CN(C)C=O.[Cu]>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:13][C:14]([N:16]([CH:25]([CH3:27])[CH3:26])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[C:7](=[O:12])[CH2:8][C:9](=[O:11])[N:10]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3cc(F)ccc32)C(C)C)cc1
Reactant: Brc1cccnc1
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3cc(F)ccc32)C(C)C)cc1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
A mixture of 0.880 g of 2-(7-Fluoro-2,4-dioxo-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (2.20 mmol), 420 mg of copper (bronze, 6.61 mmol, 3 equiv), 476 mg of potassium acetate (4.85 mmol, 2.2 equiv), and 0.290 mL of 3-bromopyridine (4.85 mmol, 2.2 equiv) in 10 mL of dimethylformamide was heated at 100° C. under nitrogen for 3 hrs. An additional 0.132 mL of 3-bromopyridine (2.43 mmol, 1.1 equiv) was added and the reaction was maintained for an additional 2 hrs. The reaction mixture was cooled to ambient temperature, filtered through a sintered glass funnel and then evaporated in vacuo to a residue. The residue was partitioned between ethyl acetate and aqueous ammonium hydroxide (5 mL conc. diluted to 100 mL). After separating the layers, the organic layer was washed with aqueous ammonium hydroxide (5 mL conc. diluted to 100 mL), and then saturated aqueous brine. The organic phase was then extracted three times with aqueous HCl (1N). The acid layers were combined and neutralized with aqueous sodium hydroxide (1N). The neutralized mixture was extracted twice with methylene chloride. The methylene chloride layers were combined, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue. The residue was triturated with hexane and then concentrated in vacuo to provide 0.705 g of the title compound as a tan solid. H NMR (300 MHz, CDCl3) d 8.60 (m, 2H), 8.08 (b, 1H), 7.54 (b, 1H), 7.39 (m, 1H), 7.15 (m, 2H), 7.00 (m, 3H), 6.57 (dd, 1H, J=2.7, 9.2), 4.95 (m, 1H), 4.32 (d, 1H, J=17.9), 4.14 (d, 1H, J=17.8), 3.85 (s, 3H), 3.61 (d, 1H, J=12.1), 3.52 (d, 1H, J=12.1), 1.06 (d, 6H, J=6.8); low resolution MS (FAB)m/e 477 (MH+).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH:10](O)[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]1([O:38][C:39]([NH:41][O:42][C:43]([O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:44])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:32]1([O:38][C:39]([N:41]([CH:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH3:11])[O:42][C:43]([O:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[O:44])=[O:40])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(O)CNC(=O)OC(C)(C)C
Reactant: O=C(NOC(=O)Oc1ccccc1)Oc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(CNC(=O)OC(C)(C)C)N(OC(=O)Oc1ccccc1)C(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 836.9 %

Procedure:
A one liter roundbottom flask was charged with N-Boc-1-amino-2-propanol (26.42 g, 0.0151 mol), triphenylphosphine (41.4 g, 0.158 mol), and N,O-bisphenyloxycarbonylhydroxylamine (43.2 g, 0.158 mol), and dry THF (550 mL). The solution was cooled to 0° C., and diethylazodicarboxylate (24.9 mL, 0.158 mol) was added in THF (50 mL). The reaction was stirred one hour after removing the cooling bath, and concentrated under vacuum. Chromatographic purification is enhanced by adding dichloromethane (200 mL) and concentrating in vacuo twice to remove THF before column chromatography (400 g silica gel, 15% EtOAc/Hex) to provide N,O-bisphenyloxycarbonyl-t-butyloxycarbonylamino-2-propylhydroxylamine (54.4 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5](NC)=[O:6].N([NH-])=O.[BH4-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.C1COCC1>[Cl:1][C:2]1[C:3]([Cl:12])=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][N:11]=1
Reactant: CNC(=O)c1ccnc(Cl)c1Cl
Agent: [BH4-]
Agent: [NH-]N=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: OCc1ccnc(Cl)c1Cl
Reaction time: 16 h

Procedure:
2,3-Dichloro-N-methyl-isonicotinamide (0.353 g, 1.72 mmol) was stirred in 6 mL DCM (not quite homogeneous). tBuONO (0.412 mL, 3.44 mmol) was added followed by the addition of two drops of TFA. After 3 h an additional 0.600 mL tBuONO (5.00 mmol) and three drops TFA were added. The resulting solution was stirred an additional 16 h. An additional 0.400 mL tBuONO (3.34 mmol) and 2 drops TFA were added. After an additional 4.5 h an 0.600 mL tBuONO (5.00 mmol) and 3 drops TFA were added. The reaction was stirred 3 days and was quenched with half-sat sat NaHCO3 (aq). The mixture was extracted 3× with DCM. The organic phases were dried over Na2SO4, filtered, and concentrated. The slightly impure N-nitrosoamide (0.425 g, 1.82 mmol) was stirred in 5 mL THF. NaBH4 (0.137 g, 3.63 mmol) was added and after 2 h the reaction was slowly quenched with 1M HCl until the bubbling stopped. The solution pH was adjusted to pH 9 with Na2CO3 (s). The mixture was extracted 3× with EtOAc. The organic phases were dried over Na2SO4, filtered, and concentrated to afford the titled compound in good purity. 1H NMR (CDCl3) δ 8.32 (d, 1H, J=4.8 Hz), 7.51 (d, 1H, J=5.0 Hz), 4.82 (s, 2H), 2.34 (bs, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][NH2:19])[N:14]=[CH:13]1>CO.[BH4-].[Na+]>[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][NH:19][CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)[N:14]=[CH:13]1
Reactant: NCCc1c[nH]cn1
Reactant: O=C1CCCc2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2NCCc1c[nH]cn1

Procedure:
Using General Procedure B: Reaction of 6,7-dihydro-5H-quinolin-8-one in MeOH, 2-(1H-imidazol-4-yl)-ethylamine and NaBH4 gave [2-(1H-imidazol-4-yl)-ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine. 1H NMR (CDCl3) δ 1.75 (m, 2H), 1.91 (m, 1H), 2.10 (m, 1H), 2.72 (q, 2H, J=8.6 Hz), 2.82 (q, 2H, J=10.0 Hz), 3.01 (t, 2H, J=6.6 Hz), 3.81 (t, 1H, J=6.1 Hz), 6.73 (s, 1H), 7.04 (q, 1H, J=4.3 Hz), 7.35 (d, 1H, J=7.6 Hz), 7.43 (s, 1H), 8.36 (d, 1H, J=4.0 Hz).