Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>[Zn]>[OH:7][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CCCCCC=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Zn]
Product: CCCCCC(O)CC(=O)OC(C)(C)C
Yield: 77.2 %

Procedure:
The reaction of hexanal (720 mg) and tert-butyl bromoacetate (2.265 g) was carried out under the presence of zinc (850 mg) according to similar manner to that of Preparation 1-(1) to afford an oil of tert-butyl 3-hydroxyoctanoate (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]([Sn](CCCC)(CCCC)CCCC)=[CH:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([CH3:16])[CH3:15].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:12]([F:11])=[CH:13][C:14]([CH3:15])([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[CH3:16])=[C:4]([CH3:10])[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C(F)=CC(C)(C)c1ccc(Cl)cc1
Reactant: Cc1nc(N)nc(N)c1I
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(N)c1C(F)=CC(C)(C)c1ccc(Cl)cc1

Procedure:
This compound is prepared in a manner analogous to that of Step E of Example 4, using 1.2 grams (0.0048 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine, 2.3 grams (0.0048 mole) of 1-fluoro-3-(4-chlorophenyl)-3-methyl-1-tributylstannyl-1-butene, 0.04 gram of tri-2-furylphosphine, 0.04 gram of tris(dibenzylidineacetone)dipalladium(0) in about 30 mL of N,N-dimethylformamide, yielding 2,4-diamino-6-methyl-5-[1-fluoro-3-methyl-3-(4-chlorophenyl)-1-butenyl]pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=O.C(=O)([O-])O.[Na+].C(O)CC>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Solvent: O
Product: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
2.5 g (14.45 mmol) of 2-amino-5-bromopyridine, 3.37 g (14.45 mmol) of 2-bromo-4′-chloroacetophenone, 1.82 g (21.67 mmol) of sodium hydrogen carbonate and 110 ml of 1-propanol are introduced into a 250 ml three-necked flask, equipped with a magnetic stirrer and maintained under a nitrogen atmosphere. After stirring for 18 hours at 80° C., the reaction mixture is brought back to ambient temperature and diluted with 400 ml of water. The precipitate formed is recovered by filtration, washed with water, and then dried at 80° C. under reduced pressure. 3.96 g of expected product are thus isolated in the form of a beige powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: COc1ccc(-c2nnn[nH]2)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-c5nnn[nH]5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(1H-tetrazol-5-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give, after chromatography on silica gel eluting sequentially with dichloromethane/methanol/concentrated ammonium hydroxide) 95/5/0.1 dichloromethane/methanol/concentrated ammonium hydroxide) 80/20/0.2, the title compound: Rf=0.81 (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide) 90/10/0.1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:6][C:7]([C:9]1[S:10][C:11]([NH2:14])=[CH:12][CH:13]=1)=[O:8])[CH3:2].[CH3:23]CN(C(C)C)C(C)C.COS(OC)(=O)=O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:6][C:7]([C:9]1[S:10][C:11]([NH:14][CH3:23])=[CH:12][CH:13]=1)=[O:8])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)s1)C(=O)OCC
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC)s1)C(=O)OCC
Temperature: 60 °C
Reaction time: 42 h
Yield: 15.5 %

Procedure:
A solution containing N-(5-aminothiophene-2-carbonyl)-L-glutamic acid diethyl ester (III-3 where R2 is H) (1.78 g, 5.42 mmol), (i-Pr)2NEt (1.0 mL, 0.74 g, 5.7 mmol), and Me2SO4 (0.59 mL, 0.79 g, 6.2 mmol) in 20 mL N,N-dimethylformamide (DMF) was warmed at 60° C. for 2 hours, then left at 20°-25° C. for 42 hours. The solution was evaporated in vacuo (1 mm, bath 25°-30° C.), and the residue was dissolved in EtOAc-cyclohexane (1:1 by volume) for application to a silica gel column. Elution by the same solvent system afforded fractions homogeneous by TLC of the product. Fractions were combined and evaporated to afford 16% yield (287 mg) of N-[5-(methylamino)thiophene-2-carbonyl]-L-glutamic acid diethyl ester (III-3) R2 =CH3 as an amber oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[F:10].[N:11]([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[C:17]([CH3:24])[N:18]=[CH:19]2)=[C:12]=[O:13].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12]([NH:11][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[C:17]([CH3:24])[N:18]=[CH:19]3)=[O:13])=[CH:4][C:3]=1[F:10]
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: NCc1ccc(Br)c(F)c1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(Br)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-bromo-3-fluorobenzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.46 (s, 1H), 8.51 (m, 2H), 8.01 (d, 1H, J=7.8 Hz), 7.80 (t, 1H, J=7.8 Hz), 7.67 (m, 2H), 7.36 (dd, 1H, J=9, 1.5 Hz), 7.18 (dd, 1H, J=9, 1 Hz), 4.39 (d, 2H, J=6 Hz), 2.77 (s, 3H); MS (ESI) 388/390 (M+H)+; Anal. Calcd for C18H15BrFN3O.HCl: C, 50.91; H, 3.80; N, 9.89. Found: C, 50.81; H, 3.74; N, 9.87.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(Cl)(Cl)=O>CCOCC>[CH2:10]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[NH2:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCC[C@H](N)C(=O)O
Reactant: OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCCC[C@H](N)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
According to the general procedure outlined in J. Med. Chem. 1986, Vol. 30, p. 3575, 15.0 g norleucine (Nle) was mixed with 200 ml benzyl alcohol and cooled to 0° C. Thionyl chloride (25 ml) was added dropwise over 15 minutes and the mixture was slowly heated to 90° C. with a fierce evolution of SO2 occurring at about 50° C. After 2 hours at 90° C. the mixture was cooled to 0° C. and 25 ml more thionyl chloride was added. The mixture was then heated again at 90° C. for 2 hours, cooled, diluted with 1.6 liters ether and stored overnight at 0° C. The crystals which formed were filtered, washed with ether and dried to give 23.1 g of a damp solid which was recrystallized from 1:10 ethanol-ether, using 23 ml ethanol. The filtered and dried solid weighed 17.1 g, TLC Rf 0.25 in System C (the spotted plate was exposed to ammonia vapor and dried prior to elution).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16]CC)=O)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:16])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)nc2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)nc2)sc1C(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
A mixture of ethyl 2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazole-5-carboxylate i98 (0.47 g, 1 eq, 1.84 mmol), morpholine (0.19 g, 1.2 eq, 2.21 mmol) and triethylamine (0.5 ml, 2 eq, 3.68 mmol) in dichloromethane (15 ml) is cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.39 g, 1.1 eq, 2.02 mmol) and 1-hydroxybenzotriazole (0.05 g, 0.2 eq, 0.37 mmol) are then added to the solution and the mixture is stirred 24 h at room temperature. The mixture is then washed with water and a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum to give 0.53 g of 4-{[2-(6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-5-yl]carbonyl}morpholine i99.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:35])[CH2:30][CH2:31][N:32]([CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([C:6]4[C:5]5[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=5[O:8][N:7]=4)=[CH:14][CH:13]=3)[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(4-chlorophenyl)-4-hydroxypiperidine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=497.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[C:16]3[S:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:37][C:38]1[C:39]([O:53][CH3:54])=[C:40]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:41]=[C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:43]=1>CN(C=O)C>[C:44]([C:42]1[CH:41]=[C:40]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[C:39]([O:53][CH3:54])=[C:38]([NH:37][C:20]([C:18]2[S:17][C:16]3[C:11]([NH:10][C:8](=[O:9])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=4)=[CH:12][CH:13]=[CH:14][C:15]=3[CH:19]=2)=[O:22])[CH:43]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(Nc1cccc2cc(C(=O)O)sc12)c1ccc(Cl)nc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)c4ccc(Cl)nc4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
To a solution of the above carboxylic acid (50 mg) in DMF (1.5 mL) was added EDC (1.5 eq) and HOBT (1.5 eq). The reaction was stirred at room temperature for 15 min, then N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (1.2 eq) was added. The reaction was stirred 12 h, then the DMF was removed in vacuo, the residue was taken up in EtOAc and washed with water, followed by brine. The organics were dried over MgSO4, filtered, and concentrated and the residue was purified by flash chromatography on silica gel (20%-60% EtOAc/hexane) to give the title compound as a white solid (36 mg, 41% yield for two steps).
Reaction SMILES: COC1C=C(NC2N=CC3CC(=O)NC4C=CC(C(O)=O)=CC=4C=3N=2)C=CC=1OC.C(OC(=O)NC1CCNCC1)(C)(C)C.C(OC(=O)[NH:51][CH:52]1[CH2:57][CH2:56][N:55]([C:58]([C:60]2[CH:86]=[CH:85][C:63]3[NH:64][C:65](=[O:84])[CH2:66][C:67]4[CH:72]=[N:71][C:70]([NH:73][C:74]5[CH:79]=[CH:78][C:77]([O:80][CH3:81])=[C:76]([O:82][CH3:83])[CH:75]=5)=[N:69][C:68]=4[C:62]=3[CH:61]=2)=[O:59])[CH2:54][CH2:53]1)(C)(C)C>>[NH2:51][CH:52]1[CH2:53][CH2:54][N:55]([C:58]([C:60]2[CH:86]=[CH:85][C:63]3[NH:64][C:65](=[O:84])[CH2:66][C:67]4[CH:72]=[N:71][C:70]([NH:73][C:74]5[CH:79]=[CH:78][C:77]([O:80][CH3:81])=[C:76]([O:82][CH3:83])[CH:75]=5)=[N:69][C:68]=4[C:62]=3[CH:61]=2)=[O:59])[CH2:56][CH2:57]1
Reactant: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)N4CCC(NC(=O)OC(C)(C)C)CC4)ccc2NC(=O)C3)cc1OC
Agent: CC(C)(C)OC(=O)NC1CCNCC1
Agent: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)O)ccc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(C(=O)N4CCC(N)CC4)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic acid (I-43) and piperidin-4-yl-carbamic acid tert-butyl ester were converted to {1-[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carbonyl]-piperidin-4-yl}-carbamic acid tert-butyl ester, which was subsequently deprotected according to Method K. Purification by C-18 RP LC-MS chromatography afforded I-74 (19%): HRMS Calcd. for C26H28N6O4: 489.2250, Found 489.2253.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[CH:19]1(O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Reactant: OC1CCCCC1
Product: C=CCOC(=O)NC1CC(=O)OC1OC1CCCCC1
Yield: 85 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using cyclohexanol to afford the title compound as a mixture of diastereomers (pale yellow oil) (4.62 g, 85% yield). Flash column chromatography using hexanes/EtOAc (90/10 to 80/20) gave 394 mg (7% yield) of the syn diastereomer of the title compound. 1H NMR (500 MHz, CDCl3) 6.1.11-2.09 (m, 10H), 2.35-2.61 (dd, 1H), 2.72-2.98 (dd, 1H), 3.60-3.83 (m, 1H), 4.32-4.72 (m, 3H), 5.06-5.43 (m, 2H), 5.60 (d, 1H), 5.82-6.03 (m, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: COc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 4-methoxyphenylmagnesium bromide. Yield: 51 mg of a white solid. LC-MSD, m/z for C23H17BrN2O3 [M+H]+=449.0, 451.0; HPLC retention time: 2.3 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:28])[CH2:17][C:18]2[CH:23]=[C:22]([Br:24])[C:21]([O:25][CH3:26])=[C:20]([Br:27])[CH:19]=2)=[CH:9][C:8]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:30]([O:29][C:8]1[CH:9]=[C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:28])[CH2:17][C:18]2[CH:23]=[C:22]([Br:24])[C:21]([O:25][CH3:26])=[C:20]([Br:27])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(Br)cc(CC(=O)NCCc2ccc(N)c(OCc3ccccc3)c2)cc1Br
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1c(Br)cc(CC(=O)NCCc2ccc(NS(C)(=O)=O)c(OCc3ccccc3)c2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (0.148 g, 0.0013 mol) was added dropwise a solution of N-[2-(4-amino-3-benzyloxy-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxy-phenyl)-acetamide (0.712 g, 0.0013 mol) in 6 mL of pyridine. The reaction mixture was stirred overnight at room temperature, diluted with 10 mL of chloroform, washed with 1N HCl and 1N NaOH, dried over Na2SO4 and concentrated. A residue was crystallizedfrom ethyl acetate-hexanes mixture. Yield 0.635 g (78%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23](F)([F:31])[C:24]1[S:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:29][C:27]5[S:28][C:24]([CH:23]([F:31])[F:22])=[CH:25][CH:26]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(C(F)(F)F)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)F)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 40.9 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (78 mg), (5-(trifluoromethyl)-2-thienyl)methanol (77 mg) and tributylphosphine (168 mg) in THF (3 ml) was added 1,1′-(azodicarbonyl)dipiperidine (210 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (48.5 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.CO[C:12]([CH3:15])([CH3:14])[CH3:13]>[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[C:12]([C:7]1[C:2]([F:1])=[CH:3][C:4]([OH:9])=[CH:5][C:6]=1[F:8])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(C)(C)C
Reactant: Oc1cc(F)cc(F)c1
Agent: [Zr+4]
Agent: [Cl-]
Product: CC(C)(C)c1c(F)cc(O)cc1F
Temperature: 55 °C
Reaction time: 12 h
Yield: 54.2 %

Procedure:
A mixture of 3,5-difluorophenol (TCI, 14 g, 107 mmol), tert-butyl methyl ether (12.8 ml, 108 mmol) and zirconium(IV) chloride (25 g, 107 mmol) was stirred for 12 hours at 55° C., followed by addition of tert-butyl methyl ether (6.4 ml, 54 mmol). The additional injection of tert-butyl methyl ether (6.4 ml, 54 mmol), was repeated 8 times at intervals of 24 hours and then the reaction was quenched with saturated ammonium chloride aqueous solution and 2 M HCl aqueous solution. The whole was extracted with DCM, washed with brine, and dried over magnesium sulfate. The organic layer was evaporated to give a crude residue which was purified by silica gel column chromatography, eluting with gradually from hexane only to hexane/EtOAc (10:1), to give the title compound (10.8 g, 54%) as white solids.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CC#N>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(NCCCO)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
A cooled (0° C.) solution of 4-[(3-hydroxypropyl)amino]benzonitrile (see step (i) above; 17 g, 96.5 mmol) in dry MeCN (195 mL) was treated with triethylamine (9.8 g, 96.5 mmol) and then p-toluenesulfonyl chloride (20.2 g, 106 mmol). The mixture was stirred at 0° C. for 90 minutes before being concentrated in vacuo. Water (200 mL) was added to the residue, and the aqueous solution was extracted with DCM. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by crystallisation from iso-propanol to yield 24.6 g (77%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].[CH3:22][N:23]([CH3:29])[CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N:26]3[CH2:27][CH2:28][CH:24]([N:23]([CH3:29])[CH3:22])[CH2:25]3)=[N:16][CH:15]=2)[C:3]=1[CH3:21]
Reactant: CN(C)C1CCNC1
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(N3CCC(N(C)C)C3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 19 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.1 g, 0.32 mmol) in DMF (3.0 mL) was added 3-(dimethylamino)-pyrrolidine (0.041 mL, 0.32 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 100° C. and stirring continued for 19 h. After which, the reaction mixture was cooled to rt and water was added. The crude mixture was extracted with EtOAc and dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 1-(5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyridin-2-yl)-N,N-dimethylpyrrolidin-3-amine as a white solid. Mass Spectrum (ESI) m/e=403.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6](O)=[O:7])#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:29][NH2:30]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([NH:29][NH2:30])=[O:7])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(C(=O)NN)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (0.300 g, 1.46 mmol) in tetrahydrofuran (10.0 mL) was treated with 1,1′-carbonyldiimidazole (0.261 g, 1.61 mmol). After stirring 2 h at ambient temperature, hydrazine monohydrate (0.213 mL, 4.39 mmol) was added. After stirring an additional 2 h at ambient temperature, the reaction mixture was concentrated in vacuo. Purification via flash column chromatography (0-5% MeOH/EtOAc) gave the title compound as a white solid (0.304 g; 95%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.51 (br. s., 1H) 8.06 (d, J=2.3 Hz, 1H) 8.02 (dd, J=8.8, 2.3 Hz, 1H) 7.00 (d, J=8.8 Hz, 1H) 5.15 (br. s., 2H) 4.71 (qq, J=6.1 Hz, 1H) 1.40 (d, J=6.1 Hz, 6H). MS (ES+) m/e 220 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14]C(N3CCCCC3)[CH2:12][CH2:11]2)=[CH:6][N:5]=1)([O-:3])=[O:2].[CH:22]([N:25]1CCN(C2C=CC(N)=NC=2)CC1)([CH3:24])[CH3:23].CN1CCN(C2C=CC(N)=NC=2)CC1>>[CH:22]([N:25]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCN(c2ccc(N)nc2)CC1
Reactant: O=[N+]([O-])c1ccc(N2CCC(N3CCCCC3)CC2)cn1
Agent: CN1CCN(c2ccc(N)nc2)CC1
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1

Procedure:
1-isopropyl-4-(6-nitro-3-pyridyl)piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5-[4-(1-piperidyl)-1-piperidyl]pyridine which was then converted to 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine in a manner similar to that used in the synthesis of 5-(4-methylpiperazin-1-yl)pyridin-2-amine. 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.06 (d, J=6.44 Hz, 6H) 2.59-2.75 (m, 5H) 2.97-3.10 (m, 4H) 4.13 (s, 2H) 6.45 (d, J=8.78 Hz, 1H) 7.15 (dd, J=9.08, 2.93 Hz, 1H) 7.76 (d, J=2.93 Hz, 1H). LCMS (ESI) 221 (M+H).