Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:41][C:42]1[CH:43]=[C:44]([CH:49]=[CH:50][C:51]=1[NH:52][C:53](OC1C=CC([N+]([O-])=O)=CC=1)=[O:54])[C:45]([O:47][CH3:48])=[O:46].C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:53]([NH:52][C:51]2[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][C:42]=2[Cl:41])=[O:54])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c(Cl)c1
Reaction time: 8 h
Yield: 131.8 %

Procedure:
To a solution of 181 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate and 0.114 mL of triethylamine in 3.0 mL of THF was added 171 mg of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate at room temperature, followed by stirring overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 352 mg of methyl 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}amino)-3-chlorobenzoate as a crude product. ESI+: 656
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:25]1[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]1)[N:8]([CH:14]1[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(Cl)cc2c1=O
Reactant: OC1CCNCC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(O)CC3)c(Cl)cc2c1=O

Procedure:
When the product from Example A is reacted with 4-hydroxypiperidine in analogy to Example 17, then 6-chloro-1-cyclopropyl-8-fluoro-1,4-dihydro-7-(4-hydroxy-1-piperidinyl)-4-oxo-3-quinolinecarboxylic acid of melting point 226°-231° (with decomposition) is obtained.
Reaction SMILES: [Na+].[Cl-].[Cl-].[K+].[C:5]([O-:8])([OH:7])=O.[Na+].[O:10]=[CH:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])O>>[CH2:11]([OH:10])[C@H:12]1[O:7][C@H:5]([O:8][C@:12]2([CH2:11][OH:10])[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@@H:14]2[OH:15])[C@H:18]([OH:19])[C@@H:16]([OH:17])[C@@H:14]1[OH:15]
Reactant: O=C([O-])O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
The Ringer solution contained: 124 mM NaCl, 3 mM KCl, 1.3 mM NaH2PO4. 2 mM MgCl2H2O, 2 mM MgCl2-6H2O, 26 mM NaHCO3, and 10 mM Dextrose. The pH was adjusted to 7-7.5 using bubbled 95% O2-5% CO2. This Ringer solution was used for storing nerves and for filling the two stimulating pools (500 ul) and the recording “intracellular” pool.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:24])[CH2:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:7][CH:8]=1.O.[NH2:26][NH2:27]>ClCCl>[ClH:2].[ClH:1].[C:20]([NH:19][CH2:18][CH:17]([OH:24])[CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[N:5]=[N:4][C:3]([NH:26][NH2:27])=[CH:8][CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(Cl)nn1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(NN)nn1

Procedure:
A stirred mixture of 3-chloro-6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]pyridazine hydrochloride (0.3 g.) and hydrazine hydrate (3 ml.) was heated under reflux for 50 minutes. After cooling, dichloromethane was added and this mixture was extracted with water, the dichloromethane was removed by evaporation and the residue was treated with a mixture of n-propanol (1.2 ml.) and concentrated hydrochloric acid (0.13 ml.) to give 3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine dihydrochloride, m.p. 163°-168°.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[C:8]([C:10]1[NH:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[N:14]=1)#[N:9].[H-].[Na+]>>[C:8]([C:10]1[N:11]([S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-:23])=[O:22])[N:14]=1)#[N:9]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N#Cc1nc(-c2ccccc2[N+](=O)[O-])c[nH]1
Agent: [H-]
Agent: [Na+]
Product: CN(C)S(=O)(=O)n1cc(-c2ccccc2[N+](=O)[O-])nc1C#N
Temperature: 0 °C

Procedure:
Dimethylsulphamoyl chloride (0.54 ml) was added to a mixture of 2-cyano-4-(2-nitrophenyl)-1H-imidazole (0.865 g) and sodium hydride (150 mg of 80% in oil). The mixture was heated under reflux for one hour and then poured into ice/water and extracted with ethyl acetate. The extract was washed with brine, dried and evaporated. The residual oil slowly solidified and was washed with ether and filtered to give 2-cyano-1-(dimethylsulphamoyl)4-(2-nitrophenyl)imidazole, m.p. 111°-4°. (Compound 4)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(S(=O)(=O)O)cn1
Agent: O=S(=O)(O)O
Product: Nc1ncc(S(=O)(=O)O)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h

Procedure:
6-Aminopyridine-3-sulfonic acid (20 g) in concentrated H2SO4 (80 mL) was heated at 50° C. until it was completely dissolved. To this solution was added fuming HNO3 slowly over 20 minutes, so the internal temperature did not exceed 55° C. After the addition was complete, the reaction mixture was heated at 50° C. for 1 hour. After it was cooled to room temperature, it was poured into 150 g of ice. The mixture was stirred for another hour. The flask was cooled to 0° C., and was kept at 0° C. for another 2 hours. The solid was collected by filtration, and washed with cold 1:1 water/ethanol (20 mL), followed by diethyl ether (10 mL). The solid was dried in a vacuum oven overnight to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>CC#N>[CH3:23][O:22][C:18](=[O:21])[CH:19]=[CH:20][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2=CCCc3ccccc32)cc1
Reactant: C=CC(=O)OC
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(C2=CCCc3ccccc32)cc1
Yield: 74 %

Procedure:
Prepared by Heck coupling 4-(4-bromophenyl)-1,2-dihydro-naphthalene (2i) and methyl acrylate in accordance with the general method described in Example IV (J. Chem. Soc. B, 1969, 638–643). Yield 74%; APcI m/z: 332 (M+H+CH3CN+, 100%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[CH:24][CH:25]=3)[N:17]=[CH:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[N+:11]([C:7]1[CH:6]=[C:5]([C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:26]([F:29])([F:28])[F:27])=[N:22][CH:23]=[CH:24][CH:25]=3)[N:17]=[CH:16][N:15]=2)[CH:4]=[C:3]([OH:2])[C:8]=1[OH:9])([O-:13])=[O:12]
Reactant: COc1cc(-c2ncnc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2ncnc(-c3cccnc3C(F)(F)F)n2)cc(O)c1O
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A portion of 2-(3,4-dimethoxy-5-nitrophenyl)-4-(2-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine (1.221 g, 3 mmol) was taken up in dichloromethane (25 mL). The yellowish solution was cooled to −78° C. under argon and boron tribromide (2.55 mL, 27 mmol) was added dropwise. The red reaction mixture was allowed to warm to room temperature and stirred for 18 hours. It was then carefully poured into ice-water (100 mL) and stirred for 1 hour. The yellow precipitate was filtered off, washed with water and dried over P2O5 under vacuum. Recrystallisation from a dichloromethane-ethanol mixture gave 3-nitro-5-(4-(2-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazin-2-yl)benzene-1,2-diol as a yellow solid, 0.966 g (85%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14](O)=O)[CH2:10]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.COC1C=CC(C[S:33][C:34]2[CH:35]=[C:36]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:37]=[CH:38][C:39]=2[NH2:40])=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:41]1([C:36]2[CH:37]=[CH:38][C:39]3[N:40]=[C:14]([CH:11]4[CH2:12][CH2:13][CH:9]([NH2:8])[CH2:10]4)[S:33][C:34]=3[CH:35]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: COc1ccc(CSc2cc(-c3ccccc3)ccc2N)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC1CCC(c2nc3ccc(-c4ccccc4)cc3s2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
To a suspension of (1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid (35.7 mg, 0.156 mmol) in DMF (1 mL) was added DIPEA (0.082 mL, 0.47 mmol), 3-((4-methoxybenzyl)thio)-[1,1′-biphenyl]-4-amine (50 mg, 0.16 mmol) and HATU (89 mg, 0.23 mmol). The reaction was stirred rt for 16 h. The mixture was concentrated, and the residue was dissolved in DCM and washed with 1 N HCl and water. The organics were combined and dried over Na2SO4 and concentrated. TFA (1 mL) was added to the residue and the solution was heated at 100° C. for 15 min in microwave. The reaction was heated at 60° C. for 16 h. The reaction was concentrated and dissolved in ACN and purified by Prep HPLC (5-90% B over 12 min, Column: PHENOMENEX® Luna Axia 5 u C18 30×100 mm; Solvent A: 10% ACN−90% H2O-0.1% TFA; Solvent B: 90% ACN−10% H2O-0.1% TFA, flow rate=40 mL/min) to give Intermediate 47 (22 mg, 48%) as a white solid. LC-MS (ESI) 295.0 (M+H), RT=1.86 min (Method B).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH2:10][CH:9]1C1C=CC=CC=1OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[CH3:23][OH:24]>[OH-].[OH-].[Pd+2]>[CH3:23][O:24][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:1]=1[N:8]1[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]1
Reactant: COc1ccccc1C1CC(=O)C=CN1Cc1ccccc1
Reactant: CO
Agent: [Pd+2]
Agent: [OH-]
Product: COc1ccccc1N1CCC(O)CC1

Procedure:
To a solution of N-benzyl-2,3-dihydro-2-(2-methoxyphenyl)-4-pyridone (5.5 g, 18.77 mmol) (which was prepared by the procedures of Yamamoto et al., Tetrahedron, 1993, 49, 1749) in methanol (80 mL) was added Pd(OH)2 (1.7 g) and the resulting suspension was hydrogenated (50 psi) for 20 hours. Pd-C was then filtered off and the crude reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel flash chromatography (5% MeOH-0.5% NH3♦H2O-94.5% CH2Cl2) to afford the title compound as a solid (1.5 g). 13C NMR (CDCl3, 100 MHz) ) δ: 156.5, 131.4, 128.1, 126.9, 120.8, 110.3, 69.6, 55.3, 53.8, 45.1, 41.7, and 35.6.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=1>C1COCC1>[CH3:25][O:24][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22])[CH2:14][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: COc1cc(CBr)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Pyrrolidine (0.2 g, 2.8 mmol) and triethylamine (0.28 g, 2.8 mmol) were added to a solution of 4-(bromomethyl)-2-methoxy-1-nitrobenzene (Preparation 104, 0.22 g, 0.894 mmol) in THF (5 mL). The reaction mixture was stirred for 1 hour at room temperature before being concentrated under reduced pressure and purified by silica gel column chromatography eluting with 10% methanol in ethyl acetate to afford the title compound as a pale yellow powder (0.18 g, 94%). 1H-NMR (500 MHz, CDCl3): δ 1.8 (t, J=6.7 Hz, 4H), 2.51 (t, J=6.7 Hz, 4H), 3.65 (s, 2H), 3.96 (s, 3H), 6.96 (dd, J=9.7 Hz, 1.5 Hz 1H), 7.12 (s, 1H), 7.8 (d, J=8.3 Hz, 1H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].C[O:10][C:11](=O)[C:12]#[C:13][CH3:14].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[CH3:14][C:13]1[N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[NH:8][C:11](=[O:10])[CH:12]=1
Reactant: NNc1ccccn1
Reactant: CC#CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(=O)[nH]n1-c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.7 %

Procedure:
To a solution of pyridin-2-yl-hydrazine (1 g) in tert-butanol (15 mL) at 30° C. was added but-2-ynoic acid methyl ester (1 g). The reaction vessel was then cooled in an ice bath was treated with potassium tert butoxide (2 g) portionwise. The resulting suspension was stirred at ambient temperature for 16 hours. The tert-butanol was reduced in vacuo and the residue was taken up in water. The aqueous layer was extracted once with DCM. The aqueous layer was then acidified with AcOH to pH=3 and the resulting precipitate was collected by filtration and washed with water. The solid was collected and dried over P2O5 in a dessicator to give 5-methyl-1-pyridin-2-yl-1,2-dihydro-pyrazol-3-one (0.3 g) as a white solid. MS (ESI+): 176.3 [M+H]+).
Reaction SMILES: [CH2:1]=[O:2].C(N(CC)CC)C.[CH:10]([O:13][PH:14](=[O:19])[O:15][CH:16]([CH3:18])[CH3:17])([CH3:12])[CH3:11]>>[OH:2][CH2:1][P:14](=[O:19])([O:15][CH:16]([CH3:18])[CH3:17])[O:13][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)O[PH](=O)OC(C)C
Reactant: C=O
Solvent: CCN(CC)CC
Product: CC(C)OP(=O)(CO)OC(C)C
Reaction time: 4 h
Yield: 86.9 %

Procedure:
To a suspension of paraformaldehyde (3.4 g) in diisopropylphosponate (25 g) was added triethylamine (2 mL). The reactants were heated in a 130° oil bath with vigorous stirring for 4 h. The volatiles were removed on a rotavap and the residue was chromatographed on silica gel using ethyl acetate to afford 19.3 g of material. 1H NMR(DMSO-d6) δ 1.23 (d, 12H), 3.62 (dd, 2H), 4.59 (m, 2H), 5.31 (m, 1H)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)#[CH:18]>>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]#[C:18][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:21]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: Cc1ccc(C#Cc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Yield: 63.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 4-ethynyltoluene (0.08 mL, 0.65 mmol) to provide 258 (85 mg, 64% yield) as a brown solid. LC-MS (M+H=311 obsd.=311).
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:10]=[CH:9][C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.CN(C)C=O>BrN1C(=O)CCC1=O.O>[Br:20][C:9]1[C:8](=[O:19])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1ccc(-c2ccccn2)cn1-c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 4 °C
Reaction time: 2.5 h
Yield: 77.9 %

Procedure:
1-Phenyl-5-(pyridin-2-yl)-2(1H)-pyridone (186 g), N-bromosuccinimide (141.7 g) and N,N-dimethylformamide (900 ml) were stirred at room temperature. After 2.5 hr, 6.45 g of N-bromosuccinimide was added thereto. After depletion of the reactant was confirmed, the reaction solution was poured into water (4.5 L) under ice-cooling, followed by stirring in a cold-room (approximately 4° C.) overnight. The resulting crystals were collected by filtration under reduced pressure, followed by dissolving in isopropanol (3.25 L) and water (650 ml) under heating. After the complete dissolution was confirmed, the solution was left to cool gradually, and then ice-cooled. Then, the mixture was stirred in a cold-room overnight. The resulting crystals were collected by filtration under reduced pressure and air-dried at 60° C., to give 191 g (81%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:22]([O:23][CH:24]([CH3:26])[CH3:25])=[CH:21][CH:20]=[C:19]([F:27])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH:40][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[C:19]([F:27])=[CH:20][CH:21]=[C:22]([O:23][CH:24]([CH3:25])[CH3:26])[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:16])[CH3:17])=[N:36]2)[CH2:31][O:30]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2c(F)ccc(OC(C)C)c2F)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2c(F)ccc(OC(C)C)c2F)=CC1=O
Temperature: 0 °C
Yield: 64.4 %

Procedure:
To a solution of (S)-2-[4-(2,6-difluoro-3-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.530 g, 1.38 mmol) in N,N-dimethylformamide (10 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.354 g, 1.79 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (1.21 g, 2.73 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.356 g, 2.75 mmol) was added. The mixture was stirred at room temperature for 5 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 10% to 70% ethyl acetate/hexanes) which afforded (S)-2-[4-(2,6-difluoro-3-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.500 g, 64%) as a off-white solid.
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:10]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]=2[CH2:8][CH2:7][C:6]1=[O:21])(=[O:4])[CH3:3].[O:22]1CCCC1>>[C:2]([NH:5][CH2:14][CH2:13][CH2:12][C:11]([C:10]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:9]=1[CH2:8][CH2:7][C:6]([OH:21])=[O:22])=[O:15])(=[O:4])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Agent: Cl
Product: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
500 ml of 2N hydrochloric acid are added to a solution of 103 g (0.35 mol) of 4-acetyl-11-chloro-1,2,4,5,6,7-hexahydro-4-benzazecine-3,8-dione in 1 l of tetrahydrofuran and the mixture is stirred at room temperature overnight. The mixture is concentrated in a vacuum, treated with methylene chloride and extracted twice with 2N sodium hydroxide solution; the aqueous phase is then acidified with 6N hydrochloric acid and extracted with methylene chloride. Removal of the solvent by distillation in a vacuum and chromatography on silica gel with methylene chloride/methanol (20:1) yields 2-(4-acetamidobutyryl)-5-chlorohydrocinnamic acid with melting point 90°-92°.
Reaction SMILES: [CH3:1][C@H:2]1[O:6][CH:5]([CH2:7][OH:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:8][CH2:7][CH:5]2[CH2:4][CH2:3][C@@H:2]([CH3:1])[O:6]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H]1CCC(CO)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CC[C@@H](C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a solution of Example 64A (4.0 g, 25.8 mmol) in dichloromethane (100 mL) were added triethylamine (10.8 mL, 77.0 mmol) and p-toluenesulfonyl chloride (4.9 g, 25.8 mmol). The reaction mixture was stirred at room temperature overnight and then washed with water (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-25% ethyl acetate in hexanes) to provide 3.5 g (50%) of the title compound. MS (DCI+) m/z 288 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:13][C:14]=1[CH2:15][CH3:16].C(C1C(N[CH:41]2[C:46]3[CH:47]=[CH:48][O:49][C:45]=3[CH2:44][CH2:43][CH2:42]2)=NC(CC)=CN=1)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:41]2[C:46]3[CH:47]=[CH:48][O:49][C:45]=3[CH2:44][CH2:43][CH2:42]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1cnc(CC)c(NC2CCCc3occc32)n1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2occc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(4,5,6,7-tetrahydro-1-benzofuran-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.50, 7.34, 5.30, 4.53, 2.68, 2.62, 2.51, 2.09, 1.94 1.26, 1.20; HRMS (EI) calcd for C22H23Cl2N3O 415.1218, found 415.1217.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:19]=1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]>>[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:19]=2)[CH:35]=[C:34]([F:47])[C:33]=1[OH:48]
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1cccc(CCN2CCCC2)c1)C1CC1
Yield: 31.4 %

Procedure:
Following general procedure A-1, {6-bromo-4-[3-(2-(pyrrolidin-1-yl)ethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (56 mg, 0.120 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.180 mmol) to afford the desired product (20 mg, 32%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.45 (s, 1H), 8.22 (dd, J=8.8, 1.9 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.91 (s, 1H), 7.65-7.58 (m, 1H), 7.54 (d, J=7.8, 1H), 7.46 (s, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.12 (dd, 11.5, 2.3 Hz, 1H), 6.95 (s, 1H), 3.72-3.64 (m, 2H), 3.45-3.36 (m, 2H), 3.17-3.05 (m, 4H), 2.92-2.83 (m, 1H), 2.20-2.09 (m, 2H), 2.08-1.99 (m, 2H), 1.31-1.16 (m, 4H); ESI MS m/z 530 [C31H29ClFN3O2+H]+; HPLC>99% (AUC), tR=10.82 min.