Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:21]3[CH:26]=[C:25]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[C:24]([F:37])=[CH:23][C:22]=3[F:38])[C:14](=[O:20])[N:15]2[CH2:18][CH3:19])=[CH:10][N:9]=1)C(=O)C)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O>CO>[C:1]([NH:4][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:21]3[C:22]([F:38])=[CH:23][C:24]([F:37])=[C:25]([NH:27][C:28]([NH:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:29])[CH:26]=3)[C:14](=[O:20])[N:15]2[CH2:18][CH3:19])=[CH:10][N:9]=1)(=[O:3])[CH3:2]
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(N(C(C)=O)C(C)=O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2F)cc2cnc(NC(C)=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To a solution of N-acetyl-N-{3-[2,4-difluoro-5-(3-phenyl-ureido)-phenyl]-1-ethyl-2-oxo-1,2-dihydro-[1,6]naphthyridin-7-yl}-acetamide (100 mg, 0.19 mmol) in MeOH (2 mL) was added K2CO3 (79 mg, 0.57 mmol) and water (1 mL), and the mixture was stirred overnight at RT. MeOH was removed under reduced pressure and the residue was diluted with water (8 mL). The mixture was extracted with EtOAc to give a crude product which purified by prep-HPLC to give 1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-phenylurea (32 mg, 23% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 9.08 (s, 1H), 8.74 (s, 1H), 8.61 (s, 1H), 8.27 (s, 1H), 8.21-8.16 (m, 1H), 8.07 (s, 1H), 7.45-7.40 (m, 3H), 7.30-7.26 (m, 2H), 7.00-6.96 (m, 1H), 4.24-4.18 (q, J=6.8 Hz, 2H), 2.16 (s, 3H), 1.28-1.25 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 478.3 [M+H]+.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH2:9]([O:16][CH2:17][CH2:18][C@H:19]([OH:41])[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(O[CH2:47][CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=O)=O>CS(C)=O.O>[CH2:9]([O:16][CH2:17][CH2:18][C@H:19]([O:41][CH2:47][CH2:48][O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:20][O:21][C:22]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)OCCOCc1ccccc1
Reactant: O[C@@H](CCOCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(COCCO[C@@H](CCOCc2ccccc2)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Sodium hydride (6.32 g, 0.158 mmol, 60% in oil) was loaded under argon circumstance in three-necked flask and hexane (100 ml) was added thereto. After stirring for a while, it was allowed to stand and the supernatant was removed by syringe. By repeating this procedure three times, the oil of sodium hydride was removed. After drying in vacuo anhydrous dimethyl sulfoxide (DMSO) (30 ml) was added and the solution was stirred at 60° C. for 1 hour. After cooling to room temperature, (S)-4-benzyloxy-1-trityloxy-2-butanol (55.89 g, 0.132 mol) in DMSO (40 ml) was gradually dropped at room temperature to the solution and then the solution was stirred for 30 minutes. To the solution was gradually dropped 2-benzyloxyethyl methanesulfonate (33.4 g, 0.145 mol) in DMSO (40 ml) at room temperature and then the solution was stirred for 12 hours. To the reaction mixture was added water (120 ml) and the solution was extracted with ethyl acetate. The extract was washed with water (150 ml) twice and with saturated brine once, dried on sodium sulfate, filtered and condensed in vacuo. The residue was subjected to silica gel chromatography to give (S)-4-benzyloxy-2-(2-benzyloxyethoxy)-1-trityloxybutane (55.0 g, yield 75%).
Reaction SMILES: [C:1]1([C:7]2[CH2:11][C:10]3([CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:62]([C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1)([CH3:65])([CH3:64])[CH3:63]>C1COCC1>[C:62]([C:66]1[CH:67]=[CH:68][C:69]([NH:70][C:17]([CH:14]2[CH2:15][CH2:16][C:10]3([O:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:11]3)[CH2:12][CH2:13]2)=[O:19])=[CH:71][CH:72]=1)([CH3:65])([CH3:63])[CH3:64]
Reactant: O=C(O)C1CCC2(CC1)CC(c1ccccc1)=NO2
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)C2CCC3(CC2)CC(c2ccccc2)=NO3)cc1
Reaction time: 8 h

Procedure:
3-Phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid (400 mg, 1.5 mmol) was slowly added to a solution of N-ethyldiisopropylamine (662 mg, 4.6 mmol), 1-hydroxybenzotriazole hydrate (206 mg, 1.5 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (496 mg, 1.5 mmol) and 4-tert-butylaniline (230 mg, 1.5 mmol) in abs. THF (11 ml). The reaction mixture was stirred overnight and the solvent removed under vacuum. The residue was taken up in EtOAc (75 ml). The organic phase was washed successively with sat. aq. NaCl solution, sat. aq. NaHCO3 solution, sat. aq. ammonium sulphate solution and sat. aq. NaCl solution, dried over magnesium sulphate and the solvent removed under vacuum. The desired product 3-phenyl-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carboxylic acid-(4-tert-butylphenyl)amide was obtained as a diastereomer mixture in a yield of 220 mg (37% of the theoretical amount).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[O:12])[CH:5]=1.[CH2:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl[O-].[Na+]>C(Cl)Cl.O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:11]([C:6]2[CH:5]=[C:4]([C:3]3[CH2:23][CH:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[O:1][N:2]=3)[N:9]=[C:8]([CH3:10])[N:7]=2)=[O:12])=[CH:20][CH:19]=1
Reactant: COc1ccc(CNC(=O)c2cc(C=NO)nc(C)n2)cc1
Reactant: C=Cc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CNC(=O)c2cc(C3=NOC(c4ccccc4)C3)nc(C)n2)cc1
Reaction time: 2 h
Yield: 34.8 %

Procedure:
To a stirred suspension of 6-((hydroxyimino)methyl)-N-(4-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.15 g, 0.50 mmol, Preparation #B.1.1) and styrene (0.057 g, 0.50 mmol) in DCM (10 mL) was added 4% sodium hypochlorite solution (1.5 mL, Sd Fine Chem.) drop wise for about 10 min at RT and stirred for about another 2 h. The reaction mixture was diluted with water (50 mL) and the product extracted with DCM (3×25 mL). The organic layer was dried over sodium sulphate and evaporated to dryness under reduced pressure. The resulting mixture was purified by silica gel (60-120 mesh) chromatography eluting with 20 to 30% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford N-(4-methoxybenzyl)-2-methyl-6-(5-phenyl-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide as a white solid 0.07 g (34%). LC/MS (Table 1, method-b) Rt=1.93 min; MS m/z: 403 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[CH:7][S:6][N:5]=1)[CH3:2].[F:9][S:10]([O:13][CH3:14])(=[O:12])=[O:11]>>[F:9][S:10]([O-:13])(=[O:12])=[O:11].[CH2:1]([O:3][C:4]1[CH:8]=[CH:7][S:6][N+:5]=1[CH3:14])[CH3:2]
Reactant: CCOc1ccsn1
Reactant: COS(=O)(=O)F
Product: CCOc1ccs[n+]1C
Product: O=S(=O)([O-])F
Yield: 50 %

Procedure:
3-Ethoxyisothiazole (2.0 g, 0.015 ml) and 2 ml of methyl fluorosulfonate were heated at 50° for 1 hr. The solid was washed with ether to yield 1.9 g (50%) of 3-ethoxy-2-methylisothiazolium fluorosulfonate, mp 65°-68°. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: ClC1C=C(C=CC=1)C[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:16][CH2:17]Cl)[C:8]([S:19]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:7]1.[N-:35]=[N+:36]=[N-:37].[Na+]>CS(C)=O.O>[N:35]([CH2:17][CH2:16][O:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[NH:6][N:7]=[C:8]2[S:19]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:20])=[O:21])=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cccc12
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCCOc1cccc2c(S(=O)(=O)c3cccc4ccccc34)n[nH]c12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-3-(naphthalene-1-sulfonyl)-1-H-indazole (0.25 g, 0.49 mmoles) and sodium azide (0.04 g, 0.58 mmoles) in DMSO (3 mL) was stirred together in a round bottom flask under nitrogen at 90° C. for 3 hours. Reaction mixture was cooled to room temperature, diluted with water, extracted with EtOAC, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.23 g, 0.44 mmoles).
Reaction SMILES: I[CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[Na+].[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[C@H:25]([NH:26][C:27](=[O:36])/[C:28](/[C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)=[N:29]\[OH:30])[C:24](=[O:37])[N:19]2[C:20]=1[C:21]([O-:23])=[O:22])(=[O:12])[CH3:11].CCO.C([O-])(=O)C>CS(C)=O>[C:10]([O:13][CH2:14][C:15]1[CH2:16][S:17][C@@H:18]2[C@H:25]([NH:26][C:27](=[O:36])/[C:28](/[C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)=[N:29]\[O:30][CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4])[C:24](=[O:37])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])(=[O:12])[CH3:11]
Reactant: NC(=O)NC(=O)CI
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\O)c3ccco3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)NC(N)=O)c3ccco3)[C@H]2SC1
Yield: 34 %

Procedure:
This compound was prepared from iodoacetylurea and (6R,7R)-3-acetoxymethyl-7-[Z-2-(fur-2-yl)-2-hydroxyiminoacetamido]-ceph-3-em-4-carboxylic acid sodium salt by the method described in Example 1. λmax (EtOH) 274 nm (ε 17,300), νmax (Nujol) 3420, 3260 (--NH--, --NH2), 3700-2100 (bonded OH), 1780 (β-lactam), 1720(--CO2H, acetate), 1700, 1570, 1545 cm-1 (CONH, CONH2), τ (DMSO d6) 2.11, 3.3, 3.18 (furyl), 5.28 (--O--CH2 --), 0.09 (--CONHCO--), 2.5 (CONH2), 0.11 (CONH), 4.1 (7 H), 4.78 (6 H), 6.29, 6.51 (2--CH2), 4.95, 5.28 (3 --CH2), 7.93 (CH3CO--). Yield: 34%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]N)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.C=O.[C:27]([BH3-])#[N:28].[Na+].[C:31](O)(=O)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:28]([CH3:27])[CH3:31])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: NCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)Cc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 23, a solution of 8-fluoro-1-(aminomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is treated with formalin, sodium cyanoborohydride and acetic acid to give 8-fluoro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[CH2:19]1[C:25](=O)[CH2:24][S:21](=[O:23])(=[O:22])[CH2:20]1>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:20]3[S:21](=[O:23])(=[O:22])[CH2:24][CH2:25][C:19]=3[NH:1][C:2]3[N:6]([CH3:7])[NH:5][C:4](=[O:8])[C:3]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=C1CCS(=O)(=O)C1
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Cn1[nH]c(=O)cc1N
Solvent: CCO
Product: Cn1[nH]c(=O)c2c1NC1=C(C2c2ccc(F)c(Br)c2)S(=O)(=O)CC1
Yield: 66 %

Procedure:
5-Amino-1-methyl-1,2-dihydropyrazol-3-one (0.17 g, 1.5 mmol), 3-bromo-4-fluorobenzaldehyde (0.3 g, 1.5 mmol), and tetrahydrothiophene-3-oxo-1,1-dioxide (0.2 g, 1.5 mmol) in ethyl alcohol (3 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was cooled and the resulting precipitate was filtered off and washed with ethyl acetate to provide 0.41 g of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 2.88 (m, 1H), 3.03 (m, 1H), 3.4 (m, 2H), 3.48 (s, 3H), 4.92 (s, 1H), 7.21 (m, 1H), 7.24 (t, 1H), 7.4 (d, 1H), 9.55 (s, 1H), 9.89 (s, 1H);MS (ESI−) m/z 414 (M−H)−; Anal. Calcd for C15H13N3BrFO3S: C, 43.49;H, 3.16; N, 10.14. Found: C, 43.64;H, 3.50; N, 9.84.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.ClC[C:11]([N:13](CC)CC)=[O:12].C(N(C(C)C)CC)(C)C.C(COC)[O:28]C>C(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[C:3]=1[C:2]([NH2:1])=[O:28]
Reactant: COCCOC
Reactant: CCN(CC)C(=O)CCl
Reactant: NCc1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccnc1C(N)=O

Procedure:
Pyridine diamide 2 was prepared according to the general procedure described in Example 8 using 2-(aminomethyl)pyridine (0.015 mol), 2-chloro-N,N-diethylacetamide (0.045 mol), diisopropylethylamine (0.060 mol) and dimethoxyethane (25 mL). The product was isolated from the methylene chloride extraction of the basic aqueous layer. The residue was distilled (140° C., 0.10 mm) to afford 3.7 g of pure product.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1>C1(C)C(C)=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[I-:27].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([P+:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:23][CH:22]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Clc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: Clc1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [I-]
Temperature: 150 °C
Reaction time: 9.5 h
Yield: 96 %

Procedure:
In 100 mL-volume egg-plant type flask, 3.30 g (11.4 mmol.) of triphenylphosphine and 3.00 g (12.6 mmol.) of p-chloroiodobenzene were dissolved in 40 mL of xylene. To the solution was added 30.0 mg (0.134 mmol.) of palladium acetate, and the resulting mixture was stirred at 150° C. for 9.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and the precipitate was collected on a filter by suction. The collected precipitate was washed with xylene and dried under reduced pressure at 130° C. for 3 hours. There was obtained 5.48 g (yield: 87%) of p-chlorophenyltriphenylphosphonium iodide (m.p.: 219°-222° C., elemental analysis: found: C 57.84%, H 3.74%, calculated: C 57.57%, H 3.82%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][CH:5](OS(C)(=O)=O)[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1>C1(C)C=CC=CC=1>[CH3:4][CH:5]([N:2]([CH3:3])[CH3:1])[CH2:6][C:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1
Reactant: CC(CC1(c2ccccc2)C=CCC=C1)OS(C)(=O)=O
Reactant: CNC
Solvent: Cc1ccccc1
Product: CC(CC1(c2ccccc2)C=CCC=C1)N(C)C
Reaction time: 16 h

Procedure:
1.1 ml. (about 3 equivalents) of condensed dimethylamine are added at -10° C. to 1.5 g. of methanesulfonic acid 1-methyl-2-(1-phenyl-2,5-cyclohexadien-1-yl)-ethyl ester in 5 ml. of toluene. The mixture is then held at 150° C. in a pressure vessel for 16 hours. Subsequently, the mixture is cooled down and worked-up as follows: The toluene phase is washed with water, concentrated, treated with ether and 3 N aqueous hydrochloric acid and shaken out. The aqueous extract is made basic with concentrated ammonia and extracted with ether. There is obtained an oily residue which is chromatographed on a thick-layer plate with methylene chloride/methanol (10:1). There is obtained α,N,N-trimethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine which is converted in the usual manner into the hydrochloride.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CCO>C(O)C.CC(C)=O>[ClH:1].[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]4[CH:16]=[C:15]5[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]5)=[CH:9][CH:8]=4)[CH2:30][CH2:31]3)=[N:24][O:25][C:21]=2[CH:20]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C1CCc2ccc(OCCCCCl)cc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: O=C1CCc2ccc(OCCCCN3CCC(c4noc5cc(F)ccc45)CC3)cc2N1
Yield: 42.2 %

Procedure:
7-(4-chlorobutoxy)-3,4-dihydro-2(1H)-quinolinone (297 mg, 1 mmol), 4-(6-fluoro-1,2-benzisoxazolyl)-piperidine (242 mg, 1.1 mmol), and anhydrous potassium carbonate powder (414 mg, 3.3 mmol) are added to 10 ml and react at reflux for 24 hours. The reaction solution is evaporated to dryness and dispersed with 20 ml of dichloromethane and 20 ml of water respectively. The organic layer is extracted with water (20 ml×2) and saturated saline (20 ml) successively, dried over anhydrous magnesium sulfate, and evaporated to dryness to obtain a light yellow powder. The powder is dissolved with 5 ml of acetone and stirred in an ice bath. A white solid precipitates and is filtered, washed with small amount of acetone, and dried to obtain 260 mg of a whiter powder. The powder is dissolved in anhydrous ethanol and then thereto is drop-added HCl/EtOH to adjust to pH=2. A white deposit precipitates and is filtered out and recrystallized in anhydrous ethanol to obtain 200 mg of a product, with a yield of 42%.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[C:13]([C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14].[NH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][C:42]2[CH:47]=[CH:46][N:45]=[C:44]([NH:48][C:49]([N:51]3[CH2:55][CH2:54][CH2:53][CH2:52]3)=[O:50])[CH:43]=2)=[CH:33][CH:32]=1>C(Cl)Cl>[C:13]([C:17]1[CH:21]=[C:20]([NH:22][C:6](=[O:7])[NH:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([O:41][C:42]3[CH:47]=[CH:46][N:45]=[C:44]([NH:48][C:49]([N:51]4[CH2:55][CH2:54][CH2:53][CH2:52]4)=[O:50])[CH:43]=3)=[CH:33][CH:32]=2)[N:19]([C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)c2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(NC(=O)N4CCCC4)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of Intermediate K2 (110 mg, 0.29 mmol) in MeOH (20 mL) containing AcOH (4 drops) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 25° C., 70 mm 10% Pt/C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo. The crude product was partitioned between DCM (20 mL) and aqueous NaHCO3 (10 mL) and the organic layer was washed with brine (10 mL) and evaporated in vacuo to afford N-(4-(4-aminonaphthalen-1-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide as a brown solid (680 mg, 66%); Rt 1.43 min (Method 2); m/z 349 (M+H)+ (ES+), which was used directly in the next step. To a solution of CDI (100 mg, 0.197 mmol) in dry DCM (1.0 mL) was added 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (85 mg, 0.370 mmol), portionwise, over 20 min and the resulting solution maintained at RT for 16 hr. A portion of this solution (0.6 mL) was added to a solution of N-(4-(4-aminonaphthalen-1-yloxy)pyridin-2-yl)pyrrolidine-1-carboxamide (680 g, 0.255 mmol) in DCM (1.0 mL) and the mixture maintained at RT for 18 hr. The reaction was quenched by the addition of MeOH (2.0 mL) and the resulting mixture was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 4 g, [5% MeOH in DCM] in DCM, 0-100%, gradient elution) to afford the title compound, Example 55, as a yellow brown solid (29 mg, 24%); Rt 5.00 min (Method 1 basic); m/z 604 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.28 (9H, s), 1.78 (4H, m), 2.39 (3H, s), 3.30 (4H, m, partially obscured by HOD peak), 6.40 (1H, s), 6.60 (1H, dd), 7.30 (1H, d), 7.37 (2H, d), 7.45-7.47 (3H, overlapping m), 7.56 (1H, m), 7.64 (1H, m), 7.84 (1H, d), 7.95 (1H, d), 8.07 (1H, d), 8.09 (1H, d), 8.63 (1H, s), 8.77 (1H, s), 9.10 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[B:9]1(B2OC(C)(C)C(C)(C)O2)[O:13]C(C)(C)C(C)(C)[O:10]1>[Ir+].ClC1CCC=CCCC=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([B:9]([OH:13])[OH:10])[CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Clc1cccc(Cl)n1
Agent: [Ir+]
Agent: ClC1=CCCC=CCC1
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: ClCCCl
Product: OB(O)c1cc(Cl)nc(Cl)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 82.2 %

Procedure:
To a mixture of 2,6-dichloropyridine (3.28 g, 22.2 mmol) and bis(pinacolato)diboron (6.2 g, 24.4 mmol) was added 1,10-phenanthroline (0.24 g, 1.3 mmol) and chloro-1,5-cyclooctadiene iridium (I) dimer (0.44 g, 0.66 mmol) under nitrogen followed by anhydrous 1,2-dichloroethane. Nitrogen was bubbled through the mixture for 5 minutes and the reaction was then heated with stirring at 100° C. for 15 hours under an atmosphere of nitrogen. The mixture was allowed to cool to room temperature, poured onto diethylether/4N sodium hydroxide (50 ml 200 ml) and the phases separated. The aqueous phase was acidified with 6N hydrochloric acid and the resulting solid was filtered, washed with water and dried on the sinter to yield the pinacol ester of 2,6-dichloropyridin-4-ylboronic acid (3.5 g, 58%) as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([O:8][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:7]=1
Reactant: CC(=O)c1ncc(O)cc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ncc(OCC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
To 1.0 g of 1-(3-chloro-5-hydroxypyridin-2-yl)ethanone in 15 ml of N,N-dimethylformamide, 1.2 g of potassium carbonate and 1.6 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate were added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was mixed with 40 ml of water and extracted with ethyl acetate (50 ml×1), the resulting organic layer was washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 1.2 g of the desired product as white crystals.