Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C[CH:13]([S:17][CH:18](S(C)=O)C)[S:14]([CH3:16])=[O:15].CO>C1COCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[C:13](/[S:14]([CH3:16])=[O:15])\[S:17][CH3:18]
Reactant: CC(SC(C)S(C)=O)S(C)=O
Reactant: COc1cccc(C=O)c1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(/C=C(\SC)S(C)=O)c1Cl

Procedure:
To a solution of 2-chloro-3-methoxybenzaldehyde (1.74 g, 10.0 mmol, 1.0 eq.) and methyl(methylsulfinyl)methyl sulfide (1.72 mL, 16.1 mmol, 1.6 eq.) in THF (9 mL), benzyltrimethylammonium hydroxide solution in methanol (2.3 mL, 10.0 mmol, 1.0 eq.) was added. The resulting solution was refluxed for 18 hours. The solvent was removed in vacuo. The residue was taken up in AcOEt and washed with 1M aq. HCl soln., water, and sat. aq. NaCl soln. The org. layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane+20% AcOEt to Heptane+65% AcOEt) to yield 2-chloro-1-((E)-2-methanesulfinyl-2-methylsulfanyl-vinyl)-3-methoxy-benzene as a pale orange oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.Cl.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17]2[N:18]([CH2:31][CH2:32][CH3:33])[N:19]=[C:20]3[C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=[C:21]3[NH2:30])[CH2:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][NH:16][C:17]2[N:18]([CH2:31][CH2:32][CH3:33])[N:19]=[C:20]3[C:29]=2[C:28]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=[C:21]3[NH2:30])[CH2:12][CH2:13]1)(=[O:4])=[O:3]
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.7 %

Procedure:
Methanesulfonyl chloride (0.30 g, 0.20 mL, 2.58 mmol) was added to a stirring suspension of N1-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine dihydrochloride (1.0 g, 2.35 mmol) and triethylamine (0.59 g, 0.82 mL, 5.88 mmol) in dichloromethane (10 mL). The resulting suspension was stirred at ambient temperature 16 hours. Additional dichloromethane (90 mL), triethylamine (4.2 g, 5.7 mL, 41.1 mmol) and methanesulfonyl chloride (0.19 g, 0.13 mL, 1.66 mmol) were added to the mixture and the resulting cloudy suspension was stirred at ambient temperature 3 days. The reaction mixture was concentrated and the resulting brown solid was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 5-20% methanol in dichloromethane). The resulting oil was crystallized from acetonitrile and isolated by filtration to yield 169 mg of N1-{2-[1-(methylsulfonyl)piperidin-4-yl]ethyl}-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine as an off-white solid, mp 204-207° C. Anal. calcd for C21H30N6O2S: C, 58.58; H, 7.02; N, 19.52. Found: C, 58.77; H, 6.92; N, 19.54.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:33]=[CH:32][C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:31])=[C:20]3[C:24]=2[N:23]([CH3:25])[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21]3)=[CH:12][CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][C:10]1[CH:33]=[CH:32][C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:31])=[C:20]3[C:24]=2[N:23]([CH3:25])[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21]3)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccc(CNC(=O)OC(C)(C)C)cc3)c2n1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(Cl)ccc(OCc3ccc(CN)cc3)c2n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
A mixture of 0.75 g (1.59 mmol) of ethyl 7-[4-(tert-butoxycarbonylaminomethyl)benzyloxy]-4-chloro-1-methyl-2-indolecarboxylate, 5 ml of trifluoroacetic acid and 50 ml of dichloromethane was stirred at 0° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. Thereafter ice water was poured onto the resulting residue and 28% aqueous ammonia was added thereto to render alkaline (pH=9 to 10). The mixture was then extracted three times with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 0.60 g (>99%) of ethyl 7-[4-(aminomethyl)benzyloxy]-4-chloro-1-methyl-2-indolecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:9](F)(F)F)[CH:5]=[CH:6][C:7]=1[F:8].[Al+3].[Cl-:15].[Cl-:16].[Cl-:17]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:9]([Cl:17])([Cl:16])[Cl:15])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [Cl-]
Reactant: Fc1ccc(C(F)(F)F)c(F)c1Cl
Agent: [Al+3]
Solvent: ClCCl
Product: Fc1ccc(C(Cl)(Cl)Cl)c(F)c1Cl
Temperature: 42 °C
Yield: 86.9 %

Procedure:
216.5 g of 3-chloro-2,4-difluoro-benzotrifluoride in 440 ml of methylene chloride are initially introduced into a stirred apparatus, and 150 g of AlCl3 are introduced in small portions. The reaction is slightly exothermic. When the addition has ended, the mixture is heated under reflux (42° C.) for 2 hours, cooled and poured onto 1 l of ice-water. After intensive thorough mixing, the mixture is filtered over a suction filter and the organic phase is then separated off. After drying, the methylene chloride phase is distilled. 231 g of 3-chloro-2,4-difluoro-benzotrichloride with a boiling range of 124-126° C./18 mbar are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][CH2:16][C:17]([NH2:19])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22](=O)[CH2:23][CH3:24].C(=O)([O-])O.[Na+].CCCCCC>CC(CC)=O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([CH:21]=[C:22]([CH2:23][CH3:24])[C:15]=2[CH2:16][C:17]([NH2:19])=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)CBr
Reactant: NC(=O)CCc1ncccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCCCCC
Product: CCc1cn2cccc(OCc3ccccc3)c2c1CC(N)=O
Yield: 48.2 %

Procedure:
A mixture of the pyridine derivative (16, 4.00 g, 15.6 m mol), 1-bromo-2-butanone (3.53 g, 23.4 m mol) and sodium hydrogencarbonate (6.55 g, 78 m mol) in methylethylketone (30 ml) was heated under reflux for 60 hours. The solid was filtered off. The volatile materials were removed by distillation under reduced pressure. The residue was chromatographed on silica gel eluting with hexane:ethyl acetate (1:2) and with ethyl acetate. The first fraction was crystallized from benzene:hexane to give 2.32 g (48.2% yield) of the titled compound 17b and, mp, 117-119° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=1.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>CS(C)=O.CCOCC>[Br:20][C:21]1[CH:26]=[CH:25][C:24]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)=[CH:23][CH:22]=1
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Reactant: Fc1ccc(Br)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCN(CC)CCCCOc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
260 mg (1 mmol) Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine in 2 ml DMSO were treated with 175 mg (1 mmol) 1-bromo-4-fluorobenzene and 26.4 mg (0.1 mmol) 18-crown-6 and 182 mg (1 mmol) KF on alox. The suspension was stirred at 120° C. for 2 h, additional 175 mg (1 mmol) 1-bromo-4-fluorobenzene, 26.4 mg (0.1 mmol) 18-crown-6 and 182 mg (1 mmol) KF on alox were added. The suspension was stirred for 1 h, cooled to RT and diluted with ether and filtered. The solution was washed with 1M NaOH and water, and dried over Na2SO4. Column chromatography on silica gel with CH2Cl2/MeOH 4:1 yielded 205 mg (48%) {4-[1-(4-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine as light yellow oil, MS: 415 (MH+, 1Br). (analogously to William J. Smith III, J. Scott Sawyer, Tetrahedron Letters 1999, Vol.37, No.3, 299-302.)
Reaction SMILES: C(O[C:4](=[O:30])[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:10]([C:24]2[N:25]=[N:26][N:27]([CH3:29])[N:28]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[CH3:29][N:27]1[N:26]=[N:25][C:24]([CH:10]2[CH2:9][CH:8]([C:6]3[O:7][NH:33][C:4](=[O:30])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[N:28]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnn(C)n2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nnc(C2CC(c3cc(=O)[nH]o3)CCN2C(=O)OCc2ccccc2)n1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 70.9 %

Procedure:
Benzyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-2H-tetrazol-5-yl)piperidine-1-carboxylate (0.499 g, 1.20 mmol) was dissolved in MeOH (6 mL) and cooled to −40° C. 3.8 M NaOH (0.316 mL, 1.20 mmol) dissolved in water (0.6 mL) was added and the reaction stirred at −40° C. for 40 min. Hydroxylamine (50% by weight in water, 0.074 mL, 1.20 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a preheated 80° C. solution of 6 M HCl (6.01 mL, 36.03 mmol) and stirred for 20 min. The reaction mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM and the combined organic phase was dried and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Benzyl 2-(2-methyl-2H-tetrazol-5-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (327 mg, 71%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.96-2.15 (m, 2H), 2.41 (dt, 1H), 2.64-2.74 (m, 1H), 3.12-3.19 (m, 1H), 3.61-3.72 (m, 1H), 4.07-4.20 (m, 4H), 5.13 (s, 2H), 5.43 (s, 1H), 5.58-5.64 (m, 1H), 7.25-7.41 (m, 5H). MS m/z 385 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH:22][CH2:23][CH2:24][CH3:25]>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:22]([CH3:21])[CH2:23][CH2:24][CH3:25])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Reactant: CCCNC
Solvent: CS(C)=O
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N-methyl-propylamine (3.72 ml, 34.7 mmol) in DMSO (20 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.75 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[C:19]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[Cl:1])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc([N+](=O)[O-])cc1Cl)c1ccccc1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
A mixture of 2-chloro-4-nitroaniline (15.0 g, 86.9 mmol), triethylamine (13.3 ml, 95.6 mmol) and benzoyl chloride (11.1 ml, 95.6 mmol) were heated in toluene (200 ml) at reflux for 2 hours under an inert atmosphere. The reaction was allowed to cool to ambient temperature overnight, causing precipitation of a white solid. The solid was collected by suction filtration, washed with toluene (3×50 ml) and dried in vacuo. The crude product was taken up in dichloromethane (300 ml) and washed with 2.0 N aqueous hydrochloric acid (3×100 ml), water (100 ml), saturated aqueous sodium bicarbonate solution (3×100 ml) and water (100 ml). Drying of the organic layer over magnesium sulphate, followed by solvent evaporation in vacuo, yielded N-benzoyl 2-chloro-4-nitroaniline (6.83 g, 28% yield) as a yellow crystalline solid:
Reaction SMILES: [Br-].[Br-].[Br-].B.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:17])=[CH:9][CH:8]=1.CO>C(Cl)Cl>[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][N:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:24])[C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)C(=O)N(c1cnccc1C)CC2
Agent: B
Agent: [Br-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccncc1N1CCc2ccc(O)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
1M solution of boran tri-bromide in DCM (0.839 mL, 0.839 mmol) was added to a stirred solution of 7-methoxy-2-(4-methyl-pyridin-3-yl)-3,4-dihydro-2H-isoquinolin-1-one (26A: 90 mg, 0.335 mmol) in DCM (3 mL) at 0° C. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (5% methanol in DCM). The reaction mixture was quenched with chilled water and extracted with DCM. The organic layer was washed with NaHCO3 solution, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (3% methanol in DCM) afforded 40 mg of the product (47% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH2:9][CH3:10].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:21]([CH2:23][CH2:24][N:25]3[CH2:28][CH:27]([F:29])[CH2:26]3)[CH:22]=2)=[CH:14][C:13]=1[C:36]([F:39])([F:38])[F:37].CCN(C(C)C)C(C)C>CS(C)=O>[CH2:9]([C:3]1[C:4]([NH2:8])=[N:5][CH:6]=[N:7][C:2]=1[N:33]1[CH2:32][CH2:31][CH:30]([C:20]2[N:21]([CH2:23][CH2:24][N:25]3[CH2:28][CH:27]([F:29])[CH2:26]3)[CH:22]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[C:13]([C:36]([F:39])([F:37])[F:38])[CH:14]=3)[N:19]=2)[CH2:35][CH2:34]1)[CH3:10]
Reactant: CCc1c(N)ncnc1Cl
Reactant: Fc1ccc(-c2cn(CCN3CC(F)C3)c(C3CCNCC3)n2)cc1C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CC(F)C2)CC1
Reaction time: 1 h
Yield: 19.3 %

Procedure:
The reaction mixture of 6-chloro-5-ethyl-pyrimidin-4-ylamine (50.00 mg; 0.32 mmol; 1.00 eq.), 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine (138.05 mg; 0.33 mmol; 1.05 eq.) and DIEA (65.77 mg; 0.48 mmol; 1.50 eq.) in DMSO (1.5 ml) was placed in microwave at 125° C. for 1 hr. found small amount desired, mostly was sm, 140° C. for another 1 hr, more product formed, 150° C. for another 1 hr, purified the product by HPLC, collected title compound 33 mg, yield 16%. LC-MS (M+1=536, obsd.=536).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9](Br)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([F:34])[C:26]=1[O:35][CH3:36].[F-].[Cs+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([O:35][CH3:36])[C:27]=2[F:34])[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(Br)cc(NC(C)=O)c1OCc1ccccc1
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1OCc1ccccc1
Temperature: 100 °C

Procedure:
Methyl 4-acetamido-3-(benzyloxy)-6-bromopicolinate (prepared as in Kong, L. C. C. et al. U.S. Patent Application Publication 2005/0176767; 1.5 g, 4.0 mmol), (4-chloro-2-fluoro-3-methoxyphenyl)boronic acid (1.2 g, 5.9 mmol), bis(triphenylphosphine)-palladium(II) dichloride (PdCl2(PPh3)2; 278 mg, 0.4 mmol), cesium fluoride (CsF; 1.2 g, 7.9 mmol), 1,2-dimethoxyethane (DME; 7 mL), and H2O (7 mL) were combined and heated in a Biotage microwave at 100° C. for 15 min. H2O was added to the reaction mixture, and the product was extracted with EtOAc. The combined organic extracts were washed with satd aq NaCl, dried with sodium sulfate (Na2SO4), filtered and concentrated. Flash chromatography (SiO2; 0-45% EtOAc/cyclohexane gradient) afforded methyl 4-acetamido-3-(benzyloxy)-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate as a yellow solid: mp 115-120° C.; 1H NMR (400 MHz, CDCl3) δ 8.87 (d, J=1.6 Hz, 1H), 7.66 (s, 1H), 7.59 (dd, J=8.5, 7.7 Hz, 1H), 7.45 (s, 5H), 7.24 (dd, J=8.6, 1.7 Hz, 1H), 5.13 (s, 2H), 4.03 (s, 3H), 3.99 (d, J=1.0 Hz, 3H), 1.88 (s, 3H); ESIMS m/z 459 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:6][C:7]([O:9][CH:10](Cl)[CH3:11])=[O:8])[CH2:3][CH2:4][CH3:5].[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O-:36])=[O:35])=[C:21]([C:24]3[S:28][C:27]4=[C:29]([S:32][CH3:33])[N:30]=[CH:31][N:26]4[CH:25]=3)[C@H:22]([CH3:23])[C@H:18]12)[CH3:16].[Na+].O>CN(C=O)C.[Ag]I>[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O:36][CH:10]([O:9][C:7]([O:6][C:2]([CH3:13])([CH3:1])[CH2:3][CH2:4][CH3:5])=[O:8])[CH3:11])=[O:35])=[C:21]([C:24]3[S:28][C:27]4=[C:29]([S:32][CH3:33])[N:30]=[CH:31][N:26]4[CH:25]=3)[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: CSc1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: CCCC(C)(C)OC(=O)OC(C)Cl
Agent: [Ag]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(C)(C)OC(=O)OC(C)OC(=O)C1=C(c2cn3cnc(SC)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
A solution of 156.6 mg of 1-(1,1-dimethyl-1-butyloxycarbonyloxy)ethyl chloride in 2.0 ml of DMF was added to a suspension of 176.1 mg of silver iodide in 2.0 ml of DMF. The mixture was stirred in an argon atmosphere at room temperature for one hr. A solution of 200.0 mg of sodium(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate in 1.0 ml of DMF was added thereto, followed by stirring for 3 hr. Water (10 ml) was added to the reaction solution to terminate the reaction. The system was extracted three times with 10 ml of ethyl acetate, followed by washing three times with 30 ml of semisaturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue was purified by chromatography on silica gel (chloroform:methanol=20:1) to give 82.3 mg of the title compound.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[N+]=[N-].[H][H]>[Pd].CO>[NH2:1][CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC1CN(Cc2ccccc2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: NC[C@@H]1CN(Cc2ccccc2)C(=O)O1
Yield: 84.6 %

Procedure:
A 40 ml vial was charged with 5-(azidomethyl)-3-benzyl-1,3-oxazolidin-2-one (100 mg, 0.43 mmol, INTERMEDIATE 14), palladium on carbon (5 mg), and methanol (15 ml). The reduction was effected using a balloon filled with hydrogen at room temperature overnight. The catalyst was removed through filtration on a pad of Celite pre-rinsed with methanol. The Celite pad was further rinsed with methanol (2×5 ml) and the eluent concentrated in vacuo to provide 75 mg (85%) of the title compound. Mass spectrum (ESI) 207.2 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3ccnc3)nc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
A mixture of 0.31 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.14 g of imidazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at room temperature for 1.5 hours, and then at 60° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.31 g of 2-[3-(imidazole-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 56”).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Br:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cc2c(cc1Br)C(C)CNCC2
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1-methyl-2,3,4,5tetrahydro-1H-3-benzazepine (1.18 g, 3.00 mmol) in methanol (35 mL) was treated with 15% aqueous NaOH (35 mL), and stirred overnight at 20 C. The product mixture was diluted with water (200 mL), extracted twice with EtOAc (200 mL), the combined organic phases were washed with brine (100 mL), dried with Na2SO4 and concentrated to give 0.880 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.29 (s, 1 H), 6.63 (s, 1 H), 6.04 (m, 1 H), 5.47 (d, J=17 Hz, 1 H), 5.29 (d, J=11 Hz, 1 H), 4.58 (s, 2 H), 3.01 (m, 3 H), 2.89 (m, 3 H), 2.75 (m, 1 H), 1.31 (d, J=7 Hz, 3 H). MS calculated for C14H18BrNO+H: 296, observed: 296.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)=[C:12]([CH3:19])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]3[N:15]=[CH:16][N:17]([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:18]=3)=[C:12]([CH3:19])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1-c1c[nH]cn1
Reactant: Clc1ncccn1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1-c1cn(-c2ncccn2)cn1
Yield: 47 %

Procedure:
As described for Example 53, 3-(3,4-difluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (78 mg, 0.3 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (48 mg, 47%) which was obtained as an off-white solid. MS: m/e=406.3 [M+H]+.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=2)[C:10]#[N:11])=[CH:4][CH:3]=1.C[Sn](C)(C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1.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>[F:15][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([C:5]2[O:6][C:2]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:3][CH:4]=2)[CH:14]=1)[C:10]#[N:11]
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: N#Cc1cc(F)cc(-c2ccc(Br)o2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)cc(-c2ccc(-c3ccccn3)o2)c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 43.4 %

Procedure:
Pd(PPh3)4 (10 mg, 0.009 mmol) was added to a solution of 3-(5-bromofuran-2-yl)-5-fluoro-benzonitrile (180 mg, 86% purity, 0.59 mmol) and 2-trimethylstannylpyridine (193 mg, 0.80 mmol) in toluene (2.5 mL) under argon. The resulting solution was stirred at 110° C. for 48 h. After cooling to room temperature, the solvent was removed in vacuo. Flash chromatography (silica gel, 35-100% dichloromethane in hexane) afforded 67.7 mg (43%) of 3-fluoro-5-(5-(2-pyridyl)-2-furyl)-benzonitrile. 1H-NMR (CDCl3), δ (ppm): 8.64 (d, 1H), 7.76-7.83 (m, 3H), 7.66 (m, 1H), 7.24 (m, 2H), 7.19 (d, 1H), 6.92 (d, 1H).