Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:17]([O-])=O.C(O)C>[Pd].O1CCCC1>[O:2]=[C:3]1[CH2:4][CH2:5][C:6]2[C:7](=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=2)[NH:17]1
Reactant: CCOC(=O)c1ccc(/C=C/C(=O)OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a mixture of 1.8 g of ethyl 4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-3-nitrobenzoate, 32 ml of ethanol and 32 ml of tetrahydrofuran was added 640 mg of 10% palladium/carbon under an argon atmosphere, followed by 2 hours of stirring at room temperature under a hydrogen atmosphere. The reaction solution was filtrated through celite and the organic solvent in the filtrate was removed under reduced pressure. To the residue were added 50 ml of methanol and 2 drops of concentrated hydrochloric acid, followed by 30 minutes of stirring at 60° C. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and water and chloroform were added to the residue, followed by an analytical operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 1.16 g of ethyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate as a white solid.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22](#[N:25])[CH:23]=[CH2:24].C(N(CC)CC)C>O1CCOCC1>[CH2:2]([N:9]1[C@@H:14]2[C@H:23]([C:22]#[N:25])[CH2:24][C@@:10]1([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:15])[CH:12]=[CH:13]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc[n+](Cc2ccccc2)c1-c1ccccc1
Reactant: C=CC#N
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#C[C@@H]1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Yield: 24 %

Procedure:
N-benzyl-3-hydroxy-2-phenylpyridinium bromide (20 g, 58.3 mmol), acrylonitrile (50 ml, 755 mmol) and triethylamine (20 ml, 143 mmol) were mixed and stirred at reflux for 20 hours in 1,4-dioxane (150 ml). The mixture was partitioned between saturated sodium hydrogen carbonate and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated. The residue was chromatographed on silica gel eluting with 25, 35 and 45% diethyl ether/iso-hexanes to yield the title compound (4.4 g, 24%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Cl[CH2:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=1>>[C:23]1([C:20]2[CH:19]=[C:18]([CH2:17][N:7]3[C:8]4[C:4](=[C:3]([C:2]([F:14])([F:1])[F:15])[C:11]([C:12]#[N:13])=[CH:10][CH:9]=4)[CH:5]=[CH:6]3)[O:22][N:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: ClCc1cc(-c2ccccc2)no1
Product: N#Cc1ccc2c(ccn2Cc2cc(-c3ccccc3)no2)c1C(F)(F)F

Procedure:
Synthesized in a manner similar to Example 23 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-(chloromethyl)-3-phenylisoxazole: MS (ES) m/z 368 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(O[N:13]([CH2:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[C:20]=2[N:19]=1)[CH:14]=C=O)(C)(C)C>C(Cl)Cl>[CH3:14][NH:13][CH2:17][C:18]1[NH:19][C:20]2[C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: COC(=O)c1cccc2[nH]c(CN(C=C=O)OC(C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1nc2cccc(C(=O)OC)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (15 ml) was added to a cooled solution (0° C.) of methyl 2-((tert-butoxy-carbonyl(methyl)amino)methyl)-1H-benzo[d]imidazole-4-carboxylate (12.54 mmol) in methylene chloride (60 ml) and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated off completely, in vacuo, and the residue was co-distilled 2× with methylene chloride and employed in the next stage.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:20][C:21]([O:23]CC)=O)[CH2:12][CH2:13][C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH:17]1([NH:16][C:14]([CH:13]2[C:21](=[O:23])[CH2:20][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12]2)=[O:15])[CH2:19][CH2:18]1
Reactant: CCOC(=O)CN(CCC(=O)NC1CC1)C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CN(C(=O)OCc2ccccc2)CC1C(=O)NC1CC1
Reaction time: 2 h

Procedure:
To a solution of ethyl N-benzyloxycarbonyl-N-{(2-cyclopropylaminocarbonyl)ethyl}aminoacetate (200 mg, 0.574 mmol) in toluene (2.0 mL) was added potassium tert-butoxide (136 mg, 1.21 mmol) as a base at an outer temperature set of 40° C., followed by stirring for 2 hours. Then, the HPLC measurement of this reaction mixture was carried out. The results are shown in Table 5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28]Cl)[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][N:30]=[N+:31]=[N-:32])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CCl)c2)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CN=[N+]=[N-])c2)c1

Procedure:
3-[2-[5-[[1-(tert-Butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]ethyl]phenylmethyl chloride is dissolved in DMF, and sodium azide (1-4 equiv.) is added. The reaction mixture is stirred with exclusion of moisture at ambient or elevated temperature until all starting material has been converted. The solvent is then distilled into a cooled receiver in an oil pump vacuum at a bath temperature of up to 40° C. (caution should be observed not to exceed this temperature, as organic azides may explode upon heating). The residue is diluted with EtOAc and water, and the phases are separated. The organic phase is washed with brine, dried over MgSO4, and evaporated, and the residue is chromatographed on silica gel with EtOAc or a mixture of EtOAc with a nonpolar solvent. Evaporation of the product-containing fractions and drying yields the azide. Before the subsequent step, the azide is preferably evaporated with toluene to remove residual EtOAc, which may react with the amine to be prepared. In order to obtain the following intermediate directly in a form that does not require further purification, it may be convenient to further purify the azide by preparative HPLC (for example, acetonitrile/water gradient on C18).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[C:9]3[N:10]([C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH2:3]1.[OH-].[Li+].Cl>C1COCC1.CO>[F:24][C:2]1([F:1])[CH2:5][CH:4]([CH2:6][O:7][C:8]2[C:9]3[N:10]([C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH2:3]1
Reactant: CCOC(=O)c1c(C)nc2c(OCC3CC(F)(F)C3)cc(C)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCC2CC(F)(F)C2)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.39 g (7.06 mmol) of ethyl 8-[(3,3-difluorocyclobutyl)methoxy]-2,6-dimethylimidazo[1,2-a]-pyridine-3-carboxylate Example 106A were dissolved in 151 ml of THF/methanol (5:1), 35.3 ml (35.3 mmol) of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at RT for 2 d. The reaction mixture was acidified with 1 N aqueous hydrochloric acid solution to pH 4 and concentrated. The solid was filtered off, washed with water and dried under high vacuum. This gave 1.63 g (71% of theory; purity 95%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:6]2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(F)cc23)CC1
Product: CN1CCC(c2cn(C(=O)c3ccc(F)cc3)c3ccc(F)cc23)CC1

Procedure:
(25.1 mg, 71%); from 5-fluoro-3-(1-methyl-4-piperidinyl)-1H-indole (Example 5c, 23.0 mg, 0.10 mmol) and 4-fluorobenzoyl chloride (23.8 mg, 0.15 mmol), HRMS-FAB+ for C21H20N2OF2, calculated MH+ : 355.16220; found: 355.16313.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH:34]([C:37]([N:14]2[CH2:13][C@@H:12]([N:10]([C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:24])[CH3:11])[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15]2)=[O:38])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)C2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound 3-{(3R,4S)-3-(4-chloro-phenyl)-4-[(4-fluoro-phenoxycarbonyl)-methyl-amino]-pyrrolidine-1-carbonyl}-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using rac-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a light yellow oil. MS m/e: 546.2 [M]+.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1.[CH3:18]O>>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:6]=1
Reactant: CO
Reactant: O=C(O)c1ccnc2ccccc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccnc2ccccc12
Temperature: -2.5 °C
Yield: 42 %

Procedure:
Thionyl chloride (4.5 ml) was added dropwise, under argon to a cooled, stirring slurry of 4-quinolinecarboxylic acid (5.32 g) in methanol (120 ml) maintaining an internal temperature of 0 to −5° C. Once addition was complete the reaction mixture was heated at reflux for 16 h. After cooling to ambient temperature the volatiles were removed at reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate and diethyl ether. The organic phase was washed with brine, dried (Na2SO4) and the solvent removed at reduced pressure to give the title compound as a pale yellow oil (4.82 g).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13]Cl)[CH:10]=2)[NH:5][CH:4]=1)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][N:15]=[N+:16]=[N-:17])[CH:10]=2)[NH:5][CH:4]=1)#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1c[nH]c2ccc(CCCl)cc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2ccc(CCN=[N+]=[N-])cc12
Temperature: 80 °C
Yield: 95.4 %

Procedure:
A mixture of 1.92 g (9.38 mmol) 3-cyano-5-(2-chloroethyl)indole (reference example 4) and 1.53 g (23.5 mmol) sodium azide in 10 mL DMF is heated to 80° C. for three hours, followed by azeotroping with toluene. The resulting residue is chromatographed (2:1 hexane:ethyl acetate) to provide 1.89 g of the product as a brown solid in 95% yield. 1H NMR (CDCl3): δ 3.03 (2H, t, J=7.1 Hz), 3.57 (2H, t, J=7 Hz), 7.20 (1H, dd, J=8, 1 Hz), 7.43 (1H, d, J=8 Hz), 7.62 (1H, s), 7.73 (1H, d, J=3 Hz), 8.81 (1H, br). MS (ion spray) m/z 212 (M+H)+, 169 (M−N3)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[N:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[C:13]([CH:14]=[CH:15][CH:16]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:4]=1
Reactant: Brc1ccncc1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cccc(-c2ccncc2)c1
Yield: 84.6 %

Procedure:
Part A. A solution of 4-bromopyridine (1.0 g, 5.2 mmol) in acetonitrile-water (10 mL/5 mL) is treated with 3-carboethoxybenzeneboronic acid (0.93 g, 5.2 mmol), sodium carbonate (2.2 g, 21 mmol) and catalytic tetrakis(triphenylphosphine)palladium. The solution is heated to reflux for 12 h., then cooled and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, filtered and evaporated. The residual material is separated by flash chromatography to afford ethyl 3-pyridin-4-yl-benzoate (1.0 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13][C:14]#N)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:19]>C(OCC)C.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>[C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13][CH:14]=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H](CC#N)S1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](CC=O)S1
Reaction time: 2 h

Procedure:
To a stirred solution of trans-5-tert-butoxycarbonyl-2-cyanomethyltetrahydrothiophene (2.3 g) in diethylether (100 ml), 1M diisobutyl-aluminiumhydride dissolved in hexane (12.1 ml) is added at -30° C. and the mixture is stirred for 2 hours at -20°--10° C. 10% aqueous citric acid solution is added to the mixture and extracted with ethyl acetate - benzene (1:1). The organic layer is washed with 10% aqueous citric acid solution, water and saturated sodium chloride solution. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give trans-5-tert-butoxycarbonyl-2-formylmethyltetrahydrothiophene.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(OCCOc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCOc2ccc(N)cc2)cc1
Reaction time: 6 h

Procedure:
68.4 g (0.22 M) of methyl 4-[2-(4-nitrophenoxy)ethoxy]benzoate and 1.3 g of palladium-on-charcoal are added to a mixture of 800 ml of methanol and 200 ml of tetrahydrofuran in a 2000 ml reactor, and the mixture is then maintained under ambient pressure of hydrogen at 60° C. with vigorous stirring for 6 hours.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].C(#N)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:3]=[C:2]=[S:1])=[O:17])=[CH:11][CH:10]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(F)cc1)N=C=S
Temperature: 60 °C
Reaction time: 2 h

Procedure:
After adding potassium thiocyanate (65.3 mg) and acetonitrile (4 ml) to 2-(4-fluorophenyl)acetyl chloride (58 mg) under a nitrogen atmosphere, the mixture was stirred for 2 hours at 60° C. The reaction mixture was cooled to room temperature, and then ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture and stirring was continued for 30 minutes. After partitioning the reaction mixture, the separated organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to provide a crude product of 2-(4-fluorophenyl)acetyl isothiocyanate as a yellow oil. After dissolving 4-(azetidin-1-yl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (70 mg) in ethanol (2 ml), D-10-camphorsulfonic acid (43 mg) was added and the mixture was stirred for 5 minutes under a nitrogen atmosphere. Then, 2-(4-fluorophenyl)acetyl isothiocyanate-acetonitrile (0.5 ml×3) was added and the mixture was stirred for 2 hours. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5), and then fractions containing the target compound were concentrated under reduced pressure. Diethyl ether (0.5 ml) and hexane (4 ml) were added to the resultant residue to produce a suspension of the solid. After filtering the solid, it was subjected to aeration drying to provide the title compound (36.9 mg, 37.8%) as white powder.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1)#[N:2].[NH2:15][OH:16]>CCO>[NH2:2][C:1](=[N:15][OH:16])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH3:14])[CH:4]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C#N)cc1OC
Solvent: CCO
Product: COC(=O)c1ccc(C(N)=NO)cc1OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of methyl 4-cyano-2-methoxybenzoate, obtained in step 1 (155 mg; 0.81 mmol; 1 eq.) in EtOH (1.55 mL) was added hydroxylamine (50% in water) (0.24 mL; 4.05 mmol; 5 eq.). The reaction mixture was stirred at 60° C. for 60 min. Solvents were removed to dryness, to afford the title compound as a yellow powder. 1H NMR (DMSO-d6, 400 MHz) δ 10.62 (br s, 1H), 9.85 (s, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.40 (s, 1H), 7.35-7.31 (m, 2H), 5.95 (br s, 2H), 3.85 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CC(C)=O>[N:10]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)=[N+:11]=[N-:12]
Reactant: Clc1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCc1ccc(Cl)cc1

Procedure:
A solution of 4-chlorobenzyl bromide in acetone was treated with NaN3 and refluxed for 3 hours. The reactions was concentrated by 50% and diluted with saturated sodium chloride solution. The reaction was then extracted with Et2O, washed with brine, dried (Na2SO4) and concentrated to give 1-(azidomethyl)-4-chlorobenzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]=[CH:9][CH:10]2[C:15](=[O:16])OC(C)(C)OC2=O)[CH:5]=[N:6][CH:7]=1.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:15]([OH:16])=[CH:10][CH:9]=[N:8]2)=[N:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(C=Nc2cncc(Br)c2)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Oc1ccnc2cc(Br)cnc12
Temperature: 236.5 °C
Yield: 76 %

Procedure:
5-{[(5-Bromopyridin-3-yl)imino]methyl}-2,2-dimethyl-1,3-dioxane-4,6-dione (59 g, 0.18 mol) was slowly added to DOWTHERM A heat transfer fluid (2000 mL) over a period of 5 minutes at 235-238° C. Following addition, the reaction was maintained for an additional 5 minutes and then allowed to cool to 40° C. A brown precipitate formed, which was filtered and washed with hexanes (150 mL). The brown solid was suspended in an ethanol/water mixture (90:10, 1500 mL), heated to a boil for 30 minutes, isolated by filtration, and washed with ethanol (200 mL) to yield 30.8 g of 7-bromo[1,5]naphthyridin-4-ol as a dark brown powder. 1H NMR (300 MHz, CDCl3) δ 11.81 (br s, 1H), 8.69 (d, J=1.9 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.95 (d, J=7.7 Hz, 1H), 6.22 (d, J=7.5 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11](Cl)[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:30][CH2:31][N:32]([C:11]2[C:12]([F:17])=[CH:13][N:14]3[C:9]([C:10]=2[CH3:19])=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:33][CH2:34]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CC#N
Product: Cc1c(N2CCN(c3ccccn3)CC2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12

Procedure:
A 60 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with 4-(2-pyridyl)piperazine (63.5 mg, 0.39 mmol, Aldrich Chem. Co.), and carried forward as described in Example 253j-k to give the title product. MS 423 (M+H)+ ; 1H NMR (CDCl3) ∂: 0.71 (m, 2H), 1.05 (m, 2H), 2.30 (m, 1H), 2.86 (s, 3H), 3.59 (m, 4H), 3.78 (m, 4H), 6.76 (m, 2H), 7.57 (m, 1H), 8.25 (m, 1H), 8.40 (s, 1H), 8.25 (d, 1H), 13.83 (bs, 1H). Anal. Calcd for C23H23N4O3F.1.5 H2O: C, 61.46; H, 5.83; N, 12.46; Found: C, 61.76; H, 5.54; N, 11.64.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13](=O)[NH:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)=O)[N:10]([C:26](=[O:36])[CH:27]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]([CH3:30])[CH3:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:41]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:41]=2)[N:10]([C:26](=[O:36])[CH:27]([NH:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]([CH3:30])[CH3:29])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)NCC(=O)c1ccc(Br)cc1)C(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 135 °C
Reaction time: 0.75 h
Yield: 62.4 %

Procedure:
4-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-3-(2-methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1-carboxylic acid tert-butyl ester (723 mg) was dissolved in m-xylenes (6.0 mL) and heated at 135° C. Solid ammonium acetate (500 mg, 6.48 mmol) was added and the reaction was stirred at 135° C. After 45 minutes, the reaction was cooled to room temperature and the volatiles were removed in vacuo. The crude material was purified via silica gel chromatography (eluent: EtOAc w 10% MeOH/hexanes) to yield the product 4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid tert-butyl ester (436 mg): LCMS-ESI+: calc'd for C24H32BrN5O5: 550.4 (M+). Found: 551.2/553.2 (M+H+).