Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH:12]=C)=[CH:4][CH:3]=1.FC1C=CC(OCCCC=C)=CC=1>>[CH2:9]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCCOc1ccc(Cl)cc1
Agent: C=CCCCOc1ccc(F)cc1
Product: C=CCCOc1ccc(Cl)cc1

Procedure:
The 1-(3-butenyloxy)-4-chlorobenzene (5, R2 =4--Cl) was prepared by the procedure of Rius-Alonso and Wain, Ann. Apl. Biol. 88, 299 (1978), as were 4-chloro-1-(4-pentenyloxy)-benzene and 4-fluoro-1-(4-pentenyloxy)benzene.
Reaction SMILES: [CH:1]1([B-](F)(F)F)[CH2:3][CH2:2]1.[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH:20]=[O:21].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[Cl:26][C:24]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[C:18]([CH:1]2[CH2:3][CH2:2]2)[CH:25]=1
Reactant: O=Cc1ccc(Cl)cc1Br
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(Cl)cc1C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.9 %

Procedure:
To a degassed mixture of toluene (60 mL) and water (9 mL) was added potassium cyclopropyl-trifluoroborate (0.91 g, 6.2 mmol) and tribasic potassium phosphate (6.37 g, 30 mmol). The resulting mixture was stirred for 15 min at rt, thereafter, 2-bromo-4-chlorobenzaldehyde (1.50 g, 6.84 mmol, WO2006044454), palladium(II) acetate (0.11 g, 0.5 mmol) and 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (0.48 g, 1.0 mmol) were added and the mixture was heated under reflux, overnight. After cooling to rt, water (50 mL) and ethyl acetate (50 mL) were added and the layers were separated. The organic layer was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/hexanes 1:3) to give 4-chloro-2-cyclopropyl-benzaldehyde (0.48 g, 2.6 mmol, 39%) as a colorless semi solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 0.80 (2 H, m), 1.08-1.17 (2 H, m), 2.58 (1 H, m), 7.10 (1 H, d, J=2 Hz), 7.29 (1 H, dd, J=8 Hz, 2 Hz), 7.75 (1 H, d, J=8 Hz), 10.6 (1 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:17]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1cc(F)ccc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)ccc1Cl

Procedure:
To a solution of 2-chloro-5-fluorobenzoic acid (22) (35.0 g, 200 mmol) in methanol (350 mL) was added cone. H2SO4 (5 mL). The mixture was heated at reflux for 24 h. Most of the solvent was evaporated, and the resulting mixture was diluted with water (300 mL). The mixture was extracted with EtOAc (150 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated to give methyl 2-chloro-5-fluorobenzoate (23).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[S:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.O>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:29][C:27]5[S:28][C:24]([C:23]([F:32])([F:31])[F:22])=[CH:25][CH:26]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: OCc1ccc(C(F)(F)F)s1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)(F)F)s4)cc3=O)cn12
Yield: 20.2 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (5-(trifluoromethyl)thiophen-2-yl)methanol (130 mg) and tributylphosphine (0.27 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg) at 60° C., and the mixture was heated at the same temperature for 2 h. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated, and purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (EtOAc/MeOH). The resulting solid was purified by preparative HPLC (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (32.0 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].[CH3:11][O:12][CH2:13][CH2:14][NH:15][CH3:16].C(N(C(C)C)CC)(C)C>CCO>[CH3:11][O:12][CH2:13][CH2:14][N:15]([CH3:16])[C:7]1[CH:6]=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: CNCCOC
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COCCN(C)c1ccc([N+](=O)[O-])nc1
Temperature: 90 °C
Yield: 41 %

Procedure:
A solution of 2-nitro-5-bromopyridine (500 mg, 3.15 mmol) in EtOH (15 mL) was treated with methoxyethyl-N-methylamine (1.12 g, 12.6 mmol) and diisopropylethylamine (2.2 mL, 12.6 mmol). The resulting mixture was then heated in a sealed tube at 90° C. for 4 days then cooled and partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes gradient to afford the product as a thick yellow oil that crystallized slowly upon standing (270 mg, 41% yield). HRMS m/z calcd for C9H13N3O3 [M+Na]+: 234.0849; Found: 234.0850.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>ClCCl>[C:37]([NH:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3)CC2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)c4ccccc4)cc3)CC2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
3-((4-(4-Aminobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.203 mmol, 0.080 g) and triethylamine (1.015 mmol, 0.103 g) were dissolved in dichloromethane (12 mL) and the stirred mixture was cooled to 0° C. Benzoyl chloride (0.305 mmol, 0.043 g) was added and the reaction mixture was allowed to reach room temperature and stir overnight. Water was added to the reaction and the organic layer was then separated, dried (sodium sulfate) and concentrated under vacuum. The residue was purified by silica column chromatography (dichloromethane/methanol (5% to 10%)) and coevaporated with dichloromethane (×3) and diethyl ether (×3) to give the title compound (93 mg). MS (ESI) m/z 499.8 [M+H]+
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:40][CH:41]=2)[CH2:31][CH2:30]1>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1) and 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography). Title compound: ESI-MS: 535.1 [M+H]+; tR=3.45 min (System 1); TLC: Rf=0.19 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].O>C1COCC1>[Br:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[S:3][C:4]=2[CH:10]=1
Reactant: Nc1nc2ccc(Br)cc2s1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(Br)cc2s1
Yield: 74 %

Procedure:
To a solution of 2-amino-6-bromobenzothiazole (10 g, 43.65 mmol) and triethylamine (12.2 mL, 87.3 mmol) and N,N-dimethylaminopyridine (269 mg) in THF (100 mL) is added acetyl chloride (4.7 mL). After stirring for 17 hours water (100 mL) is added and the mixture is extracted twice with EtOAc (75 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford N-(6-bromo-benzothiazol-2-yl)-acetamide (8.79 g, 74%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]([O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=O)=[CH:21][CH:20]=1)[CH2:16][CH3:17]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:25](/[CH:24]=[CH:23]/[C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:15][CH2:16][CH3:17])=[CH:29][CH:28]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: CCCOc1ccc(C=CC(=O)O)cc1
Product: CCCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CC)c(=O)n3CC)cc1
Yield: 54.3 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.43 g (16.6 mmol) of 4-propoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.02 g (yield 54%) of Compound 100 as pale yellow needles.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]#[N:14])=[C:11]([Cl:15])[S:10][N:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N:24]=[C:25]=[O:26]>C1COCC1>[Cl:15][C:11]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH:24][C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[F:16])=[O:26])=[CH:3][CH:4]=2)[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(-c2ccc(N)cc2)nsc1Cl
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3nsc(Cl)c3C#N)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.3 %

Procedure:
A solution of 3-(4-amino-phenyl)-5-chloro-isothiazole-4-carbonitrile (4.565 g, 19.4 mmol) and 2-fluoro-5-methylphenyl isocyanate (5.85 g, 38.7 mmol) in 100 mL of dry THF was heated to reflux overnight. TLC indicated presence of considerable amount of starting material. Additional 2 g of 2-fluoro-5-methylphenyl isocyanate was added and the reaction was continued for another 24 h. The reaction was cooled to room temperature. THF was removed in vacuo and the resulting solid was stirred in 200 mL of Et2O for 1 h. Product was collected by filtration and washed with Et2O/hexanes to afford the title compound as a light yellow solid (6.78 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.I[CH2:28][CH:29]1[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: ICC1CC1
Product: COc1cn(C(CC2CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
464 mg (1.24 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate and 293 mg (1.61 mmol) of (iodomethyl)cyclopropane were reacted according to General Method 7A. Yield: 379 mg (71% of theory)
Reaction SMILES: [O-]CC.[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1.Br[CH2:15][CH:16]([O:19][CH3:20])[O:17][CH3:18]>C(O)C>[CH3:18][O:17][CH:16]([O:19][CH3:20])[CH2:15][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[CH:8][CH:9]=1
Reactant: COC(CBr)OC
Reactant: COc1ccc(S)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(SCC(OC)OC)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.4 %

Procedure:
To an ice cooled solution of sodium ethoxide (3.26 g, 48.0 mmol) in ethanol (25.0 mL) was slowly added 4-methoxybenzenethiol (6.73 g, 48.0 mmol). The reaction mixture was stirred for 15 min. 2-Bromo-1,1-dimethoxyethane (5.64 mL, 48.0 mmol) was added, and the reaction mixture was refluxed for 2 h. After the precipitate was isolated by filtration, the mother liquor was evaporated under reduced pressure. The resultant residue was diluted with diethyl ether (100 mL) and washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give the desired crude product (11.0 g) which was directly used in next step reaction without further purification. 1H-NMR (400 MHz, CDCl3): 7.40 (m, 2H), 6.85 (m, 2H), 4.47 (t, J=5.6 Hz, 1H), 3.80 (s, 3H), 3.34 (s, 6H), 3.01 (d, J=5.6 Hz, 2H).
Reaction SMILES: C(OC([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[CH2:19][C@H:18]3[N:15]([C:16](=[O:23])[C@@H:17]3[C@H:20]([OH:22])[CH3:21])[C:14]=2[C:24]([O:26]CC=C)=[O:25])[CH2:9][CH2:8]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)CC(=O)CC(=O)C1.O>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[OH:22][C@@H:20]([C@H:17]1[C:16](=[O:23])[N:15]2[C@@H:18]1[CH2:19][C:13]([C:10]1[CH2:11][CH2:12][NH:7][CH2:8][CH:9]=1)=[C:14]2[C:24]([OH:26])=[O:25])[CH3:21]
Reactant: C=CCOC(=O)C1=C(C2=CCN(C(=O)OCC=C)CC2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: [Pd]
Agent: CC1(C)CC(=O)CC(=O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(C3=CCNCC3)C[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
To a solution of allyl (5R,6S)-3-(1-allyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.280 g) in tetrahydrofuran (9 ml) were added successively triphenylphosphine (0.094 g), 5,5-dimethyl-1,3-cyclohexanedione (dimedone) (0.201 g) and tetrakis(triphenylphosphine) palladium(0) (41.5 mg). After stirring at ambient temperature for 1 hour, the mixture was poured into a mixture of cold water (50 ml) and ethyl acetate (30 ml). The separated aqueous layer was washed with ethyl acetate (30 ml×2) and concentrated in vacuo to remove the organic solvent. The residue was chromatographed on acid aluminum oxide (3 ml) eluting with water. The fractions containing the desired compound were collected and chromatographed on nonionic adsorption resin, "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (20 ml) eluting with water. The fractions containing the desired compound were collected and lyophilized to give (5R,6S)-6-[ (1R)-1-hydroxyethyl]-7-oxo-3-(1,2,3,6-tetrahydropyridin-4-yl)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (68 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][C:5]=2[CH:4]=1)[NH:12][CH:11]=[C:10]([C:15]#[N:16])[C:9]3=O.P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[Cl:22][C:9]1[C:8]2[C:13](=[CH:14][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:19]=[CH:18][C:6]=3[CH:7]=2)[N:12]=[CH:11][C:10]=1[C:15]#[N:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2cc3c(=O)c(C#N)c[nH]c3cc2c1
Solvent: CN(C)C=O
Product: COc1ccc2cc3c(Cl)c(C#N)cnc3cc2c1
Yield: 81.6 %

Procedure:
According to the procedure of example 101, 446.7 mg (1.8 mmol) of 8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile is refluxed in 102 mL of phosphorus oxychloride and 4 drops of N,N-dimethylformamide (DMF) for 1.5 hours to give 389.0 mg (81.6%) of 4-chloro-8-methoxy-benzo[g]quinoline-3-carbonitrile as a bright yellow solid, mp 258–260° C.
Reaction SMILES: [NH2:1][C:2]1([NH:7][C:8](=[O:17])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][NH:4][C:3]1=[O:6].N1C=CC=CC=1.[C:24](OC=O)(=[O:26])C>ClCCl>[CH:24]([NH:1][C:2]1([NH:7][C:8](=[O:17])[CH2:9][O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][NH:4][C:3]1=[O:6])=[O:26]
Reactant: NC1(NC(=O)COc2ccccc2)CNC1=O
Reactant: CC(=O)OC=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CNC1(NC(=O)COc2ccccc2)CNC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
The amine (27) (66 mg) in dry dichloromethane (5 ml) was cooled to 0° and treated with pyridine (49 mg) followed by formic-acetic anhydride (27 mg). The mixture was stirred at 0° for 15 minutes then allowed to warm to room temperature over 15 minutes, and evaporated to dryness. The residue was chromatographed on silica gel to give the product (28) (53 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:26]2[CH2:31][C@@H:30]3[CH2:32][C@H:27]2[CH2:28][NH:29]3)=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:24][CH3:25])[NH:9][C:6]2=[N:7][CH:8]=1.[CH3:33][C@H:34]1[CH2:36][O:35]1.N1C=CC=CC=1.CCN(C(C)C)C(C)C>CO>[Cl:2][C:3]1[C:4]([N:26]2[CH2:31][C@@H:30]3[CH2:32][C@H:27]2[CH2:28][N:29]3[CH2:33][C@@H:34]([OH:35])[CH3:36])=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:24][CH3:25])[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: C[C@H]1CO1
Reactant: COc1cc(N2CCOCC2)ccc1-c1nc2c(N3C[C@@H]4C[C@H]3CN4)c(Cl)cnc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: c1ccncc1
Product: COc1cc(N2CCOCC2)ccc1-c1nc2c(N3C[C@@H]4C[C@H]3CN4C[C@H](C)O)c(Cl)cnc2[nH]1
Temperature: 80 °C

Procedure:
6-Chloro-7-(1S,4S)-2,5-diaza-bicyclo[2.2.1]hept-2-yl-2-(2-methoxy-4-morpholin-4-yl-phenyl)-3H-imidazo[4,5-b]pyridine hydrochloride (Compound XXXVII) (50 mg, 0.1 mmol), (S)-2-methyl-oxirane (7.30 mg, 0.126 mmol), pyridine (10.2 μL, 0.126 mmol), and methanol (3.0 mL) were stirred in a sealed tube at room temperature overnight. An additional equivalent each of epoxide and Hunig's base were added and the mixture was heated at 80° C. overnight. The mixture was concentrated and the material was subjected to purification via reverse phase chromatography (Gilson) to afford the title compound as a yellow lyophilate (26 mg, 50%). 1H NMR (d-chloroform): 13.63 (br s, 1H), 8.10 (m, 1H), 7.90 (s, 1H), 7.71 (s, 1H), 7.55 (s, 1H), 6.59 (m, 1H), 6.46 (s, 1H), 4.62 (m, 1H), 4.35 (m, 1H), 4.24 (t, J=7 Hz, 2H), 4.15 (s, 3H), 3.92 (s, 4H), 3.35 (s, 4H), 3.14 (m, 2H), 2.38 (m, 1H), 1.71 (m, 1H), 1.44 (m, 2H), 1.32 (m, 1H), 0.94 (m, 3H). MS: 499.18 (M+H). HPLC retention time: 1.83 minutes (G Method).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:48][C:49]1[CH:50]=[C:51]([N:55]2[CH2:59][CH2:58][CH:57]([C:60](O)=[O:61])[C:56]2=[O:63])[CH:52]=[CH:53][CH:54]=1>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:60]([CH:57]1[CH2:58][CH2:59][N:55]([C:51]2[CH:52]=[CH:53][CH:54]=[C:49]([F:48])[CH:50]=2)[C:56]1=[O:63])=[O:61]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2cccc(F)c2)C1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2cccc(F)c2)C1=O
Yield: 41.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.104 g; 0.448 mmol), PyBOP (0.350 g; 0.672 mmol), N,N-diisoprpylethylamine (0.232 mL; 1.34 mmol) and 1-(3-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.448 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulphate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.074 g (41%) of the title compound as a white solid.
Reaction SMILES: C1(CCO)C=CC=CC=1.[CH:10]1[C:22]2[CH:21]([CH2:23][OH:24])[C:20]3C(=CC=CC=3)C=2C=C[CH:11]=1.C1C2C(=CC3C(C=2CO)=CC=CC=3)C=CC=1.Cl[CH2:42][CH2:43][O:44][CH:45]=[CH2:46].C12OC1CCCC2.C1C(C2OC2)CC2OC2C1.C(C1(COCC2(CC)COC2)COC1)C>>[CH3:46][C:45]12[O:44][CH:43]1[CH2:42][CH:22]([C:21]1([CH3:20])[O:24][CH2:23]1)[CH2:10][CH2:11]2
Reactant: C=COCCCl
Reactant: OCC1c2ccccc2-c2ccccc21
Agent: C1CC2OC2CC1C1CO1
Agent: C1CCC2OC2C1
Agent: CCC1(COCC2(CC)COC2)COC1
Solvent: OCCc1ccccc1
Product: CC1(C2CCC3(C)OC3C2)CO1

Procedure:
The benzyl alcohols, 2-phenylethanol, 9-fluorenemethanol, 9-anthracenemethanol, 2-chloroethylvinyl ether, cyclohexene oxide and 4-vinylcyclohexene dioxide (VCHDO) were used as purchased from the Aldrich Chemical Co. (Milwaukee, Wis.) unless otherwise noted. PC-1000 was supplied by the Polyset Co. (Mechanicville, N.Y.). Bis(3-ethyl-3-oxetanylmethyl)ether was kindly supplied by Toagosei Chemical Company, LTD (Nagoya, Japan). Limonene dioxide (LDO) was obtained as a gift from the Witco Chemical Co. (Blooming Prairie, Minn.). 3,4-Epoxycyclohexyl methyl 3′,4′-epoxycyclohexancarboxylate (ERL-4221E, ERL) was purchased from the Union Carbide Corp. (Bound Brook, N.J.). Bisphenol-A diglycidyl ether (BPADGE) was obtained from the Dow Chemical Co. (Midland, Mich.). Onium salt cationic photoinitiators, (4-n-decyloxyphenyl) phenyliodonium hexafluoroantimonate (IOC10), (4-n-decyloxyphenyl)diphenylsulfonium hexafluoroantimonate (SOC10) and S-methyl-S-n-dodecylphenacylsulfonium hexafluoroantimonate (DPS-C1C12) were prepared as described in the following references: IOC-10—Crivello, J. V.; Lee, J. L. J. Polym. Sci. Part A: Polym. Chem. Ed. 1989, 27, 3951, SOC10—Akhtar, S. R.; Crivello, J. V.; Lee, J. L. J. Org. Chem. 1990, 55, 4222 and DPS-C1C12—Crivello, J. V.; Kong, S Macromolecules 2000, 33, 833. The structures of the respective monomers and photoinitiators are shown in Table 1. 1H NMR spectra were obtained using a Varian XL 500 MHz spectrometer at room temperature in CDCl3 using tetramethylsilane as an internal standard.