Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][C:19]#[N:20])[C:7]=2[CH:21]=1.[C:22]([O-])(=[O:24])[CH3:23].[Na+]>C(OC(=O)C)(=O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][CH2:19][NH:20][C:22](=[O:24])[CH3:23])[C:7]=2[CH:21]=1
Reactant: COc1ccc2c(c1)N(CC#N)C(c1ccccc1)CO2
Reactant: CC(=O)[O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2c(c1)N(CCNC(C)=O)C(c1ccccc1)CO2
Reaction time: 36 h

Procedure:
The compound obtained in Step C (200 mg; 0.71 mmol) is dissolved in a Parr reactor with acetic anhydride. Raney nickel (30% by weight, 60 mg) and sodium acetate (1.5 eq.; 1.07 mmol; 88 mg) are then added. The mixture is left at 50° C. for 36 hours under a hydrogen pressure of 40 psi. After returning to ambient temperature, the solution is filtered over Celite and the filtrate is evaporated. The crude reaction product is purified by flash chromatography on silica gel (eluant: AcOEt). The title product is obtained in the form of white crystals, which are recrystallised from an Et2O/i-PrOH mixture.
Reaction SMILES: [OH-].[Na+].Cl.[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][C:13]([OH:15])=O>C(Cl)(=O)C.ClCCl>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[CH2:12][C:13](=[O:15])[O:19][C:17](=[O:18])[CH2:16]1
Reactant: Cc1ccccc1C(CC(=O)O)CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: Cc1ccccc1C1CC(=O)OC(=O)C1
Reaction time: 12 h

Procedure:
To a solution of commercial 2-methylbenzaldehyde (18 g) and ethyl acetoacetate (39 g) in ethanol (30 ml) piperidine (3 ml) was added with stirring at rt. The mixture was kept at rt for 2 d. The precipitate was collected by suction filtration, washed with ethanol, and dried in vacuo to give 25.66 g of a yellowish solid (the bis-adduct of acetoacetate to the benzaldehyde). The powdered solid was added in portions to 40% NaOH (300 g) with stirring. The resulting yellow slurry was stirred at reflux for 2 h. After cooling in an ice bath the mixture was acidified by portionwise addition of conc. HCl (280 ml) to give a colourless precipitate. The solid was collected by suction filtration and washed with water. After drying in vacuo 3-(2-methylphenyl)glutaric acid (9.01 g) was obtained. The suspension of finely divided 3-(2-methylphenyl)glutaric acid in acetyl chloride (14.4 ml) was heated to reflux with stirring for 2 h. After cooling to rt petrol ether (50 ml) is added and the mixture is kept in the refrigerator for 12 h. The precipitate is isolated by suction filtration, washed with petrol ether, and dried in vacuo to give a crude which is dissolved in dichloromethane (400 ml). Insolubles are removed by filtration and the filtrate is concentrated in vacuo to provide 3-(2-methylphenyl)glutaric anhydride (6.79 g) as colourless solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6]([NH:9][NH2:10])=[N:7][CH:8]=1)#[N:2].Cl.[N:14]([O-])=O.[Na+]>O>[N:9]([C:6]1[N:5]=[C:4]([NH:11][CH3:12])[C:3]([C:1]#[N:2])=[CH:8][N:7]=1)=[N+:10]=[N-:14]
Reactant: O=N[O-]
Reactant: CNc1nc(NN)ncc1C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CNc1nc(N=[N+]=[N-])ncc1C#N
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
To a cold (5° C.) solution of 5-cyano-2-hydrazino-4-methylamino-pyrimidine (21.7 g) from Example 4 in a mixture of water (260 mL) and concentrated HCl (26.5 mL) was added dropwise a solution of NaNO2 (10.03 g) in water (25 mL) with overhead mechanical stirring. A white precipitate formed and after the addition was completed, the reaction was stirred for an additional 20 minutes at 5° C. The insoluble product was filtered and washed with cold water to give 22.4 g of the title compound after drying at 23° C. under high vacuum overnight. Crystallization from ethanol provided an analytically pure sample of 2-azido-5-cyano-4-methylamino-pyrimidine; mp 225°-230° C.
Reaction SMILES: S(Cl)(Cl)=O.C1(CCC(O)=O)C=CC=CC=1.C1(CCC(Cl)=O)C=CC=CC=1.[C:27]1([CH2:33][CH2:34][C:35]([N:37]=[C:38]=[S:39])=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[C:57]([F:62])[CH:56]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:38]([NH:37][C:35](=[O:36])[CH2:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[S:39])=[C:57]([F:62])[CH:56]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(CCc1ccccc1)N=C=S
Agent: O=C(Cl)CCc1ccccc1
Agent: O=C(O)CCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)CCc4ccccc4)c(F)c3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-phenylpropanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-phenylpropanoyl isothiocyanate was prepared using the resultant 3-phenylpropanoyl chloride as a starting compound according to the description of the literature. 3-Phenylpropanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 74%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH:8]2[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)([O-:3])=[O:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:24](=[O:26])[CH3:25])[CH:8]2[C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1c2ccccc2-c2c([N+](=O)[O-])cnn2C1c1ccc(Cl)cc1
Yield: 95 %

Procedure:
1-Nitro-5-(p-chlorophenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline is treated with acetic anhydride as described in Example 27 to give 1-nitro-5-(p-chlorophenyl)-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline with a yield of 95%. M.p.: 183°-184° C.
Reaction SMILES: FC(F)(F)C(O)=O.COC1C=C(OC)C=CC=1C[N:13]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)=[CH:35][C:34]=1[F:48])[S:14]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH2:23][N:22]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:21][CH2:20]2)(=[O:16])=[O:15].C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1.C(Cl)(Cl)Cl>[F:48][C:34]1[CH:35]=[C:36]([O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=2)[CH:37]=[CH:38][C:33]=1[NH:13][S:14]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH2:23][N:22]([C:27](=[O:32])[C:28]([F:29])([F:31])[F:30])[CH2:21][CH2:20]2)(=[O:15])=[O:16]
Reactant: COc1ccc(CN(c2ccc(OCCc3ccccn3)cc2F)S(=O)(=O)c2ccc3c(c2)CCN(C(=O)C(F)(F)F)C3)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: COc1ccccc1
Product: O=C(N1CCc2cc(S(=O)(=O)Nc3ccc(OCCc4ccccn4)cc3F)ccc2C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of N-(2,4-dimethoxybenzyl)-N-{2-fluoro-4-[2-(pyridin-2-yl)ethoxy]phenyl}-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (350 mg) in a mixture of anisole (5 mL) and chloroform (5 mL) while cooling in ice, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution while cooling in ice, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=70:30→chloroform:methanol=95:5) to afford N-{2-fluoro-4-[2-(pyridin-2-yl)ethoxy]phenyl}-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as a colorless oil (12 mg).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[F:43][C:44]1[CH:49]=[CH:48][C:47]([C@:50]([C:59]2[CH:64]=[C:63]([O:65][C:66]([F:71])([F:70])[CH:67]([F:69])[F:68])[CH:62]=[C:61]([F:72])[CH:60]=2)([NH2:58])[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:46][C:45]=1[O:73][CH:74]([CH3:76])[CH3:75].CN1CCOCC1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([NH:58][C@:50]([C:47]1[CH:48]=[CH:49][C:44]([F:43])=[C:45]([O:73][CH:74]([CH3:76])[CH3:75])[CH:46]=1)([C:59]1[CH:64]=[C:63]([O:65][C:66]([F:71])([F:70])[CH:67]([F:69])[F:68])[CH:62]=[C:61]([F:72])[CH:60]=1)[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:6]
Reactant: O=C(O)CCC(F)(F)F
Reactant: CC(C)Oc1cc([C@](N)(Cc2ccccc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)CCC(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of 4,4,4-trifluorobutyric acid (13 mg, 0.09 mmol) in DCM (0.8 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (52 mg, 0.1 mmol), (R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (40 mg, 0.08 mmol), followed by NMM (28 μl, 0.25 mmol). The reaction mixture was stirred at room temperature for 16 h, then another 16 h at 60° C. The reaction mixture was diluted with EtOAc (10 mL) and the organic layer was washed with H2O, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC Phenomenex Luna C18 column, 30×50 mm eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm; 40-100% ACN (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm. (R)-4,4,4-trifluoro-N-(1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2,-tetrafluoroethoxy)phenyl)-2-phenylethyl)butanamide (Example 312) was isolated as a lyophillate (27 mg, 55% yield). LCMS: RT=2.15 min [M+H] 608.2 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.79 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% ACN/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 1.18 (d, J=6.05 Hz, 3H), 1.24 (d, J=6.05 Hz, 3H), 2.34-2.48 (m, 2H), 2.51-2.61 (m, 2H), 3.79 (d, J=13.19 Hz, 1H), 3.98 (d, J=13.19 Hz, 1H), 4.29-4.39 (m, 1H), 6.12-6.44 (m, 1H), 6.67-6.82 (m, 4H), 6.91-7.07 (m, 4H), 7.10-7.19 (m, 3H), 8.29 (s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[O:19][C:16]1[CH:17]=[CH:18][C:13]([NH2:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccc(N)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 87.2 %

Procedure:
To a solution of 1-fluoro-2-methyl-4-nitrobenzene (2.02 g, 13.0 mmol) and 4-amino-3-nitrophenol (2.22 g, 14.4 mmol) in DMF (20 mL) was added cesium carbonate (5.28 g, 16.2 mmol). After heating to 60° C. for 10 hours, the mixture was diluted with water (100 mL) and filtered. The precipitate was washed with water and air-dried to provide the product (3.28 g, 87%) as dark solid.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:12]=[N:13][N:14]3[C:19]=2[C:18]2[CH:20]=[CH:21][NH:22][C:17]=2[N:16]=[CH:15]3)[CH2:7][CH2:6]1)=[N+:2]=[N-:3].[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].O>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[C:11]1([C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][N:1]3[CH:27]=[C:26]([C:24]([OH:28])([CH3:25])[CH3:23])[N:3]=[N:2]3)[CH2:6][CH2:7]2)[N:12]=[N:13][N:14]2[C:19]=1[C:18]1[CH:20]=[CH:21][NH:22][C:17]=1[N:16]=[CH:15]2
Reactant: C#CC(C)(C)O
Reactant: [N-]=[N+]=NC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)c1cn(C[C@H]2CC[C@H](c3nnn4cnc5[nH]ccc5c34)CC2)nn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1-[trans-4-(Azidomethyl)cyclohexyl]-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine (30.0 mg, 0.101 mmol) and 2-methyl-3-butyn-2-ol (12.0 μL, 0.122 mmol) in dichloromethane (3 mL) were mixed with copper(II) sulfate (24.0 mg, 0.152 mmol) and sodium ascorbate (60.0 mg, 0.304 mmol) and then stirred at 80° C. for 2 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→0/1-ethyl acetate/methanol=20/1 (v/v)) to give the title compound as a colorless solid (13.2 mg, yield 34%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:38]=[C:37]([NH:39][C@@H:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:41][OH:42])[C:36]([F:47])=[CH:35][C:32]=1[C:33]#[N:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(#N)C.O>[F:47][C:36]1[C:37]([NH:39][C@@H:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:41][OH:42])=[N:38][C:31]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:9]=2)=[C:32]([CH:35]=1)[C:33]#[N:34]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CC(C)(C)[C@@H](CO)Nc1nc(Cl)c(C#N)cc1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](CO)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Temperature: 120 °C

Procedure:
A solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (1.84 g, 4.42 mmol), (S)-2-chloro-5-fluoro-6-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile, 97a, (1.00 g, 3.68 mmol) and K3PO4 (2.40 g, 11.22 mmol) in 2-methyl-THF (12 mL) and water (2 mL) was purged with nitrogen for 30 minutes. X-Phos (0.14 g, 0.294 mmol) and Pd2(dba)3(0.07 g, 0.07 mmol) were added and the reaction mixture was heated at 120° C. in a pressure vial for 2 hours. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-40% EtOAc/Hexanes gradient) to afford 1.88 g as a foamy solid: 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.26 (m, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.46 (d, J=12 Hz, 2H), 7.33 (d, J=7.5 Hz, 1H), 5.34 (m, 1H), 4.42-4.31 (m, 1H), 4.02 (m, 1H), 3.75 (m, 1H), 2.40 (s, 3H), 1.26 (s, 9H); LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 526.49 (M+H), retention time=1.83 minutes.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H]>CO.[C].[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)c(C(=O)O)c1
Yield: 83.5 %

Procedure:
2-Fluoro-5-nitrobenzoic acid (60 g) was suspended in 300 ml of methanol, 6.0 g of 5% palladium-carbon was added thereto and the mixture was reduced at 40 ° C. with hydrogen pressure of 6.5 atm. The catalyst was removed, the solvent was evaporated and the crystals separated out therefrom were filtered to give 42 g of 5-amino-2-fluorobenzoic acid, m.p. 189°-192° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2/[C:37](=[CH:42]\[O:43][CH3:44])/[C:38]([O:40][CH3:41])=[O:39])[CH:25]=1>C1(C)C=CC=CC=1.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:24]1[N:29]=[CH:28][N:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2/[C:37](=[CH:42]\[O:43][CH3:44])/[C:38]([O:40][CH3:41])=[O:39])[CH:25]=1)#[N:2]
Reactant: N#Cc1ccccc1O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Oc2ccccc2C#N)ncn1
Temperature: 105 °C
Reaction time: 1 h

Procedure:
A mixture of 2-cyanophenol (13.2 g), potassium carbonate (20.7 g), N-methyl-2-pyrrolidinone (15.0 g), (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate (32.8 g) and water (35 g) was heated at 105° C. for 15 hours. Any distillates were allowed to come off under atmospheric conditions. The reaction mixture was mixed with toluene. The organic layer was then separated. Toluene and N-methyl-2-pyrrolidinone were removed from the organic phase by vacuum distillation (110° C., 20 mmHg). The melt was cooled to 90° C. after which methanol (40 ml) was added to help cooling to 65-75° C. The resulting mixture was cooled to ambient and kept at this temperature overnight. It was then further cooled to 0-5° C. and held for another 1 hour period. The mixture was filtered to leave (E)-methyl 2-[2-(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl]-3-methoxypropenoate as the residue (68.2% isolated yield).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]([CH3:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:9][N:8]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]([CH2:12][Br:25])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1onc(-c2ccc(Br)o2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccc(Br)o2)c1CBr
Yield: 83.8 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-4-methylisoxazole-5-carboxylate (1.7 g, 5.67 mmol), NBS (1.2 g, 6.8 mmol), and benzoyl peroxide (0.14 g, 0.567 mmol) were added to 50 mL of carbon tetrachloride and the mixture was refluxed for 16 h. Reaction mixture was concentrated and purified by chromatography (0-30% EtOAc/hexanes) to give 1.8 g of the title compound along with small amount of unreacted starting material. 1H NMR (CDCl3, 200 MHz): δ=7.09 (d, 1H, J=3.4 Hz), 6.54 (d, 1H, J=3.6 Hz), 4.84 (s, 2H), 4.51 (q, 2H, J=7.0 Hz), 1.49 (t, 3H, J=7.4 Hz).
Reaction SMILES: C([S:4]([CH:6]1[N:9]([CH:10]([C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=S)[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:34])[CH2:7]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[F:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:24]2[S:4][CH:6]3[N:9]([C:8](=[O:34])[CH2:7]3)[C:10]=2[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])=[CH:28][CH:29]=1
Reactant: C=CCS(=O)C1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=S)Oc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Oc2ccc(F)cc2)SC2CC(=O)N12
Yield: 12.3 %

Procedure:
A mixture of 1.15 g of 4-nitrobenzyl 2-(4-allylsulphinylazetidin-2-on-1-yl)-3-(4-fluorophenoxy)-3-thioxo-propanate, 600 mg of triphenylphosphine, and dioxan was heated under an argon atmosphere at 100° for 15 minutes. Then, the mixture was evaporated in vacuo to dryness, and the resulting oil was chromatographed on silica gel. Elution with ethyl acetate-hexane mixtures afforded 116 mg of the title compound (12% of the theoretical yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(COc3ccc(F)cc3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 57 %

Procedure:
Using a procedure analogous to that described in Example 98, the title compound, m.p. 143°-144° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 4-fluorophenol. The yield was 57% of theory.
Reaction SMILES: [O:1]=[C:2]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1.CO.[ClH:25]>>[ClH:25].[NH:7]1[CH2:8][CH2:9][C:4]2([C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:2](=[O:1])[CH2:3]2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc12
Agent: Cl
Solvent: CO
Product: O=C1CC2(CCNCC2)c2ccccc21
Reaction time: 8 h
Yield: 97.6 %

Procedure:
The mixture of tert-butyl 3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (20 g, 66.4 mmol) and MeOH/HCl (2.5 mol/L, 100 mL) were stirred overnight. After evaporation the residue was washed by petroleum ether to provide spiro[indene-1,4′-piperidin]-3(2H)-one hydrochloride (15.4 g, 97.6%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[O:8]([CH2:15][CH2:16][NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][C:19]=1[NH2:28])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCC>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][C:5]([NH:28][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:18]=1[NH:17][CH2:16][CH2:15][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:6]
Reactant: COCCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1NCCOc1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COCCC(=O)Nc1cnc2ccccc2c1NCCOc1ccccc1
Yield: 110.2 %

Procedure:
3-methoxypropanoyl chloride (0.86 ml, 7.9 mmol) was added dropwise over a 30 minute period to a chilled (ice bath) solution of N4-(2-phenoxyethyl)quinoline-3,4-diamine (2.0 g, 7.2 mmol) in dichloromethane (100 ml). After a few hours, a precipitate formed. The solvent volume was reduced under vacuum to near dryness and hexane (100 ml) was added. Vacuum filtration provided 2.9 g of 3-methoxy-N-{4-[(2-phenoxyethyl)amino]quinolin-3-yl}propanamide as a hydrochloride salt.