Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH2:34][CH2:35][CH2:36][OH:37])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: NCCCO
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(F)cc2F)cc1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(C(=O)NCCCO)c(Nc2ccc(F)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
4-(2,4-Difluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (0.15 g, 0.5 mmol) was dissolved in a mixture of anhydrous THF (20 ml) and anhydrous DMF (2 ml). CDI (0.18 g, 1.1 mmol) was added and the solution stirred at RT for 2 h. 3-Amino-1-propanol (0.16 g, 2.2 mmol) was then added and the solution stirred for a further 15 h. The solvent was removed under reduced pressure and the residue partitioned between 2% MeOH/EtOAc and water. The organic fraction was washed with water ×2, NaHCO3, brine, dried (Na2SO4) and concentrated to give crude 4-(2,4-difluoroanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide. Further purification by flash chromatography on silica gel (5% MeOH/CH2Cl2) afforded 4-(2,4-difluoroanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (0.12 g, 68%) as a cream solid; m.p. (EtOAc/Hexane) 129-132° C. 1H NMR [400 MHz, (CD3)2SO] δ 9.84 (br s, 1H), 8.36 (t, J=5.4 Hz, 1H), 8.22 (s, 1H), 7.51-7.37 (m, 2H), 7.16-7.10 (m, 1H), 5.32 (d, J=1.1 Hz, 1H), 4.47 (t, J=4.9 Hz, 1H), 3.47 (dd, J=11.5, 6.2 Hz, 2H), 3.35 (s, 3H), 3.27 (dd, J=12.7, 6.8 Hz, 2H), 1.67 (p, J=6.7 Hz, 2H). LCMS (ACPI−) 336 (100%). Anal. Calcd for C16H17F2N3O3.0.25 H2O: C, 56.2; H, 5.2; N, 12.3. Found C, 56.4; H, 5.3; N, 12.5.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:24]=[CH:23][C:9]2[CH2:10][CH2:11][CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[N:13]3[CH2:14][C:8]=2[CH:7]=1)=[O:5].[CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[CH:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][C:4]([C:6]2[CH:24]=[CH:23][C:9]3[CH2:10][CH2:11][CH:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[O:22])[N:13]4[CH2:14][C:8]=3[CH:7]=2)=[O:5])[CH2:29][CH2:28]1)=[O:26]
Reactant: O=C(CCCl)c1ccc2c(c1)CN1C(=O)c3ccccc3C1CC2
Reactant: O=CN1CCNCC1
Product: O=CN1CCN(CCC(=O)c2ccc3c(c2)CN2C(=O)c4ccccc4C2CC3)CC1
Yield: 84.9 %

Procedure:
Using 3.45 g of 3-(3-chloro-1-oxopropyl)7,11b,12,13-tetrahydro-5H-isoindolo[2,1-b][2]benzazepin-7-one, corresponding to Reference Example 5 Compound No. 1, and 1.4 g of 1-formylpiperazine, the procedure of Example 1 was otherwise repeated to provide about 3.6 g of 3-[3-(4-formyl-1-piperazinyl)-1-oxopropyl]-7,11b,12,13-tetrahydro-5H-isoindolo[2,1-b][2]benzazepin-7-one as a crude oil. This oil was not further purified but directly dissolved in 50 ml of methanol and the solution was refluxed with 50 ml of concentrated hydrochloric acid for 4 hours. After the methanol was distilled off, the residual aqueous solution was adjusted to pH about 10 with 10% aqueous sodium hydroxide solution and the product was extracted into dichloromethane. The extract was washed with water and the solvent was distilled off under reduced pressure to provide 3.1 g of the title compound as a powder melting at 207°-210° C.
Reaction SMILES: [OH:1][C@@H:2]([CH3:10])[C@@H:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].I(O[CH3:15])(=O)=O.[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:15][O:1][C@@H:2]([CH3:10])[C@@H:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)[C@H](C)[C@H](C)O
Reactant: CO[I+2]([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)[C@H](C)OC
Reaction time: 1 h
Yield: 76.4 %

Procedure:
Ethyl (2R, 3S)-3-hydroxy-2-methylbutyrate (8.20 g) and methyl iodate (78.0 g) were dissolved in N,N-dimethylformamide (150 ml). To this solution was added sodium hydride (about 60% in oil, 2.46 g) little by little with ice cooling and the mixture was stirred for 1 hour with ice cooling. The reaction mixture was poured into ethyl acetate (300 ml) and the mixture was stirred for 10 minutes. Insoluble materials were filtered off and the filtrate was washed 3 times with water. The organic layer was dried, concentrated and distilled under reduced pressure (b.p. 80° C./30 mmHg) to obtain ethyl (2R, 3S)-3-methoxy-2-methylbutyrate (6.87 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:8]([Cl:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ncccc1Cl
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a suspension of 3-chloropicolinic acid (1.58 g, 10 mmol) in toluene (6 mL) was added an excess of thionyl chloride (9.52 g, 5.84 mL, 80.0 mmol) at room temperature under a nitrogen atmosphere. The resulting suspension was heated to 120° C. (oil bath temperature) and stirred for 20 h. Then, the solvent and excess of thionyl chloride were removed under vacuum and the residue was dissolved one more time in toluene and the solvent was removed again. The resulting residue was dried under high vacuum and used in the next step.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: C1COCCN1
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: Brc1ccc(-c2nsc3cc(OCCN4CCOCC4)ccc23)cc1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and morpholine were converted to yield 3-(4-Bromo-phenyl)-6-(2-morpholin-4-yl-ethoxy)-benzo[d]isothiazole, MS: 420 (MH+, 1Br).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[CH:9]([C:12]1[C:13]([NH2:21])=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=12)([CH3:11])[CH3:10]>C(Cl)Cl.N1C=CC=CC=1>[CH:9]([C:12]1[C:13]([NH:21][C:4](=[O:5])[CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1])=[N:14][N:15]2[CH:20]=[CH:19][CH:18]=[N:17][C:16]=12)([CH3:11])[CH3:10]
Reactant: CC(C)c1c(N)nn2cccnc12
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1c(NC(=O)CC(C)(C)C)nn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A solution of 3,3-dimethylbutanoyl chloride (0.043 mL, 0.31 mmol) in CH2Cl2 (0.2 mL) was added to a stirring solution of the product from Example 112C (35 mg, 0.20 mmol) in pyridine (1.2 mL) in a 4 mL vial. The yellow solution was stirred at room temperature for 3 hours, and then concentrated under vacuum. The residue was dissolved in CH2Cl2 (4 mL) and concentrated under vacuum to remove excess pyridine. The residue was crystallized from 60% ethanol-water (10 mL) to provide the title compound (40 mg). 1H NMR (300 MHz, CD3OD) δ ppm 1.13 (s, 9H) 1.31-1.53 (m, 6H) 2.33 (s, 2H) 2.95-3.24 (m, 1H) 6.91 (dd, J=7.0, 4.2 Hz, 1H) 8.42 (dd, J=4.1, 2.0 Hz, 1H) 8.70 (dd, J=7.1, 1.7 Hz, 1H); MS (ESI) m/z 275 (M+H)+; Anal. Calculated for C15H22N4O: C, 65.67; H, 8.08; N, 20.42. Found: C, 65.74; H, 8.10; N, 20.46.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]([OH:23])=O)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:30]=[C:29]([C:31]([NH:33]O)=[NH:32])[CH:28]=[CH:27][N:26]=1>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:23][N:33]=[C:31]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([NH2:24])[CH:30]=4)[N:32]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: N=C(NO)c1ccnc(N)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4ccnc(N)c4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyridine-4-carboxamidine (example B.6) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (MeOH/dichloromethane/hexane) as an off-white solid (140 mg, 64%). MS (EI) 436.1 [(M)+]; mp 264° C.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])=[CH:6][CH:5]=1.C[O-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>O>[CH2:27]([O:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:12])=[CH:8][CH:9]=1)[CH:26]=[CH2:25]
Reactant: CC(C)(C)OC(=O)CNC(=O)Nc1ccc(C=NO)cc1
Reactant: C=CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCON=Cc1ccc(NC(=O)NCC(=O)OC(C)(C)C)cc1

Procedure:
A solution of N-[4-(hydroxyiminomethyl)phenyl]-N'-tertbutoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the corresponding N-[ 4-(allyloxyiminomethyl)phenyl]-N'-tert-butoxycarbonylmethylurea.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:8])[NH:6][CH:7]=1)=[O:2].[H-].[Na+].Cl[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[CH:1]([C:3]1[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:8])[N:6]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:7]=1)=[O:2]
Reactant: CCOC(=O)c1c(C=O)c[nH]c1C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C=O)cn(COCC[Si](C)(C)C)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of Example 93b (8.826 g, 48.7 mmol) in tetrahydrofuran (325 mL) was chilled in an ice bath and treated with sodium hydride (dry, 95%) (2.454 g, 97 mmol) added portionwise over 15 minutes. The mixture was stirred under N2 for 10 minutes and treated with (2-(chloromethoxy)ethyl)trimethylsilane (12 mL, 67.8 mmol), then stirred for 50 minutes. The reaction vessel was removed from the ice bath and allowed to warm to ambient temperature. The reaction mixture was carefully quenched with 200 mL of saturated aqueous ammonium chloride, reduced in volume by rotovap and shaken in a separatory funnel with 350 mL each of ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated. The crude material was chromatographed on a 330 g silica gel cartridge eluting with 0-50% ethyl acetate/heptane to provide the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])(=[O:18])=[O:17]
Reactant: CC(C)(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3,3-dimethyl-1-butanol (2 ml) in dichloromethane (48 ml), under nitrogen, was added triethylamine (4.64 ml) and the resulting solution cooled to 0/C. Methanesulphonylchloride (1.28 ml) was then added dropwise via syringe and stirring continued for 18 h as the reaction warmed to room temperature. The reaction was then concentrated onto silica and purified by flash chromatography to give the title compound as a yellow oil.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH3:6][C:7]1([CH3:17])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1.N>S(=O)(=O)(O)O>[CH3:6][C:7]1([CH3:17])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:1]([O-:4])=[O:2])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: O=[N+]([O-])[O-]
Reactant: CC1(C)Cc2ccccc2C=N1
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC1(C)Cc2ccc([N+](=O)[O-])cc2C=N1
Temperature: 60 °C
Yield: 89.8 %

Procedure:
To a stirred solution of potassium nitrate (2.53 g) in sulfuric acid (14 ml ) at 0° C. was added dropwise a solution of 3,4-dihydro-3,3-dimethyl isoquinoline (3.68 g; 23 mmol) [prepared according to the procedure of T. J. N. Watson, J. Org. Chem., 1998, 63, 406] in sulfuric acid (13.5 ml). The resultant solution was stirred at room temperature for 1.5 h and then heated to 60° C. for 4.5 h. The solution was then cooled to room temperature, and poured on to ice.; 0.880 ammonia was added until the solution was neutral, and the product was extracted into dichloromethane (×3). The combined organic phases were, dried over magnesium sulphate, and then evaporated in vacuo to afford the title compound (4.22 g). 1H NMR (CDCl3)δ: 1.27 (6H, s), 2.85 (2H, s), 7.34 (1H, d, J=8 Hz), 8.17 (1H, d, J=2Hz), 8.23 (1H, dd, J=8, 2Hz), 8.33 (1H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH2:9][NH:10][C:11]([NH2:13])=[S:12].O>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[N:9][NH:10][C:11]([NH2:13])=[S:12]
Reactant: O=Cc1ccccn1
Reactant: NNC(N)=S
Solvent: O
Solvent: CCO
Product: NC(=S)NN=Cc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The corresponding pyridine-2-formaldehyde (23, 23a or 28a-k, 10 mmol) was dissolved in ethanol-water (2:1 v/v, 150 mL). To the solution was added thiosemicarbazide (11 mmol). The solution was stirred for 30 min at ambient temperature. After addition of water (50 mL), the reaction mixture was stirred vigorously for 2 h at room temperature. The yellow precipitate was collected by filtration, washed with ethanol-water (1:4 v/v) and dried in vacuum to afford the corresponding pyridine-2-carboxaldehyde thiosemicarbazone (24, 24a, 29a-k).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[O:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:16][O:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH2:28][C@@H:29]([CH3:32])[CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:32][C@@H:29]([CH2:30][CH3:31])[CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[O:15][CH2:16][C@H:17]([CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:18][O:19]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C=CCCCC1COC(c2ccc(-c3ccc(O)cc3)cc2)OC1
Reactant: CC[C@H](C)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCC[C@H]1CO[C@H](c2ccc(-c3ccc(OCCC[C@@H](C)CC)cc3)cc2)OC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 0.9 g of 2-(4'-hydroxy-4-biphenylyl)-5-(4-pentenyl)-m-dioxane and 1.25 g of (S)-1-bromo-4-methylhexane in 25 ml of N,N-dimethylformamide was treated with 1.2 g of finely powdered potassium carbonate and the mixture was stirred overnight in an oil bath of 60° C. The suspension was suction filtered and the filtrate was concentrated in a vacuum. A solution of the residue in diethyl ether was washed twice with water, dried over sodium sulphate and concentrated. Chromatography of the crude product on 40 g of silica gel with hexane/ethyl acetate (vol. 23:2) and two-fold recrystallization from ethyl acetate gave pure (S)-trans-2-[4'-(4-methylhexyloxy)-4-biphenylyl]-5-(4-pentenyl)-m-dioxane; phase transition (S-S) 99.5° C., phase transition (S-SC *) 127° C., phase transition (SC *-Ch) 130° C., cl.p. (Ch-I) 148° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>C(OCC)(=O)C.CCCCCC>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:5]1[C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:29]3[CH:28]=[CH:27][C:26]([N:23]4[CH2:22][CH2:21][O:20][CH2:25][CH2:24]4)=[CH:31][CH:30]=3)[CH:3]=2)[NH:8][CH2:7][CH2:6]1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Clc1cccc(OC2CCNc3ncc(-c4ccc(N5CCOCC5)cc4)cc32)c1
Yield: 73 %

Procedure:
6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20 mg) was reacted with 4-morpholinophenylboronic acid (20.7 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-100% ethyl acetate/hexane as the eluting solvent gave the title compound as a yellow solid (73% yield). M.p. 124-126° C., LCMS: m/z=422.28 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.0-2.11 (m, 1H), 2.22-2.5 (m, 1H), 3.17 (t, J=4.7 Hz, 4H), 3.38-3.48 (m, 1H), 3.54-3.67 (m, 1H), 3.87 (t, J=4.7 Hz, 4H), 5.10 (s, 1H), 5.37 (t, J=1.0 Hz, 1H), 6.88-7.02 (m, 4H), 7.03-7.07 (m, 1H), 7.21-7.26 (m, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.56 (d, J=1.9 Hz, 1H), 8.25 (d, J=1.9 Hz, 1H).
Reaction SMILES: Cl.CO[C:4](=[O:13])[CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[CH2:8][CH2:7][NH:6]1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:14]1([C:4]([CH:5]2[CH2:10][C:9]([CH3:11])([CH3:12])[CH2:8][CH2:7][NH:6]2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: COC(=O)C1CC(C)(C)CCN1
Agent: Cl
Product: CC1(C)CCNC(C(=O)N2CCCC2)C1

Procedure:
5 g (0.024 moles) of 4,4-dimethyl pipecolic acid methyl ester hydrochloride were reacted with 100 ml of pyrrolidine as described in Description 22 to yield 5.4 g of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]12[CH2:13][N:10]([CH2:11][CH2:12]1)[CH2:9][CH2:8][O:7]2.C([N-]C(C)C)(C)C.[Li+].[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>O1CCCC1>[CH2:31]([Sn:26]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:27][CH2:28][CH2:29][CH3:30])[C:5]1[S:1][C:2]([C:6]23[CH2:13][N:10]([CH2:11][CH2:12]2)[CH2:9][CH2:8][O:7]3)=[N:3][CH:4]=1)[CH2:32][CH2:33][CH3:34]
Reactant: c1csc(C23CCN(CCO2)C3)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C23CCN(CCO2)C3)s1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a cold (−78° C.) solution of the 5-(thiazol-2-yl)-4-oxa-1-azabicyclo[3.2.1]octane (632 mg, 3.22 mmol) in tetrahydrofuran (11 mL) was added a solution of lithium diisopropylamide (7.79 mmol in 10 mL tetrahydrofuran) dropwise. The solution was stirred at −78° C. for 45 minutes, and tributyltin chloride (1.05 mL, 3.86 mmol) was added dropwise. The cold bath was removed, and the reaction allowed to warm to room temperature. The ambient reaction was then quenched by the addition of saturated aqueous ammonium chloride solution and diethyl ether. The layers were separated, and the aqueous layer was extracted with additional diethyl ether. The combined organics were washed with water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS ESI(+) m/z 487.4 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1.[C:17](O)(=[O:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:1][CH2:2][C:3]1[CH:15]=[C:14]2[N:5]([C:6](=[O:16])[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: O=c1[nH]c2ccccc2c2cc(CO)nn12
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc2c3ccccc3[nH]c(=O)n2n1

Procedure:
Three grams (0.014 mole) of the product of Example 3 [2-(Hydroxymethyl)pyrazolo[1,5-c]quinazolin-5(6H)-one] is refluxed with 250 ml of glacial acetic acid for 20 hours under nitrogen. The solution is cooled and stripped to a solid residue which is dissolved in a mixture of ethyl acetate-absolute ethanol. The volume of solution is reduced and the concentrated solution set aside at 5°. The precipitate is filtered off to give 3.5 g of product. Recrystallization from ethyl acetate-absolute ethanol gives 3.1 g of analytically pure title compound, m.p. 177°-179°.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].C([O:35]CC)C.CCCCCC>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:35])=[O:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:32])[CH2:15][CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1[O:30][CH3:31])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(C=O)ccc1C(C)(C)C)c1cccc(OC)c1OC
Reactant: CCOCC
Solvent: CCCCCC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1cccc(OC)c1OC

Procedure:
Following a procedure similar to that described in Preparation 21, but using N-(2-t-butyl-5-formylphenyl)-3-(2,3-dimethoxyphenyl)octanamide (prepared as described in Preparation 24) as a starting material, the title compound was obtained as crystals, melting at 146-147° C. (from diethyl ether-hexane).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@@:8]1([C:18]([OH:20])=[O:19])[C@@H:13]([F:14])[CH2:12][C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([OH:17])=[O:16])=[O:6])[CH:2]=[CH2:3].[CH2:21](O)[CH:22]=[CH2:23].C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)(Cl)Cl>[CH2:23]([O:16][C:15]([C@@H:10]1[C@@H:9]2[C@H:11]1[CH2:12][C@H:13]([F:14])[C@@:8]2([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C:18]([OH:20])=[O:19])=[O:17])[CH:22]=[CH2:21]
Reactant: C=CCO
Reactant: C=CCOC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)OCC=C
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A solution of a mixture of (1S,2S,3S,5R,6S)-2-(((allyloxy)carbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (A-1-1, 1.41 g), allyl alcohol (336 μL), N,N-diisopropylethylamine (837 μL) and N,N-dimethylaminopyridine (60 mg) in chloroform (30 mL) was cooled to 0° C. To this solution, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (837 mg) was added, and then the mixture was heated to room temperature and stirred for 2 days. To the reaction solution, chloroform was added, and the organic layer was washed twice with 0.25 mol/L hydrochloric acid, once with water, and once with brine, sequentially. After the organic layer was dried over anhydrous magnesium sulfate, the insoluble was filtered and the filtrate was concentrated under reduced pressure to give (1S,2S,3S,5R,6S)-6-((allyloxy)carbonyl) 2-(((allyloxy)carbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2-carboxylic acid (B-1-1, 1.30 g) as a colorless amorphous.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>O1CCOCC1.Cl.O>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Reaction time: 8 h

Procedure:
To a solution of this 1,1-dimethylethyl 4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate in 1,4-dioxane (100 ml), 4M HCl in 1,4-dioxane (50 ml) and 3 drops of distilled water was added. The reaction mixture was stirred overnight. Reaction mixture was then reduced to dryness in vacuo.