Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH:6]1([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[O:15][CH:16]=2)=[O:11])[CH2:8][CH2:7]1.[C:20](=[O:22])=[O:21]>CCCCCC.O1CCCC1>[CH:6]1([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[O:15][C:16]=2[C:20]([OH:22])=[O:21])=[O:11])[CH2:7][CH2:8]1
Reactant: CC(C)c1nc(C(=O)NC2CC2)co1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)c1nc(C(=O)NC2CC2)c(C(=O)O)o1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
At -70° C. and under a nitrogen blanket, 0.12 mol of n-butyllithium (80.0 ml of a 1.5 molar solution in hexane) was dripped into a solution of 10.4 g (0.054 mol) of 2-isopropyloxazole-4-carboxylic acid-cyclopropylamide in 250 ml of tetrahydrofuran, and the mixture was stirred for 30 minutes at this temperature. The reaction mixture was then poured onto 500 g of solid CO2 and allowed to stand overnight. The residue remaining after evaporating down was taken up in 200 ml of water and 30 ml of 2N NaOH, the solution was extracted twice, each time with 100 ml of diethyl ether, the aqueous phase was acidified to a pH of 2 with concentrated hydrochloric acid and the solution extracted three times, each time with 200 ml of ethyl acetate. Drying over magnesium sulfate and removal of the solvent under reduced pressure gave 10.4 g (81%) of 4-cyclopropylaminocarbonyl-2-isopropyloxazole-5-carboxylic acid as a white powder of m.p. 109°-112° C. (active ingredient no. 3.007).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)=[O:27])=[CH:5][N:6]=1
Reactant: CS(=O)(=O)Nc1ccc(Sc2cnc(N)s2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc(S(=O)c2cnc(N)s2)cc1
Yield: 92.6 %

Procedure:
To a mixture of 2-amino-5-(4-methanesulfonylaminophenylthio)thiazole (2.0 g) in chloroform (100 ml) was added dropwise the solution of 3-chloroperbenzoic acid (1.6 g) in chloroform (50 ml) at 5° C. under ice cooling with stirring. The mixture was stirred at 5° C. for 2.5 hours. The reaction mixture was washed with aqueous sodium bicarbonate and the precipitates were collected by filtration. The solid was washed with aqueous sodium bicarbonate and water, dried in vacuo to give 2-amino-5-(4-methanesulfonylaminophenylsulfinyl)thiazole (1.95 g, yield: 92.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1cccc(-c2cccnc2)c1
Temperature: 80 °C
Yield: 55 %

Procedure:
This Example was carried out in the same manner as Example 1, except that 5.0 g (0.032 mol) of 3-chloro-phenyl boronic acid, 10.0 g (0.064 mol) of 3-bromopyridine, 150□ of tetrahydrofuran and 2M potassium carbonate solution (20□) were added and then 0.37 g (3 mol %) of palladium tetrakistriphenylphosphine [(pd(PPh3)4] was used as a catalyst. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 3-(3-chloro-phenyl)pyridine was isolated. The yield was 55%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH3:12])[C:5]2=[O:13].[CH2:14]1[CH:18]2[CH2:19][NH:20][CH2:21][CH:17]2[CH2:16][N:15]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>[CH3:12][N:6]1[C:5](=[O:13])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:20]3[CH2:19][CH:18]4[CH2:14][N:15]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][CH:17]4[CH2:21]3)[CH:3]=2)[N:8]=[CH:7]1
Reactant: Cn1cnc2ccc(Br)cc2c1=O
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc2ccc(N3CC4CN(C(=O)OC(C)(C)C)CC4C3)cc2c1=O
Temperature: 90 °C
Yield: 38 %

Procedure:
A mixture of 6-bromo-3-methylquinazolin-4(3H)-one (Intermediate 19A) (0.46 g, 1.92 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H) carboxylate (0.49 g, 2.31 mmol), potassium phosphate, tribasic (1.33 g, 5.77 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1-biphenyl (26.9 mg, 0.06 mmol) and tris(dibenzyllideneacetone)dipalladium (0) (17.6 mg, 0.02 mmol) in dioxane (10 mL) was heated at 90° C. for 20 h. The mixture was diluted with water and the product extracted into dichloromethane. The organic layer was evaporated to dryness, re-dissolved in methanol and purified using a 5 g SCX column. The mixture was then further purified on silica (25 g SNAP column on SP4). Eluting with dichloromethane to 60/40 dichloromethane/(2M NH3 in methanol) to afford tert-butyl 5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (270 mg, 0.73 mmol).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[C:11](B3OC(C)(C)C(C)(C)O3)[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=2)[CH:9]=[N:8]1.Br[C:30]1[C:31]([CH3:47])=[N:32][N:33]([CH2:40][C:41]2[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=2)[C:34]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36]>O1CCOCC1.C([O-])(O)=O.[Na+].CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:47][C:31]1[C:30]([C:11]2[CH:12]=[C:13]([C:16]([F:17])([F:19])[F:18])[CH:14]=[C:15]3[C:10]=2[CH:9]=[N:8][N:7]3[CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:33]([CH2:40][C:41]2[CH:42]=[N:43][N:44]([CH3:46])[CH:45]=2)[N:32]=1
Reactant: CC1(C)OB(c2cc(C(F)(F)F)cc3c2cnn3C2CCCCO2)OC1(C)C
Reactant: CCOC(=O)c1c(Br)c(C)nn1Cc1cnn(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2cc(C(F)(F)F)cc3c2cnn3C2CCCCO2)c(C)nn1Cc1cnn(C)c1
Temperature: 140 °C

Procedure:
To a microwave vial were added 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1H-indazole (0.993 g, 2.506 mmol), ethyl 4-bromo-3-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-5-carboxylate (0.82 g, 2.506 mmol), and PdCl2(dppf) (0.092 g, 0.125 mmol) in dioxane (25 mL) and aqueous saturated NaHCO3 (6 mL). The mixture was bubbled with nitrogen to give a light yellow suspension, which was heated at 140° C. for 60 minutes in a microwave reactor. The reaction mixture was subsequently diluted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated. The crude residue was purified by CombiFlash® chromatography (120 g column) eluting with a gradient of 10-100% EtOAc in heptane over a period of 180 minutes. The product-containing fractions were combined and concentrated to give the title compound as an off white solid (0.745 g, 57.5%). ESI-MS m/z [M+H]+ calc'd for C25H27F3N6O3, 517.22. found 517.20.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:20])=O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCOCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: ClCCOCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 2-benzyloxyethanol (11.7 g) and pyridine (6.08 g) in dichloromethane (50 ml) was added thionyl chloride (6.7 ml) under ice-cooling, and the resulting mixture was stirred at refluxing temperature for 2.5 hr. Ice-water was added to the reaction mixture, and the organic layer was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform) to give 10.3 g of 2-benzyloxyethyl chloride.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[C:32]([CH3:39])=[C:33]2[C:38]=1[O:37][CH2:36][CH2:35][CH2:34]2.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1[C:31]1[C:32]([CH3:39])=[C:33]2[C:38](=[C:29]([F:28])[CH:30]=1)[O:37][CH2:36][CH2:35][CH2:34]2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
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: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3cc(F)c4c(c3C)CCCO4)n2n1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4.5 g, 9.20 mmol), 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.22 g, 11.04 mmol) and 2N Na2CO3 (9.20 mL, 18.39 mmol) in DMF (100 mL) was degassed and flushed with N2 for 30 min. Tetrakis(triphenylphosphine)palladium(0) (0.744 g, 0.644 mmol) was then added and the reaction was flushed with N2 for another 15 min. The mixture was then heated at 100° C. for 16 h. At this point LCMS indicated completion of reaction and appearance of desired product. After cooling to rt, water was added (50 mL) and the mixture was extracted with ether (2×200 mL). The organic phase was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was then purified by silica gel chromatography (5-60% EtOAc/hexane) to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4 g, 7.58 mmol, 82% yield) as mixture of atrope isomers (approx 10% of minor atrope isomer was present). 1H NMR (500 MHz, CDCl3) δ 7.10 (s, 1H), 6.87 (d, J=10.7 Hz, 1H), 5.00 (s, 1H), 4.41 (qd, J=7.1, 3.1 Hz, 2H), 4.35 (dd, J=5.2, 4.0 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 2.80 (s, 3H), 2.79-2.73 (m, 2H), 2.23-2.15 (m, 2H), 1.82 (s, 3H), 1.41 (t, J=7.2 Hz, 3H), 1.22-1.19 (m, 4H), 1.18 (s, 9H). LCMS (M+H)=528.4.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21](Br)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)C.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:31]1([C:21]2[CH:20]=[C:19]([S:16]([NH:15][CH:10]3[CH2:11][CH2:12][CH2:13][C:14]4[N:6]([CH2:5][C:4]([OH:3])=[O:30])[N:7]=[CH:8][C:9]3=4)(=[O:18])=[O:17])[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=2)[CH2:33][CH2:32]1
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(C2CC2)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 9.5 %

Procedure:
[4-(3-Bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (51.0 mg, 0.10 mmol, example 1-8), cyclopropylboronic acid (10.4 mg, 0.12 mmol), palladium (II) acetate (1.2 mg, 0.005 mmol), tricyclohexylphosphine (2.8 mg, 0.010 mmol) and potassium phosphate (76.4 mg, 0.36 mmol) were dissolved in toluene (0.5 mL) and water (0.1 mL). The mixture was heated in a microwave oven at 180° C. for 30 minutes under an argon atmosphere. The resulting mixture was quenched with saturated ammonium chloride solution, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford [4-(3-cyclopropyl-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid (4.2 mg, 18.9%) as a white powder. 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (s, 1H), 7.85 (s, 1H), 7.70 (s, 1H), 6.65 (s, 1H), 4.80 (s, 2H), 4.41 (t, 1H), 2.50 (m, 2H), 2.20 (m, 1H), 2.00-1.73 (m, 4H), 1.15 (, 2H), 0.85 (m, 2H). MS cald. for C19H20F3N3O4S 443, obsd. (ESI+) [(M+H)+] 444.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[Cl:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.COCCO.Cl>O>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:20]([Cl:26])[CH:21]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnc(Cl)c1C=O
Reactant: Nc1ccc(OCc2ccccc2)c(Cl)c1
Agent: Cl
Solvent: COCCO
Solvent: O
Product: Nc1ncnc(Nc2ccc(OCc3ccccc3)c(Cl)c2)c1C=O
Temperature: 25 °C

Procedure:
In a 3-necked round bottom flask equipped with a thermal couple, an overhead stirrer and a condenser was added 4-amino-6-chloro-pyrimidine-5-carbaldehyde Cpd 1a (3.23 g, 19.0 mmol), 4-benzyloxy-3-chloro-phenylamine Cpd 1b (4.24 g, 18.1 mmol), 2-methoxyethanol (27 ml) and water (3 ml). The mixture was stirred at room temperature and a 6N HCl solution (0.30 ml, 0.10 eq.) was added. The mixture was heated to 80° C. for 1-2 hours until the starting materials were consumed. The mixture was cooled to room temperature and 6 N NaOH solution (3.3 ml) and water (8 ml) were added. The mixture was cooled to room temperature again and the solid was collected by vacuum filtration. The reaction flask was rinsed by 1:1 EtOH:water (2×10 ml) and the rinses were used to wash the filter cake. The filter cake was further washed by 1:1 EtOH:water (2×10 ml), suction dried, dried in an vacuum oven at 60° C. under house vacuum to afford the title Compound 1c free base as a light yellow solid (6.06 g). 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 10.14 (s, 1H), 8.11 (s, 1H), 7.90 (bs, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.48-7.32 (m, 5H), 7.21 (d, J=8.0 Hz, 1H), 5.20 (s, 2H), 3.24 (bs, 2H); mp 206° C. (by DSC).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.C([CH2:14][O:15][CH2:16][C@@H:17]1[CH2:21][C@@H:20]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19][N:18]1[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28])(O)=O.Cl.CNC>O1CCCC1.CO.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][N:2]([CH3:5])[C:3]([CH2:14][O:15][CH2:16][C@@H:17]1[CH2:21][C@@H:20]([O:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH2:19][N:18]1[C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=1)=[O:28])=[O:4]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CN(C)C=O
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C(=O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To a mixture of dimethylformamide (3.9 ml) and tetrahydrofuran (30 ml) was dropwise added phosphorus oxychloride (3.75 ml) at 0°-10° C. and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (14.50 g) in tetrahydrofuran (15 ml) at 0°-10° C. and the mixture was stirred at the same temperature for 30 minutes. The resulting mixture was dropwise added to a mixture of dimethylamine hydrochloride (50 g) and triethylamine (100 ml) in methanol (200 ml) at 0°-10° C. with stirring. The mixture was stirred at the same temperature for 2 hours. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a syrup. The syrup was dissolved in ethyl acetate (200 ml), washed with water (200 ml), 1N hydrochloric acid (200 ml), saturated aqueous sodium hydrogen carbonate (200 ml) and brine (200 ml), in turn, dried over magnesium sulfate, and concentrated under reduced pressure to give (2S,4R)-2-(dimethylcarbamoyl)methyloxymethyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (12.03 g).
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])=[N:6][N:5]=1.[CH3:20]I>CO>[CH3:20][S:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])=[N:6][N:5]=1
Reactant: CI
Reactant: NS(=O)(=O)Cc1ccccc1-c1nnc(S)o1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Temperature: 30 °C
Reaction time: 0.08 h
Yield: 63.4 %

Procedure:
To a solution containing 0.62 g of potassium hydroxide in 50 ml of methanol was added 3 g of the oxadiazole prepared in Example 2. After stirring about five minutes, 2 g of methyl iodide was added. The suspension was refluxed 0.5 hour, cooled to 30° C., an extra 10 g of methyl iodide was added, and the suspension was refluxed an additional two hours, then concentrated in vacuo. After water was added to the residue, the suspension was filtered and the solid was washed with 1×50 ml of water. The suction-dried solid was recrystallized from 2-propanol to give 2 g of the subject compound: m.p. 138°-140° C.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:18](=O)([O-])[O-].[K+].[K+]>CO>[C:1]1([C:7]2([C:10]([O:12][CH3:18])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CC1

Procedure:
To a solution of 1-phenylcyclopropanecarboxylic acid (9.8 g) in methanol (121 ml) was added conc. sulfuric acid (0.1 ml) and the mixture was refluxed under heating for 8 hr. The reaction mixture was neutralized by adding an aqueous potassium carbonate solution and concentrated under reduced pressure. The concentrate was extracted with ethyl acetate. The extract was washed with an aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (8.5 g) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][CH:31]=[CH:30][C:6]=1[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=O.[O-:34][C:35]#[N:36].[Na+]>C(O)(=O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][CH:31]=[CH:30][C:6]=1[CH2:7][N:8]1[C:9]2[C:10](=[CH:11][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:13][CH:14]=2)[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=2)=[N:36][C:35]1=[O:34]
Reactant: C#CCOc1ccc(NCc2ccccc2OCCO)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1OCCO
Reaction time: 2 h

Procedure:
To a solution of 85 mg (0.192 mmol) {2-[2-(2-Hydroxy-ethoxy)-benzylamino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanone in 2 ml acetic acid is added 25 mg (0.383 mmol) sodium cyanate. After stirring for 2 h the solvent is removed in vacuo and the residue is partitioned between CH2Cl2 and water. The organic layer is extracted with 2 M sodium hydroxide solution. After evaporation of the organic phase the product is obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@:12]3([CH3:24])[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:5][C:4]=2[CH:3]=1>CCCCCC.C(O)C>[Br:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C:12]3([CH3:24])[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:5][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)c1nc2cc(Br)sc2c(=O)[nH]1
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1(C)c1nc2cc(Br)sc2c(=O)[nH]1

Procedure:
tert-Butyl 2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate (180 mg) was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm i.d.×500 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 80 mL/min, column temperature: 30° C.). Under the above-mentioned high performance liquid chromatography conditions, the fraction solution containing an optically active form having a shorter retention time was concentrated to give tert-butyl (2R)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate (88 mg, 9.25 min, >99.9% ee). In addition, the fraction solution containing an optically active form having a longer retention time was concentrated to give tert-butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate (85 mg, 19.3 min, >99.9% ee). The analysis was performed by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mm i.d.×250 mm L, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.), mobile phase: hexane/ethanol (900/100), flow rate: 1.0 mL/min, column temperature: 30° C., detection 220 nm). The absolute configuration was determined by comparison to tert-butyl (2S)-2-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-methylpyrrolidine-1-carboxylate produced in Example 103, step A.
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]1[C:12]2[N:13]=[C:14]3[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][N:15]3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)C.Cl>C(O)(=O)C>[OH:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][CH:27]=1)[CH:7]=[C:8]1[C:12]2[N:13]=[C:14]3[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][N:15]3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1
Reactant: CCOc1cccc(C=C2CCc3c2nc2ccc(C(=O)O)cn2c3=O)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1ccc2nc3c(c(=O)n2c1)CCC3=Cc1cccc(O)c1
Yield: 74.3 %

Procedure:
3-(3-ethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid (2.7 g), prepared according to Example 4, was heated with 37% HCl (54 ml) in acetic acid (54 ml) under stirring at reflux temperature for 20 hours. After cooling the precipitate was filtered, washed with water and then treated with aqueous sodium acetate under stirring: filtration and crystallization of the precipitate from dimethylformamide gave 1.85 g of 3-(3-hydroxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid, m.p. >320° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[O:28]1[CH2:33]CC(O)[CH2:30][CH2:29]1>>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:30][CH2:29][O:28][CH2:33][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: OC1CCOCC1
Agent: [C-]#N
Agent: [K+]
Product: O=C(OC1CCOCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 mg of powdered potassium cyanide and 10 g (100 mmol) of tetrahydro-2H-pyran-4-ol is heated at 140° for 20 hours, whereupon the excess tetrahydro-2H-pyran-4-ol is distilled off and the residue is taken up in chloroform. The solution is washed with water, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate there is obtained tetrahydro-2H pyran-4-yl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 226°-227°.