Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[CH:24]4)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[CH:24]4)[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3cnccc23)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3cccc4cnccc34)cc2=O)n1

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(isoquinolin-5-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 56) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(isoquinolin-5-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionamide an off-white solid (0.56 g, 44%); ES+-HRMS m/e calcd for C28H32N6O4 [M+H+] 517.2558 found 517.2557. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.06 (s, 3H), 1.10 (m, 1H), 1.22-1.80 (m, 8H), 1.92 (m, 1H), 2.29 (m, 1H), 3.89 (s, 2H), 4.68 (s, 1H), 5.46 (dd, J=4.2, J=10.6 Hz, 1H), 5.76 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 7.52 (d, J=2.2 Hz, 1H), 7.73-7.85 (m, 3H), 8.16 (m, 1H), 8.30 (d, J=2.8 Hz, 1H), 8.58 (d, J=5.7 Hz, 1H), 9.47 (s, 1H), 10.86 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C@H:10]2[CH2:15][C@@H:14]([C:16](=[O:23])[CH2:17][C:18](OCC)=[O:19])[CH2:13][CH2:12][N:11]2[C:24]([O:26][CH3:27])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[C:1]([C:5]1[S:9][C:8]([C@H:10]2[CH2:15][C@@H:14]([C:16]3[O:23][NH:30][C:18](=[O:19])[CH:17]=3)[CH2:13][CH2:12][N:11]2[C:24]([O:26][CH3:27])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(C)(C)C)s2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(C)(C)C)s1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 49.2 %

Procedure:
Cis-methyl 2-(5-tert-butylthiophen-2-yl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (963 mg, 2.43 mmol) was dissolved in methanol (15 mL) and cooled to −40° C. NaOH (0.641 mL, 2.43 mmol) dissolved in water (1 mL) was added and stirred for 20 min. Hydroxylamine (50% by weight in water, 0.149 mL, 2.43 mmol) was added and the reaction stirred at −40° C. for 3 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M HCl (12.58 mL, 75.48 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (150 mL) and water (150 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (150 mL). The combined organic phase were dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 35-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(5-tert-butylthiophen-2-yl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (436 mg, 49.1%) was isolated as a white solid. MS m/z 363 (M−H)−
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][NH:32][CH3:33]>CN(C=O)C>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:32]([CH3:33])[CH3:31])[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: CNC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccnc(N(C)C)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
2-Chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide and dimethylamine (40% in water) in DMF (1 ml) were heated at 85° C. for 96 h in a sealed tube. The reaction mixture was concentrated under vacuum, purified by preparative HPLC and the product fractions reduced to dryness under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(dimethylamino)isonicotinamide. NMR; δH [2H6]—DMSO 10.29,(1H, s), 8.62,(1H, t), 8.22,(1H, d), 7.93,(2H, d), 7.70,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.03,(1H, s), 6.99,(1H, d), 3.16,(2H, t), 3.07,(6H, s), 2.20,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.88 min, MH+429.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1c(F)cccc1Cl
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4c(F)cccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(2-chloro-6-fluoro-phenyl)-1-methyl-propyl]-amine and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([C:9]1[O:13][C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=1)[CH3:8]>C1COCC1>[CH2:7]([C:9]1[O:13][C:12]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCc1ccc(CCC(=O)OC)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(CCCO)o1
Temperature: 0 °C
Yield: 84.7 %

Procedure:
To a mixture of 3.42 g (90.1 mmol) of LAH in THF under nitrogen and stirring at 0° C. was added dropwise 14.9 g (81.9 mmol) of methyl 3-(5-ethyl-2-furyl)propanoate in THF. The reaction mixture was quenched with 3.4 mL of water, 3.4 mL of sodium hydroxide solution, and 10.2 mL of water. Magnesium sulfate was added to the mixture with stirring, filtered and concentrated in vacuo. The residue was passed through silica gel and eluted with ethyl acetate/hexane (2:8) to yield 10.7 g (85%) of the desired product as a clear colorless oil, used in the next preparation without further purification.
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:5].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH3:1][N:2]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:3]=[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:5]
Reactant: O=C(Cl)c1ccccc1
Reactant: CNN=C(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=NN(C)C(=O)c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.1 %

Procedure:
To 100 ml of pyridine is added successively, under dry nitrogen, 8.83 gm (0.0592 mole) of 1-methyl-2-[1-(4-pyridinyl)ethylidene]hydrazine and 6.87 gm (0.0592 mole) of benzoyl chloride. Upon addition of the acid chloride the color changes from clear orange to a clear, deep rose color which changes to an orange solid within about 5 minutes. The reaction mixture is stirred at room temperature overnight, the pyridine removed via a Buchi evaporator at 70° C. and the cooled residue slurried with water to yield 6.32 gm (42%) of the title compound having a melting point of 128.3° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[C:34]([C:46]([F:49])([F:48])[F:47])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:59])=[C:34]([C:46]([F:49])([F:48])[F:47])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4)c(C(F)(F)F)c2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4)c(C(F)(F)F)c2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 27.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfanyl]-3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.36 g) in methylene chloride (10.8 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.11 g) in methylene chloride (7.2 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfinyl]-3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 236) (100 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.C([Li])CCC.CCCCCC.ClCC[I:37]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([I:37])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: ClCCI
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1nc(N2CCOCC2)c2nc(I)n(C3CCCCO3)c2n1
Reaction time: 1.5 h

Procedure:
To a solution of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1.0 g, 3.1 mmol) and N,N,N′,N′-tetramethylenediamine (0.7 mL, 4.6 mmol) in anhydrous THF (23 mL) at −42° C. was added 2.5 M n-butyllithium solution in hexane (4.3 mL, 11.0 mmol) dropwise down the side of the reaction flask. The reaction was stirred at cold temperature and maintained for 1 h before 1-chloro-2-iodoethane (1.4 mL, 15 mmol) was introduced. Stirring was continued for 1.5 h period. LC-MS indicated the reaction had reached complete conversion to the desired product. The reaction mixture was subsequently quenched and worked up with sat. NH4Cl aqueous solution which was extracted with EtOAc (3 times), dried over MgSO4, filtered and concentrated in vacuo to give 4-(2-chloro-8-iodo-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (1.4 g, 84% yield) determined by LC-MS to be >90% purity. MS (ESI+): m/z 450.1 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)Cc1cccc(CCCCO)c1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)Cc1cccc(CCCCOS(=O)(=O)c2ccc(C)cc2)c1
Yield: 63.4 %

Procedure:
A solution of {3-[4-hydroxybutyl]phenyl)acetic acid methyl ester (300 mg, 1.35 mmol) and p-toluenesulfonyl chloride (513 mg, 2.7 mmol) in pyridine (5 ml) was stirred at RT for 18 hr. The reaction was diluted with water (50 ml) and extracted with diethyl ether. The organic extracts were washed with water and cold 1N HCl, dried, and the solvent evaporated to give the title compound as an oil (322 mg, 63%). MS (ESI) 377.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[CH2:9][O:10][CH3:11])=[CH:6][N:7]=1
Reactant: COCC(O)c1ccc(Br)nc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(OC1CCCCO1)c1ccc(Br)nc1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a mixture of 1-(6-bromopyridin-3-yl)-2-methoxyethanol (15.26 g), p-toluenesulfonic acid monohydrate (0.63 g) and tetrahydrofuran (65 ml) was added 3,4-dihydro-2H-pyran (7.76 g) at room temperature over 30 min, and the mixture was stirred for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (19.66 g, yield 94%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). MS: 318 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:14])[NH:5][C:4](=[O:15])[CH:3]=1.[N:16]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C.O>[NH2:16][C:3]1[C:4](=[O:15])[NH:5][C:6](=[O:14])[N:7]([CH2:8][C:9]2[O:13][CH:12]=[CH:11][CH:10]=2)[C:2]=1[NH2:1]
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccco1
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(N)n(Cc2ccco2)c(=O)[nH]c1=O
Temperature: 70 °C
Yield: 53.4 %

Procedure:
6-Amino-1-furfuryluracil (3.0 g, 14.5-mmol) was dissolved with heating in 30% aqueous acetic acid (30 ml) and then a solution of sodium nitrite (1.7 g, 24.6 mmol) in water (5 ml) was added dropwise. The reaction was heated to 70° C. for 30 min and then cooled to 0° C. The solids were collected by filtration and rinsed with cold water (20 ml). The solids were dissolved into concentrated aqueous ammonium hydroxide solution (10 ml) and then a solution of sodium hydrosulfite (9.8 g, 47.8 mmol) in water (30 ml) was added in one portion. After heating at 80° C. for 1 hour, the slurry was cooled to ambient temperature. The solids were collected by filtration, rinsed with water (4×50 ml) and vacuum dried over phosphorus pentoxide to give 5,6-diamino-1-furfuryluracil (1.72 g, 53% yield) as a brown solid.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](I)[CH:13]=1>C(N(CC)CC)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:13]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cncc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cncc(Br)c1
Reaction time: 16 h
Yield: 99 %

Procedure:
Add trimethylsilylacetylene (54.6 mL, 389.4 mmol) to a stirred mixture of 3-bromo-5-iodopyridine (100 g, 354 mmol) in triethylamine (800 mL) and acetonitrile (800 mL). Purge the system with nitrogen and add bis(triphenylphosphine)palladium(II) dichloride (3.54 mmol, 2.48 g) and stir for 16 h. Concentrate and suspend the residue in 1800 mL of hexanes. Stir for 2 h, filter and concentrate to give the title compound as a brown solid (92g, 99%).
Reaction SMILES: [Si:1]([N:8]1[CH:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10](C(=O)CC)[C:9]1=[O:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1>[Si:1]([N:8]1[CH:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][C:9]1=[O:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(=O)C1C(=O)N([Si](C)(C)C(C)(C)C)C1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 47 %

Procedure:
A solution of 1-t-butyldimethylsilyl-3-propionyl-4- tritylthio-2-azetidinone (26 g, 50 mmol) and sodium borohydride (7.6 g, 200 mmol) in THF (400 ml) was stirred at room temperature for 18 h. It was poured onto ice-HCl (1 N) (pH 6) and extracted with ether. The acidic phase was extracted several times with ether and the combined ether solution was washed with brine, dried (NA2SO4) and evaporated to give an amorphous solid, 25.0 g. This crude product was chromatographed on SiO2 (ACT. 1, 400 g) and eluted first with CH2Cl2 to give 10.8 g of 1-t-butyldimethylsilyl-4-tritylthio-2-azetidinone. Elution with 20% ether in CH2Cl2 gave 10.3 g of the title compound as a mixture of two isomeric trans alcohols. This was separated by hplc (Water Associates, System 500), and using 10% EtOAc in CH2Cl2 as eluent. Isomer C, white solid, 3.8 g; mp (pet. ether) 134°-36° C. 1Hmr (CDCl3) δ:7.1-7.8 (15H, m, STr), 4.35 (H, d), 3.1 (H, dd), 2.5 (H, m), 0.7-1.7 (5H, m), 0.97 (9H, s) and 0.25 ppm (6H, s). Anal. calcd for C31H39NO2SSi: C 71.91, H 7.59, N 2.71; found: C 71.51, H 7.60, N 2.96. Isomer B, white solid, 5.4 g; mp (pentane-pet. ether) 97°-99° C. 1Hmr (CDCl3) δ:7.1-7.8 (15H, m, STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (H, m), 0.7-1.7 (5H, m), 0.85 (9H, s) and 0.1 ppm (6H, s). 97°-99° C. 1Hmr (CDCl3) δ:7.1-7.8 (15H, m, STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (H, m), 0.7-1.7 (5H, m), 0.85 (9H, s) and 0.1 ppm (6H, s). Total yield of these two alcohols (based on recovered starting material was 67.5%.
Reaction SMILES: [F:1]/[C:2](=[CH:8]\[CH3:9])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][CH2:9]/[CH:8]=[C:2](\[F:1])/[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: C/C=C(\F)C(=O)OCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C(F)=C/CBr
Yield: 79.3 %

Procedure:
Ethyl 2-fluorocrotonate (6.0 g) (prepared according to E. D. Bergmann and I. Shahak, J.Chem.Soc., 4033, 1961) N-bromosuccinimide (8.1 g) and benzoyl peroxide (0.15 g) was dissolved in carbon tetrachloride (120 ml) and heated at reflux for 3-5 hours. The mixture was cooled, filtered and the filtrate evaporated to dryness under reduced pressure. Chromatography on silica eluting with 10% diethyl ether: hexane gave ethyl 4-bromo-2-fluorocrotonate as a yellow oil (7.6 g). NMR 1H: 1.5(3H,t), 4.1(2H,dd), 4.4(2H,q), 6.4(1H,dt).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH2:24]>CN(C=O)C.C(O)(C)C>[ClH:2].[OH:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[CH3:28])[NH:24][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: COCCOc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Nc3ccc(C)c(O)c3)c2cc1OC
Temperature: 150 °C
Yield: 52.4 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (250 mg, 0.82 mmol) and 3-hydroxy-4-methylaniline (123 mg, 1 mmol) in DMF (5 ml) was heated at 150° C. for 30 minutes. The mixture was diluted with isopropanol and the resulting solid collected by filtration and washed with isopropanol to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (168 mg, 58%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[C:17](OC)=[O:18])=[O:6])[CH:2]=[CH2:3].[BH4-].[Na+].S(=O)(=O)(O)O>O1CCCC1.C(O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][OH:18])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)OC
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine (27.12 g: 74.0 mmole) in a mixture of tetrahydrofuran (94 ml) and ethanol (140 ml), sodium borohydride (12 g: 31.7 mmole) is added in a nitrogen atmosphere under ice cooling. The mixture is stirred for 4 hours at room temperature. To the reaction mixture concentrated sulfuric acid (8.8 ml: 158.4 mmole) is added dropwise under ice cooling. The reaction mixture is concentrated to half a volume in vacuo, and diluted with ethyl acetate (100 ml) and ice water (100 ml). The organic layer is taken, successively washed with aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and concentrated in vacuo to give (2S,4R)-1-allyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (19.33 g). Yield: 77%. Colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:14][CH:15]([OH:21])[CH2:16][C:17](OC)=[O:18]>C(O)C>[CH2:16]1[C:17](=[O:18])[N:2]([CH2:3][C:4]([NH2:6])=[O:5])[CH2:14][CH:15]1[OH:21]
Reactant: NCC(N)=O
Reactant: COC(=O)CC(O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)CN1CC(O)CC1=O
Yield: 75 %

Procedure:
In 10 ml of ethanol, 1.11 g (10 m.moles) of glycinamide hydrochloride, 1.06 g (10 m.moles) of sodium carbonate, and 1.53 g (10 m.moles) of methyl 4-chloro-3-hydroxybutyrate were stirred and refluxed simultaneously for 20 hours. After completion of the reaction, the warm reaction mixture was filtered to expel inorganic salts. The filtrate was analyzed by gas chromatography (Fluoxylate-K 1% Uniport HP 100/120, column length 0.5 m and column temperature 220° C., RT 2.8 min) (hereinafter referred to as "GC" for short). Consequently, the reaction was found to have produced oxiracetam in a yield of 75%. The filtrate was concentrated, dissolved in a small amount of water, and poured on a bed of 40 ml of Amberlite IR-120 (--SO3H form) (tradename: Rohm & Haas Co.). The adsorbate was eluted with water. The eluate was fractionated, with the first and second fractions discarded and the third and following fractions were collected. The collected fractions were concentrated. The concentrate was dissolved in methanol and the solution was ice cooled ad crystallized with crystals of oxiracetam used as mother crystals. The produced crystals were collected and vaccum dried, to afford 0.55 g (yield of isolation 35%) of oxiracetam, having a melting point of 155° to 160° C. (as compared with 161° to 163° C. reported in the specification of Japanese Patent Publication Sho 58-22,034/1983).