Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][CH2:6][CH3:7].[C:9]([CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])#[N:10].C(O)(=O)C.N1CCCCC1>>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:9]#[N:10])=[C:4]([CH2:5][CH2:6][CH3:7])[CH2:3][CH2:2][CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CCC(=O)OCc1ccccc1
Reactant: CCCC(=O)CCC
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCCC(CCC)=C(C#N)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 26.5 %

Procedure:
To a mixture of 4-heptanone (2.0 mL, 14.3 mmol) and benzyl cyanoacetate (2.51 g, 14.3 mmol) at 0° C. was added acetic acid (0.08 mL, 1.43 mmol), then piperidine (0.14 mL, 1.43 mmol) dropwise. The ice bath was removed, and stirring continued for 10 min. Additional acetic acid (0.08 mL) and piperidine (0.14 mL) were added, followed by the additional of oven-dried 4A molecular sieves such that stirring was not impeded. The mixture was stirred for 1 h, then partitioned between EtOAc and sat. sodium bicarbonate (NaHCO3) (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to provide 1.03 g (27%) of 2-cyano-3-propyl-hex-2-enoic acid benzyl ester as a colorless oil. 1H NMR (CDCl3) δ 7.35 (m, 5H), 5.24 (s, 2H), 2.71 (m, 2H), 2.52 (m, 2H), 1.60 (m, 2H), 1.49 (m, 2H), 1.00 (t, J=7.3 Hz, 3H), 0.95 (t, J=7.3 Hz, 3H). 13C NMR δ 182.46, 161.72, 135.37, 128.83, 128.58, 128.21, 115.87, 104.77, 67.26, 40.77, 35.80, 22.36, 21.86, 14.54, 14.32. LRMS: m/z 272.1 (M+1). IR (neat) 2223, 1729 cm−1. Anal. Calcd for C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.44; H, 7.80; N, 5.22.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[CH:13]=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=23)=[O:11])[C:6]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH:29]([F:31])[F:30])=[N:5]1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][NH2:39])[CH:33]=1>CC#N>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH:29]([F:31])[F:30])=[C:21]([C:6]2[C:7]([NH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][CH:18]=[N:17][C:16]=34)=[O:11])=[CH:8][N:4]([CH2:3][CH2:2][NH:39][CH2:38][C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)[N:5]=2)[CH:26]=1
Reactant: O=C(Nc1cn(CCBr)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: NCc1cccnc1
Solvent: CC#N
Product: O=C(Nc1cn(CCNCc2cccnc2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (150 mg, 0.29 mmol) and pyridin-3-ylmethanamine (158 mg, 1.46 mmol) in MeCN (3 mL) was stirred at 70° C. for 12 h. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-2): Column, C18 silica gel; mobile phase, CH3CN:H2O=5:95 increasing to CH3CN:H2O=30:42 within 12 min; Detector, UV 254 nm. This resulted in 57.7 mg (37%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-[(pyridin-3-ylmethyl)amino]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 25) [M+H]+=539.1, RT=0.87 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.69-8.67 (m, 2H), 8.50 (d, 1H, J=1.8 Hz), 8.41 (dd, 1H, J=1.5, 4.8 Hz), 8.38 (s, 1H), 7.73-7.70 (m, 1H), 7.61 (dd, 1H, J=2.7, 8.7 Hz), 7.59 (d, 1H, J=2.4 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.33-7.28 (m, 2H), 6.99 (t, 1H, J=73.2 Hz), 4.24 (t, 2H, J=6.0 Hz), 3.75-3.72 (m, 2H), 3.01-2.94 (m, 2H), 2.27 (br, 1H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].OC1OC[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[C:9]1=O>C(Cl)Cl.CN(C=O)C>[Cl:4][CH:2]1[O:3][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=2)[C:1]1=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1C(O)OCN1c1cccc(OC(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C(Cl)OCN1c1cccc(OC(F)(F)F)c1
Temperature: 25 °C

Procedure:
Oxalyl chloride (2.7 ml) was added dropwise over 1 min to a stirred solution of 5-hydroxy-3-(3-trifluoromethoxyphenyl)oxazolidin-4-one (8.17 g) in DCM (60 ml) containing DMF (1 drop) at 0° C. The mixture was allowed to warm to room temperature and once gas evolution had stopped the solvent was removed in vacuo to give the sub-title compound (8.5 g) which was used directly in the next step.
Reaction SMILES: C(OC([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl.C1(C)C=CC=CC=1>[NH2:8][C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[N:23][CH:22]=2)=[CH:17][CH:16]=1)[OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccc(CNS(C)(=O)=O)nc3)cc2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)cn1
Yield: 86.3 %

Procedure:
(4S,5R)-tert-butyl4-(fluoromethyl)-2,2-dimethyl-5-(4-(6-(methylsulfonamidomethyl)pyridin-3-yl)phenyl)oxazolidine-3-carboxylate (1800 mg, 3.64 mmol) is dissolved in dichloromethane (20 mL), and treated with trifluoroacetic acid (5.4 mL), for 4 h at room temperature. The reaction mixture is diluted with toluene (30 mL) and concentrated to a syrup. Obtained crude compound is basified with aqueous sodium bicarbonate, extracted with ethyl acetate. Extracts are dried over Na2SO4, filtered, and concentrated to give the title compound (1110 mg): m/z (CI) M+H 354.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[O:16][CH3:17])(=[O:8])=[O:7])([CH3:4])[CH3:3].C1C(=O)N([Br:25])C(=O)C1>C(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:25][CH2:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([S:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:8])=[O:7])[CH:14]=1
Reactant: COc1ccc(C)cc1S(=O)(=O)NC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Product: COc1ccc(CBr)cc1S(=O)(=O)NC(C)(C)C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
A mixture of 27 g of N-(1,1-dimethylethyl)-2-methoxy-5-methylbenzenesulfonamide (E. H. Huntress and F. H. Carten, J. Am. Chem. Soc., 62 (1940), 603), 19.6 g NBS and 0.3 g azobisisobutyronitrile in 200 ml CH2Cl2 was refluxed and illuminated with a sun lamp. After 8 hours the lamp was turned off and the reaction was refluxed for another 24 hr. The reaction was allowed to cool. The reaction mixture was washed with 200 ml of a 1:1:1:1 mixture of brine:sodium sulfite-sodium bicarbonate-water. The organic layer was dried (MgSO4), treated with charcoal and filtered through a 5 g plug of silica gel. The plug was washed with 100 ml of chloroform. The combined organic fractions were evaporated to give 34 g of solid, m.p. 137°-142° C.;
Reaction SMILES: C([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:12]2=[N:11][C:10]=1[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([CH3:41])[S:35]1(=[O:43])=[O:42])=[O:24])[CH2:17][CH2:16]3)C1C=CC=CC=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:23]([C:10]2[N:11]=[C:12]3[N:18]4[CH2:17][CH2:16][CH:15]([CH2:20][CH2:19]4)[CH2:14][N:13]3[C:21](=[O:22])[C:9]=2[OH:8])=[O:24])=[C:28]([N:34]2[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([CH3:41])[S:35]2(=[O:43])=[O:42])[CH:29]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]
Reactant: CN1C(C)(C)CN(c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CC2CCN3CC2)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(C)(C)CN(c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2O)CC2CCN3CC2)S1(=O)=O

Procedure:
A solution of 3-(benzyloxy)-N-(4-fluoro-2-(4,4,5-trimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)benzyl)-4-oxo-6,7,8,9-tetrahydro-4H-7,10-ethanopyrimido[1,2-a][1,3]diazepine-2-carboxamide (0.054 g, 0.088 mmol) in CH2Cl2 (5 mL) and trifluoroacetic acid (0.7 mL, 9.09 mmol) was stirred at room temperature for 18 h. The solution was concentrated to give a yellow oil that was purified by preparative HPLC (Solvent A=10% methanol/90% H2O/0.1% trifluoroacetic acid; Solvent B=90% methanol/10% H2O/0-1% trifluoroacetic acid; Start % B=20; Final % B=100; Gradient time=20 min; Stop time=25 min; Column=Sunfire 19×100 mm, C18, 5 μm) to give the title compound (as a trifluoroacetic acid salt) as a pale yellow solid (0.0075 g, 13% yield). LCMS (M+H) calcd for C23H30FN6O5S: 521.19; found: 521.25. 1H NMR (500 MHz, CDCl3) δ: 8.64 (1H, t, J=5.6 Hz), 7.60 (1H, dd, J=8.2, 6.4 Hz), 7.22 (1H, dd, J=9.2, 2.4 Hz), 7.11 (1H, td, J=8.1, 2.2 Hz), 4.64 (2H, d, J=5.8 Hz), 4.00-3.94 (2H, m), 3.79-3.76 (2H, m), 3.72 (2H, s), 3.58 (2H, s), 3.03 (1H, brs), 2.73 (3H, s), 2.32-2.28 (2H, m), 1.91-1.87 (2H, m), 1.46 (6H, s).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@@H:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[C@H:6]([C:19](OCC)=[O:20])[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].C(OCC)(=O)C.O>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C@@H:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[C@H:6]([CH2:19][OH:20])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CN(C(C)=O)CC[C@H]1N1CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)N1CC[C@@H](N2CCc3ccccc32)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution of trans-1-(1-acetyl-3-ethoxycarbonyl-piperidin-4-yl)indoline (780 mg) in ethanol (40 ml) was added sodium borohydride (5.7 g) in 3 portions at 30 min. intervals. After stirring at room temperature overnight, sodium borohydride (3.3 g) was added thereto and the resultant mixture was stirred for additional 4 hr. Then ethyl acetate (20 ml) and water (50 ml) were successively added carefully to the reaction mixture followed by extraction with ethyl acetate (50 ml) for three times. The organic phase was washed with water (100 ml) twice and brine once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol system) to give the title compound (250 mg) as a yellow powder (yield: 39%).
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13].[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21](Cl)=[O:22]>C1COCC1.CCOCC>[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[C:21]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:22]
Reactant: O=C(Cl)c1cc(Br)cc([N+](=O)[O-])c1
Reactant: CC(C)(C)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Reaction time: 17 h

Procedure:
A solution of n-butyllithium in hexane (12.8 mL of 2.5 M, 32 mmol) is added with stirring to t-butanol (46 mL) at 25° C. under an argon atmosphere. After 30 min the mixture is treated dropwise with a solution of 3-bromo-5-nitro-benzoyl chloride (J. Mindl, Collect. Czech. Chem. Commun. (1973), 38, 3496–505; 32 mmol) in dry THF (40 mL) and stirred for a further 17 h. The mixture is then treated with ether (250 mL) and washed with brine. The ether solution was dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by column chromatography (silica gel, eluent 20% ethyl acetate in hexane) and recrystallised from ether-hexane to afford the title compound as colourless crystalline solid, m.p. 77–78° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1)([O-])=O>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[N:8][CH:9]=1
Reactant: C[Si](C)(C)CCOc1ccc([N+](=O)[O-])cn1
Agent: O=[Pt]
Solvent: CCO
Product: C[Si](C)(C)CCOc1ccc(N)cn1
Yield: 62.1 %

Procedure:
5-Nitro-2-[2-(trimethylsilyl)ethoxy]pyridine (36.8 g) was dissolved in ethanol (270 ml) and catalytically hydrogenated at atmospheric pressure over platinum oxide (300 mg). The catalyst was removed by filtration through diatomaceous earth. The solvent was removed by evaporation and the residue triturated with hexane to give 5-amino-2-[2-(trimethylsilyl)ethoxy]pyridine (20.0 g), as dark crystals, m.p. 59°-61° C.; NMR: 0.0(s,9H), 0.95-1.05(m,2H), 3.1-3.3(br s, 2H), 4.2-4.3(m,2H), 6.5(d,1H), 6.95(dd,1H), 7.6(d,1H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]([C:11]2[CH:20]=[CH:19][C:14]3[C:15](=[O:18])[O:16][CH2:17][C:13]=3[C:12]=2[CH3:21])[OH:10])[CH2:4]1.[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[C@@H:33]1[CH2:35][O:34]1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(O)C>[OH:10][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:8][N:5]1[CH2:6][CH2:7][C@@H:3]([NH:2][CH2:35][C@H:33]([OH:34])[C:24]2[CH:25]=[CH:26][C:27]3[C:28](=[O:32])[O:29][CH2:30][C:31]=3[C:23]=2[CH3:22])[CH2:4]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c([C@@H](O)CN2CC[C@@H](N)C2)ccc2c1COC2=O
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cc1c([C@@H](O)CN[C@@H]2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)C2)ccc2c1COC2=O

Procedure:
A microwave vial was charged with 5-{(1R)-2-[(3R)-3-aminopyrrolidin-1-yl]-1-hydroxyethyl}-4-methyl-2-benzofuran-1(3H)-one hydrochloride [INTERMEDIATE 4] (100 mg, 0.32 mmol), 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one [INTERMEDIATE 2B] (61 mg, 0.32 mmol), MP-carbonate resin (200 mg), and ethanol (1 mL). The reaction mixture was heated in a microwave reactor at 150 C for 1 hour, and then cooled, filtered and concentrated in vacuo. The resulting residue was dissolved in DMSO (1 mL) and purified by HPLC to provide 5-{(1R)-1-hydroxy-2-[(3R)-3-{[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]amino}pyrrolidin-1-yl]ethyl}-4-methyl-2-benzofuran-1(3H)-one.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:8])(=[NH:7])[CH3:6].C([O:11][C:12](=O)[CH2:13][C:14](=O)[C:15]([CH3:18])([CH3:17])[CH3:16])C>CO>[CH3:6][C:5]1[N:8]=[C:12]([OH:11])[CH:13]=[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=1
Reactant: CCOC(=O)CC(=O)C(C)(C)C
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1nc(O)cc(C(C)(C)C)n1
Yield: 63.2 %

Procedure:
A suspension of 21.6 g (0.4 mol) of sodium methylate, 19.4 g (0.2 mol) of acetamidine hydrochloride, 34.4 g (0.2 mol) of pivaloylacetic acid ethyl ester and 100 ml of methanol was heated for 10 hours under reflux and then evaporated, and the residue was taken up in 350 ml of water. Concentrated hydrochloric acid was added to the aqueous solution, while cooling with ice, to a pH of about 6, and the mixture was then extracted twice with 200 ml of methylene chloride each time. The combined methylene chloride extracts were dried over sodium sulphate and then concentrated. 21 g (63% of theory) of 2-methyl-4-hydroxy-6-tert.-butyl-pyrimidine were obtained in the form of colorless crystals of melting point 131°-132° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:17]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC[O:33]CC>>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([OH:33])([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CCOCC
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: [Li]CCCC
Product: OC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 22.5 g. (0.1 mol) of p-bromobenzotrifluoride in 50 ml. of ether is stirred under argon at ice-bath temperature while 50 ml. of 2M butyl lithium solution is added dropwise. The solution is then stirred at room temperature for 15 minutes, and then cooled again to 0°C. A solution of 17.7 g. of N-benzylpiperidone in 50 ml. of ether is then added over 30 minutes and the reaction is stirred at room temperature for 3 hours. The solution is poured into cracked ice-water and filtered to remove some solid. The filtrate is diluted with methylene chloride, and the organic layer is dried and evaporated. The residue is triturated with petroleum ether (b.p. 30°-60°C.), and the solid is collected, washed with ether and dried to give white solid, m.p. 115°-117°C.
Reaction SMILES: B.[Na].[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([CH2:12][CH:13]=[O:14])=[CH:9][CH:10]=[CH:11][C:4]1=2.O.Cl>CO.C(OCC)(=O)C>[S:3]1[CH:7]=[CH:6][C:5]2[C:8]([CH2:12][CH2:13][OH:14])=[CH:9][CH:10]=[CH:11][C:4]1=2
Reactant: O=CCc1cccc2sccc12
Agent: B
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: OCCc1cccc2sccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
In 8 mL of 90% methanol is suspended 0.16 g of sodium boron hydride. At an ice-cooled temperature, a solution of 1.45 g of 2-benzo[b]thiophen-4-ylacetaldehyde in 6 mL of methanol is dropwise added to the suspension obtained above, and the resulting mixture is stirred at ambient temperature for 30 minutes. Water and ethyl acetate are added to the reaction mixture, pH is adjusted to 2.0 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: toluene:ethyl acetate=50:1 to 2:1) to obtain 0.88 g of 2-benzo[b]-thiophen-4-yl-1-ethanol.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:42])[CH2:9][CH2:10][CH:11]([C:38]([O:40][CH3:41])=[O:39])[NH:12][C:13](=[O:37])[CH:14]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH:15][C:16](=[O:32])[CH:17]([CH2:29][C:30]#[CH:31])[NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[N+:2]=[N-:3].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:21]([O:20][C:19]([NH:18][CH:17]1[CH2:29][C:30]2=[CH:31][N:1]([N:2]=[N:3]2)[CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:42])[CH2:9][CH2:10][CH:11]([C:38]([O:40][CH3:41])=[O:39])[NH:12][C:13](=[O:37])[CH:14]([CH2:33][CH:34]([CH3:35])[CH3:36])[NH:15][C:16]1=[O:32])=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#CCC(NC(=O)OCc1ccccc1)C(=O)NC(CC(C)C)C(=O)NC(CCC(=O)NCCCN=[N+]=[N-])C(=O)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1CCC(=O)NCCCn2cc(nn2)CC(NC(=O)OCc2ccccc2)C(=O)NC(CC(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
To a solution of compound 10 (0.3 g: 0.512 mmol) in dry DCM (420 mL) under N2 atmosphere, was added DBU (0.233 g; 1.53 mmol) at room temperature with vigorous stirring. After 15 min, Cu(I)Br (0.073 g; 0.512 mmol) was added and the reaction mixture was stirred for 12 h at room temperature. The reaction mixture was quenched by adding 3M HCl (100 mL) and the aqueous layer was separated and extracted with DCM (2×500 mL). The combined organic layers were washed with brine (300 mL), and dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give a crude product which was purified using flash chromatography (silica gel; methylene chloride/methanol 99:1) to give compound 11 as a white solid (0.14 g; 45% yield). 1H NMR (DMSO-d6) δ 8.5 (s, 1H), 8.1 (s, 1H), 7.5 (s, 1H), 7.3 (m, 5H), 5.0 (m, 2H), 4.3 (m, 1H), 4.1 (m, 2H), 3.6 (m, 2H), 3.3 (s, 3H), 3.11 (m, 2H), 2.88 (m, 2H), 2.98-2.24 (m, 5H), 1.49-1.8 (m, 5H), 0.86 (m, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].[C:13](=S)=[S:14].IC.[H-].[Na+].[CH3:20][S:21]([CH3:23])=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:20]([S:14][CH3:13])[S:21][CH3:23])[C:11]#[N:12]
Reactant: S=C=S
Reactant: N#CCc1nc2ccccc2o1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CSC(SC)=C(C#N)c1nc2ccccc2o1
Temperature: 10 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of benzoxazol-2-ylacetonitrile (2.07 g, 13.1 mmol) dissolved in 35 mL of DMSO at room temperature under argon atmosphere was added carbon disulfide (1.10 g, 14.4 mmol) followed by iodomethane (5.20 g, 36.7 mmol). This solution was then cooled to 10° C. and sodium hydride (1.05 g, 60% by wt in oil, 26.3 mmol) was added over a period of several minutes. The solution was allowed to warm to room temperature and stirred overnight. The reaction was then quenched with an ammonium chloride solution and was extracted with 5×50 mL of ethyl acetate. The ethyl acetate was washed with brine solution (3×50 mL) and water (3×30 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated to yield a red oil. The crude material was purified by flash column chromatography eluting with CH2Cl2:MeOH=98:2 to yield 1.96 g (57%) of the desired product as a yellow oil. MS (m/z, ES+): 236.68 (M+1, 100%). The following examples illustrate the preparation of compounds disclosed in this invention.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[C:19]([C:13](=[CH:12][NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCOC(=O)C=CNc1ccccc1OC
Reactant: CCCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(=O)C(=CNc1ccccc1OC)C(=O)OCC
Temperature: -30 °C
Yield: 62.6 %

Procedure:
50% Sodium hydride (4.8 g, 0.1 mol) was washed with petroleum ether and then suspended under nitrogen in dry tetrahydrofuran (50 ml) at -30° C. Ethyl 3-(2-methoxyphenylamino)acrylate (17.4 g, 0.1 mol) in dry tetrahydrofuran (100 ml) was added dropwise to the stirred suspension keeping the temperature below -20° C. Cooling was removed and the mixture was stirred until a deep red colour was obtained. The mixture was re-cooled to -30° C. and hexanoyl chloride (13.8 ml, 0.1 mol) in dry tetrahydrofuran (50 ml) was added dropwise. Cooling was again removed and the mixture was stirred for 2 hours. The mixture was partitioned between 10% hydrochloric acid and dichloromethane then washed with water and brine, dried and evaporated to afford an oil which was chromatographed (silica gel, chloroform) to give ethyl 2-hexanoyl-3-(2-methoxyphenyl-amino)acrylate, (20 g, 62.7%).
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C(O)(=O)CC.[OH:18][C@H:19]([CH2:24][CH3:25])[CH2:20][C:21]([O-:23])=[O:22]>>[OH:18][C@H:19]([CH3:24])[CH2:20][C:21]([OH:23])=[O:22].[OH:18][C@H:19]([CH2:24][CH3:25])[CH2:20][C:21]([OH:23])=[O:22]
Reactant: CC[C@@H](O)CC(=O)[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCC(=O)O
Product: CC[C@@H](O)CC(=O)O
Product: C[C@@H](O)CC(=O)O

Procedure:
Ralstonia eutropha NCIMB 11599 was cultured in a medium containing 10 g/L of glucose and 1 g/L of propionic acid, according to the method previously reported (Kim et al., Enzyme Microbial. Technol., 16: 556-561, 1994). Poly-(R)-(−)-3-hydroxybutyrate-co-(R)-(−)-3-hydroxyvalerate (PHB/V) copolymer (containing 8 mol % (R)-(−)-3-hydroxyvalerate) was accumulated to a content of 63% of cell dry weight, which was auto-degraded to produce (R)-(−)-3-hydroxybutyric acid and (R)-(−)-3-hydroxyvaleric acid. Cells were dispersed in water at a copolymer concentration of 27.4 g/L. Auto-degradation reaction was carried out at pH 7 and 30° C. for 35 hours. As a result, 5.8 g/L of (R)-(−)-3-hydroxybutyric acid and 0.6 g/L of (R)-(−)-3-hydroxyvaleric acid were obtained. Therefore, a mixture of (R)-(−)-3-hydroxybutyric acid and (R)-(−)-3-hydroxyvaleric acid can be efficiently prepared from the accumulated PHB/V polymer by auto-degradation of the copolymer, and they can be separated using LC or HPLC (Ref. Example 16).