Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[CH2:10](O)[CH2:11][CH:12]=[CH2:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([O:8][CH2:13][CH2:12][CH:11]=[CH2:10])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1
Reactant: C=CCCO
Reactant: Oc1ccc(Br)nc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCOc1ccc(Br)nc1Br
Yield: 84.9 %

Procedure:
To a stirred mixture of 2,6-dibromopyridin-3-ol (47.3 g, 0.188 mol) and but-3-en-1-ol (13.8 g, 0.191 mol) in anhydrous THF (200 mL) at 0° C. was added PPh3 (59.4 g, 0.226 mol), followed by diisopropylazo dicarboxylate (DIAD, 41.77 g, 0.207 mol). The mixture was heated at reflux for 1 hour and then concentrated in vacuo to give a dark brown oil. The oil was dissolved in Ethyl acetate, washed with saturated NaHCO3 solution and brine, dried with Na2SO4, and concentrated in vacuo. Petroleum (300 mL) was added to the crude product mixture. The white solid was removed by filtration, and the filtrate was purified by silica gel chromatography (petroleum/Ethyl acetate, 30/1) to afford compound the title compound as oil (49 g, 85%). 1H NMR (400 Mz, DMSO-d6): δ: 2.62-2.59 (m, 2H); 4.07-4.03 (t, J=6, 2H); 5.22-5.11 (m, 1H); 5.96-5.83 (m, 1H); 7.01 (d, J=7.2); 7.33 (d, J=9.3, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][CH:19](C)C)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].BrC1[S:30][C:31]([N+:34]([O-:36])=[O:35])=[N:32][N:33]=1>CC#N>[Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:8][B:7]([OH:17])[C:6]=2[CH:5]=[C:4]([O:18][C:19]2[S:30][C:31]([N+:34]([O-:36])=[O:35])=[N:32][N:33]=2)[CH:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC(C)C)cc(Cl)c21
Reactant: O=[N+]([O-])c1nnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(Cl)c21
Temperature: -30 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
To a solution of ethyl 2-(4-chloro-1-hydroxy-6-isopropoxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (400 mg, 1.48 mmol) in MeCN (5 mL) was added anhydrous K2CO3 (414 mg, 3 mmol) and the mixture was cooled to −30° C. To this mixture was added 2-bromo-5-nitro-1,3,4-thiadiazole (420 mg, 2 mmol). The reaction mixture was stirred at −30° C. for 5 h. The reaction was quenched by addition of ice and the mixture was extracted with EtOAc (3×5 ml). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as a yellow oil (430 mg). MS (ESI) m/z=400 [M+H]+.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].S(O)(O)(=O)=O.[NH2:17]O.Cl>O.[OH-].[Na+]>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:17]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Temperature: 60 °C
Reaction time: 18 h
Yield: 123.3 %

Procedure:
To a solution of pivaloylacetonitrile (25.03 g) and 48% sodium hydroxide (18.16 g) in water (319 ml) is added a solution of hydroxylamine sulfate (18.06 g) in water (72 ml) and the mixture is adjusted to pH 8.10±0.05 with 5% sodium hydroxide (0.38 g), stirred at 60° C. for 18 hours, mixed with 36% hydrochloric acid (26.13 g) and stirred at 70° C. for 30 minutes. Then, 36% hydrochloric acid (40.31 g) is added to the reaction mixture, which is refluxed for 40 minutes under stirring. The mixture is evaporated under atmospheric pressure to recover pinacolone (1.07 g; yield, 5.3%) and cooled to ordinary temperature. After cooling, the reaction mixture is adjusted to pH 11.8 with 48% sodium hydroxide (58.08 g) and shaken with chloroform. The chloroform layer is washed with water and concentrated under reduced pressure to give 3-amino-5-t-butylisoxazole (23.80 g). Purity, 96.6%. Yield, 84.9%. No by-product, 3-(3-t-butyl-5-isoxazolyl)amino-5-t-butylisoxazole, is detected.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][NH:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:21]1[O:22][C:23]2[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=2)[N:25]=1>COCCOC>[C:14]([O:13][C:11]([N:9]1[CH2:10][C:5]2([CH2:1][CH2:2][CH2:3][CH2:4]2)[N:6]([C:21]2[O:22][C:23]3[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=3)[N:25]=2)[CH2:7][CH2:8]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNC2(CCCC2)C1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc2oc(N3CCN(C(=O)OC(C)(C)C)CC34CCCC4)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.5 %

Procedure:
To a solution of tert-butyl 6,9-diazaspiro[4.5]decane-9-carboxylate (192 mg, 0.80 mmol) in DME (10 mL) was added NaH (60%, 96 mg, 2.4 mmol). The reaction mixture was stirred at room temperature for 10 min, followed by addition of methyl 2-chlorobenzoxazole-4-carboxylate (186 mg, 0.88 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction was quenched by adding 5 mL of H2O and extracted with EtOAc (2×30 mL). The organic layer was washed by brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 50-100% chloroform in hexane) to afford methyl 2-(9-(tert-butoxycarbonyl)-6,9-diazaspiro[4.5]decan-6-yl)benzoxazole-4-carboxylate (61.4 mg, 18.5%) as yellow oil. MS consistent.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3](OC(=O)C(O)(C1C=CC=C(OC)C=1)C1C=CC=C(OC)C=1)[CH2:2]2.OC(C1C=CC=C(OC)C=1)(C1C=CC=C(OC)C=1)C(O)=O.[OH:51][C:52]([C:62]1[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:53]([OH:55])=[O:54]>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:54][C:53](=[O:55])[C:52]([OH:51])([C:62]1[CH:63]=[CH:64][C:65]([O:68][CH3:69])=[CH:66][CH:67]=1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[CH2:2]2
Reactant: COc1ccc(C(O)(C(=O)O)c2ccccc2)cc1
Reactant: COc1cccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2cccc(OC)c2)c1
Agent: COc1cccc(C(O)(C(=O)O)c2cccc(OC)c2)c1
Product: COc1ccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1

Procedure:
This compound is prepared by an analogous method to hydroxy-bis-(3-methoxy-phenyl)-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Intermediate K) by replacing hydroxy-bis-(3-methoxy-phenyl)-acetic acid (Intermediate J) with hydroxy-(4-methoxy-phenyl)-phenyl-acetic acid (Intermediate L).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:11]C(C)(C)C)=[C:4]([CH:8]=[N:9]O)[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[Br:1][C:2]1[C:3]2[S:11][N:9]=[CH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)Sc1c(Br)cccc1C=NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: Brc1cccc2cnsc12
Yield: 17.3 %

Procedure:
A mixture of crude 1-[3-bromo-2-(tert-butylsulfanyl)phenyl]-N-hydroxymethanimine (7 g) and p-toluenesulfonic acid (730 mg, 3.88 mmol) in n-butanol (100 mL) was heated to reflux for 16 h. n-Butanol was evaporated, water (100 mL) and saturated aqueous sodium bicarbonate (50 mL) were added and the mixture was extracted with DCM (3×80 mL). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated to afford 900 mg (17%) of the crude title compound as a brown solid. 1H NMR (300 MHz, CDCl3): δ 7.26-7.40 (t, J=8.1 Hz, 1H), 7.62 (d, J=6.9 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 9.04 (s, 1H).
Reaction SMILES: CS([O:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.O[C:20]1[C:21]([C:26]#[N:27])=[N:22][CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:26]([C:21]1[C:20]([O:5][CH2:6][C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:25][CH:24]=[CH:23][N:22]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COS(C)(=O)=O
Reactant: N#Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccnc1C#N
Temperature: 100 °C
Reaction time: 6 h
Yield: 45.2 %

Procedure:
A mixture of tert-butyl (2R)-2-[(methanesulfonyloxy)methyl]pyrrolidine-1-carboxylate (7.38 g, 26.4 mmol, Tetrahedron Asymmetry, 1997, 8, 2209-2213.), 3-hydroxypicolinonitrile (4.76 g, 39.6 mmol), and potassium carbonate (10.95 g, 79.0 mmol) in N,N-dimethylformamide (150 mL) was stirred at 100° C. for 6 h. After cooling to room temperature, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 1:1) to give 3.62 g (45%) of the title compound as a colorless oil.
Reaction SMILES: Cl.C(OC(CBr)C#N)C1C=CC=CC=1.C(OC(CBr)C(N)=O)C1C=CC=CC=1.[CH2:29]([O:36][CH:37]([CH2:42]Br)[C:38]([O:40][CH3:41])=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1CN2C(=NCCC2)C1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOCC.CCCCCC.O>[CH2:29]([O:36][C:37](=[CH2:42])[C:38]([O:40][CH3:41])=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)C(CBr)OCc1ccccc1
Agent: C1CN=C2CCCN2C1
Agent: Cl
Agent: N#CC(CBr)OCc1ccccc1
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: C=C(OCc1ccccc1)C(=O)OC
Temperature: -10 °C
Reaction time: 8 h

Procedure:
A slow stream of hydrogen chloride gas was passed for 4 h through a solution of 2-benzyloxy-3-bromopropionitrile (16.75 g) in methanol (2.38 g) and ether (66 ml) which was maintained at -10° C. The mixture was allowed to stand at 5° C. overnight, and then ice was added in small portions to the mixture at 0° C. After 20 min of stirring, the mixture was poured into water and the product was extracted with ether, washed with water and aqueous sodium bicarbonate, and dried (MgSO4). After the solvent was removed, the crude product was recrystallized from ether/CH2Cl2 to afford, after a first crop of crystals of 2-benzyloxy-3-bromopropanamide, the required intermediate, methyl 2-benzyloxy-3-bromopropanoate. This bromoester was treated with DBN/potassium carbonate as described above to yield methyl α-benzyloxyacrylate, mp 44.5-45.5° C. (from hexane); 1H NMR δ3.80 (3H, s), 4.63 (1H, d, J 3 Hz), 4.83 (2H, s), 5.37 (1H, d, J 3Hz), 7.33 (5H, s); IR 1740 cm-1. Ketals of alkyl pyruvates, prepared according to the directions in The Journal of Organic Chemistry, 1967, 32,1615, also may be converted to α-alkoxyacrylates by an acidic catalyst, as described in Chemische Berichte, 1911, 44, 3514.
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16](O)([CH3:17])[O:15][C:14](=O)[C:13]=2[C:20]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=2[F:28])=[CH:8][CH:7]=1)#[CH:5]>C(O)CCC>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH3:17])=[N:3][NH:2][C:14](=[O:15])[C:13]=2[C:20]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[CH:22][C:21]=2[F:28])=[CH:8][CH:7]=1)#[CH:5]
Reactant: C#Cc1ccc(C2=C(c3c(F)cc(F)cc3F)C(=O)OC2(C)O)cc1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: C#Cc1ccc(-c2c(C)n[nH]c(=O)c2-c2c(F)cc(F)cc2F)cc1

Procedure:
Hydrazine hydrate (0.17 g) is added to a solution of 0.87 g 4-(4-ethynylphenyl)-5-hydroxy-5-methyl-3-(2,4,6-trifluorophenyl)-5H-furan-2-one in 5 ml of 1-butanol and this mixture is heated for 4 h to 120° C. The reaction mixture is evaporated under reduced pressure and the residue is purified by chromatography on silica gel, using a mixture of toluene/ethyl acetate 5:1 as eluent to obtain 5-(4-ethynylphenyl)-6-methyl-4-(2,4,6-trifluorophenyl)-2H-pyridazin-3-one (Compound No. 1) as colourless crystals, m.p. 252-254° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.CCOC(C)=O.[Fe]>[Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1
Reactant: CNc1c([N+](=O)[O-])cc(Br)nc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1c(N)cc(Br)nc1Cl
Temperature: 140 °C

Procedure:
To a solution of 6-bromo-2-chloro-N-methyl-4-nitropyridin-3-amine 2.59 (1 g, 3.75 mmol) in ethanol (10 ml) was added Fe powder (1.05 g, 18.7 mmol) and a solution of ammonium chloride (1 g, 18.8 mmol) in water (3 mL). The mixture was heated in microwave at 140° C. for 30 min. The mixture was then diluted with EtOAc, filtered and evaporated to give 6-bromo-2-chloro-N3-methylpyridine-3,4-diamine 2.59-A, which was used in the next step without purification.
Reaction SMILES: C[O:2][C:3](/[CH:5]=[C:6]1/[CH2:7][N:8]2[CH:11]([O:12]/1)[CH2:10][C:9]2=[O:13])=O.[H-].C([Al+]CC(C)C)C(C)C.CO>COCCOC.C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:2][CH2:3]/[CH:5]=[C:6]1/[CH2:7][N:8]2[CH:11]([O:12]/1)[CH2:10][C:9]2=[O:13]
Reactant: COC(=O)/C=C1/CN2C(=O)CC2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: COCCOC
Product: O=C1CC2O/C(=C\CO)CN12
Reaction time: 1 h
Yield: 5 %

Procedure:
(Z)-3-Methoxycarbonylmethylene-4-oxa-1-azabicyclo[3.2.0]-heptan-7-one (120 mg., 0.65 mmole) was dissolved in dry 1,2-dimethoxyethane (5 ml.)/dry) toluene (5 ml.) and the solution was stirred at -30° under a dry nitrogen atmosphere while a 20% solution of di-isobutyl aluminium hydride in toluene (0.5 ml.) was added dropwise. After addition was complete, the mixture was stirred at -30° to -10° for 1 hour. Methanol (1 ml.) was added to the solution which was then diluted with ethyl acetate (30 ml). The solution was washed once with saturated brine to which a few drops of 2 N. HCl had been added. The solution was dried and the solvent was evaporated under reduced pressure to yield a yellow gum. The gum was chromatographed on silica gel (10 g.) using ethyl acetate/petroleum ether (b.p. 60°-80°) to give the title compound as a colourless oil (5 mg.). νmax (CHCl 3): 3350 (hydroxyl OH), 1793 (β-lactam C=O), 1695 (olefinic C=C)cm-1. δ (CDCl3): 2.95 (d, J 16 Hz, 1H, C(6)H), 3.38 (dd, J 16, J' 2 Hz, 1H, C(6)H). 3.56 (d, 17 Hz, 1H, C(2)H), 4.18 (d, 7 Hz, 2H, CH2O), 4.52 (d, J 17 Hz, 1H, C(2)H), 4.60 (t, J 7 Hz, 1H, olefinic H), 5.47 (d, J 2 Hz, 1H, C(5)H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc(OCc2ccccc2)cc1
Yield: 95.7 %

Procedure:
4-(Benzyloxy)phenol (4.00 g, 19.98 mmol) was dissolved in dry DCM (80 mL) under nitrogen atmosphere and cooled in an ice-water bath. Methanesulfonyl chloride (2.75 g, 23.97 mmol) was added during stirring followed by TEA (3.03 g, 29.96 mmol). The reaction mixture was stirred at rt for 2 h and then washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and evaporated affording the title compound (5.32 g, 95.6%). 1H NMR (500 MHz, CDCl3): δ 3.13 (s, 3H), 5.08 (s, 2H), 7.01 (m, 2H), 7.23 (m, 2H), 7.35-7.45 (m, 5H).
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:18])[C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9].[Cl-].[NH4+]>O1CCCC1>[CH3:9][C@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:7](=[O:18])[CH3:1]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Methyl magnesium bromide (3.0M solution in diethyl ether, 4.3 ml, 12.9 mmol) was added to a stirred solution of tert-butyl (1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethylcarbamate (Tetrahedron: Asymmetry 1996, 7, 985) (1 g, 4.3 mmol) in anhydrous tetrahydrofuran (20 ml) at −60° C. under a nitrogen atmosphere. The mixture was allowed to warm to 0° C. and to then room temperature and was stirred at room temperature for 1 hour. Aqueous saturated ammonium chloride was added and aqueous phase was extracted with diethyl ether (2×76 ml). The combined organic extracts were then washed with saturated aqueous ammonium chloride solution and brine. The organic phase was then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of dichloromethane:methanol (99:1 to 98:2), to afford the title compound as a colorless solid, 412 mg, 51% yield.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].F[C:17]1[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>CS(C)=O>[C:6]([O:5][C:3]([N:10]1[CH2:14][CH2:13][CH:12]([O:15][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[CH2:11]1)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc([N+](=O)[O-])c2)C1
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
To a suspension of NaH (0.17 g, 4.4 mmol, 1.1 equiv) in DMSO (4 mL) at rt was added (3S)-1-Boc-3-pyrrolidinol (0.75 g, 4.0 mmol, 1.00 equiv) in one portion. After stirring for 20 min, 3-fluoronitrobenzene (0.51 g, 3.6 mmol, 0.90 equiv) was added drop wise and the resulting suspension was stirred an additional 1.5 hours at rt. The reaction mixture was quenched with the addition of saturated, aqueous NH4Cl and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. Purification of the crude residue by chromatography (30% ethyl acetate in hexanes) afforded 3-(3-nitro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as a bright yellow oil (0.676 g, 60%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH2:23][CH3:24])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>>[O:18]=[C:17]1[N:7]2[CH:6]=[C:5]([C:8]([NH2:10])=[O:9])[CH:4]=[CH:3][C:2]2=[N:11][C:12]2[S:13][C:14]([CH2:22][CH2:23][CH3:24])=[CH:15][C:16]1=2
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCCc1cc(C(=O)OCC)c(N)s1
Product: CCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Yield: 312 %

Procedure:
From 4.6 g (0.0029 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 8.6 g (0.040 mol) of 2-amino-5-propyl-3-thiophenecarboxylic acid, ethyl ester, following the procedure of Example 22 there is obtained 2.6 g of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 260°-264° C. after recrystallization from pyridine.
Reaction SMILES: O1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9](I)[CH:8]=1.C#CCC>[Cu](I)I.C(N(CC)CC)C>[C:2]([C:11]1[CH:12]=[C:7]([F:6])[CH:8]=[CH:9][C:10]=1[NH2:13])#[C:3][CH2:4][CH3:5]
Reactant: Nc1ccc(F)cc1I
Reactant: C1CCOC1
Agent: I[Cu]I
Agent: C#CCC
Solvent: CCN(CC)CC
Product: CCC#Cc1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
80 ml of tetrahydrofuran is placed under argon. 5 g 4-fluoro-2-iodophenylamine, 0.74 g dichlorobis(triphenylphosphine) palladium(II), 0.2 g copper iodide and 8.8 ml triethylamine are added. 4 g gaseous 1-butyne are passed through the suspension. The reaction mixture is stirred under argon for 15 hours at ambient temperature, then filtered through Celite and evaporated to dryness. 3.4 g product are obtained in the form of a solid. 1H NMR (400 MHz, DMSO): 2.45 (2H, q); 1.18 (3H, t).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[C:12]([O:21][C:22]2[CH:23]=[N:24][C:25]([O:29][C@@H:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])=[C:26]([Cl:28])[CH:27]=2)=[CH:13][C:14]([F:20])=[C:15]([CH:19]=1)[C:16](O)=[O:17].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62]>ClCCl>[Cl:10][C:11]1[C:12]([O:21][C:22]2[CH:23]=[N:24][C:25]([O:29][C@@H:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])=[C:26]([Cl:28])[CH:27]=2)=[CH:13][C:14]([F:20])=[C:15]([CH:19]=1)[C:16]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:17]
Reactant: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)O)cc2Cl)cc1Cl)C(F)(F)F
Reactant: CS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
Diisopropylethyl amine (11.7 mL, 66.8 mmol) was added to a solution of (S)-5-chloro-4-((5-chloro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)oxy)-2-fluorobenzoic acid (Preparation 299, 6.9 g, 16.7 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (9.5 g, 25.1 mmol) and methylsulfonamide (2.4 g, 25.1 mmol) in dichloromethane (125 mL). The reaction mixture was stirred at room temperature for 20 hours, then quenched with an aqueous solution of hydrogen chloride (2M, 50 mL). Organics were removed in vacuo and the aqueous residue was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude compound was purified by silica gel chromatography, eluting with dichloromethane:methanol (from 100:0 to 96:4), followed by reverse phase chromatography, eluting with acetonitrile:water (from 5:95 to 95:5) to provide the title compound as a white solid (4.8 g, 56%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:16](N1C=CN=C1)(N1C=CN=C1)=[O:17]>C1(C)C=CC=CC=1>[CH3:12][C@H:11]1[C:13](=[O:15])[O:14][C:16](=[O:17])[N:10]1[C@@H:4]([CH2:3][CH2:2][CH3:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: CCC[C@@H](C(=O)OCC)N1C(=O)OC(=O)[C@@H]1C
Temperature: 20 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Introduce into a reactor, at 0° C., 200 g of N-[(S)-ethoxycarbonyl-1-butyl]-(S)-alanine, 1.5 litres of toluene, and then 184 g of 1,1′-carbonyldiimidazole, then bring the temperature of the reaction mixture to 20° C. After stirring for 1 hour at 20° C., cool the mixture to 0° C. again, filter off the precipitate obtained, then evaporate the filtrate to yield the title product in a yield of 90%.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([S:11]([C:14]([F:17])([F:16])[F:15])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)(=O)C.[OH-].[K+]>O1CCOCC1>[F:16][C:14]([F:15])([F:17])[S:11]([C:9]1[CH:8]=[CH:7][C:6]2[O:18][CH2:19][C@H:20]([CH2:22][OH:21])[O:4][C:5]=2[CH:10]=1)(=[O:12])=[O:13]
Reactant: CC(=O)Oc1cc(S(=O)(=O)C(F)(F)F)ccc1OC[C@H]1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2c(c1)O[C@@H](CO)CO2)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Preparation according to Preparation 20 using 2-[(2R)-oxiran-2-ylmethoxy]-5-[(trifluoromethyl)sulfonyl]phenyl acetate (1.0 g, 3.7 mmol), dioxane (10 ml) and KOH (10%, 10 ml), the mixture stirred at RT for 1 h. Yield 1.0 g. MS m/z (rel. intensity, 70 eV) 298 (M+, 29), 229 (72), 165 (bp), 107 (67), 79 (33).
Reaction SMILES: [N:1]([C:4]1[C:5](=[O:19])[C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[CH:10][C:9]([CH2:15][CH3:16])=[C:8]([CH2:17][CH3:18])[CH:7]=2)=[N+]=[N-].S(=O)(=O)(O)O>>[C:4]([CH:13]=[C:12]1[C:11]2[C:6](=[CH:7][C:8]([CH2:17][CH3:18])=[C:9]([CH2:15][CH3:16])[CH:10]=2)[C:5](=[O:19])[O:14]1)#[N:1]
Reactant: CCc1cc2c(cc1CC)C(=O)C(N=[N+]=[N-])=CC2=O
Agent: O=S(=O)(O)O
Product: CCc1cc2c(cc1CC)C(=CC#N)OC2=O
Temperature: 0 °C
Yield: 91.7 %

Procedure:
2-Azido-6,7-diethyl-1,4-naphthoquinone (6.0 g; 0.024 mole) was added portionwise to cold (0°-5° C.), stirred concentrated sulphuric acid (100 ml) over 2 hours and the red solution stirred at this temperature till no further nitrogen evolution was noticed (ca. 15 mins.). The products from two such reactions carried out simultaneously were poured into 1200 ml of ice-water and the lilac solid filtered off and washed well with water. Recrystallisation from ethanol in the presence of charcoal give the title compound 5.00 g (47%) as an off-white solid of m.p. 147°-158° C. Further recrystallisation gave a white sample of m.p. 159°-168° C. shown by nmr to be a mixture of E and Z isomers. (Found; C, 73.70; H, 5.95; N, 5.94; C14H13NO2 requires; C, 73.99; H, 5.77; N, 6.16%).