Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH:6]1[C:10](=[O:11])[N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2([CH2:24][CH2:23][N:22]([CH2:25][CH2:26][C:27](=O)[C:28]([O:30]CC)=[O:29])[CH2:21][CH2:20]2)[S:7]1)C.[OH-].[Na+].C(OCC)(=[O:39])C.Cl>C(O)C>[C:4]([CH2:5][CH:6]1[C:10](=[O:11])[N:9]([CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2([CH2:24][CH2:23][N:22]([C:25](=[O:39])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:21][CH2:20]2)[S:7]1)([OH:3])=[O:34]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CC1SC2(CCN(CCC(=O)C(=O)OCC)CC2)N(CCc2ccccc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC(=O)N1CCC2(CC1)SC(CC(=O)O)C(=O)N2CCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 2.5 ml of ethanol was dissolved 0.51 g of ethyl 4-[2-(2-ethoxy-2-oxoethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-oxobutanoate. After adding 2.5 ml of 1 mol/L aqueous solution of sodium hydroxide at 0-5° C., the resulting mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 0.34 g of 4-[2-(carboxymethyl)-3-oxo-4-phenethyl-1-thia-4,8-diazaspiro[4.5]decan-8-yl]-4-oxobutanoic acid was obtained as a yellow oily product.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[NH:9][N:8]=[N:7][C:6]=1[CH2:10][N:11]1[CH2:16][CH2:15][O:14][C@H:13]([O:17][C@@H:18]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([S:30][CH3:31])[CH:21]=2)[CH3:19])[C@@H:12]1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH3:3].FC(F)(F)C(OO)=[O:42].C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH3:1][N:2]([CH2:4][C:5]1[NH:9][N:8]=[N:7][C:6]=1[CH2:10][N:11]1[CH2:16][CH2:15][O:14][C@H:13]([O:17][C@@H:18]([C:20]2[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[C:22]([S:30]([CH3:31])=[O:42])[CH:21]=2)[CH3:19])[C@@H:12]1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH3:3]
Reactant: CSc1cc([C@@H](C)O[C@H]2OCCN(Cc3nn[nH]c3CN(C)C)[C@H]2c2ccc(F)cc2)cc(C(F)(F)F)c1
Reactant: O=C(OO)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O[C@H]1OCCN(Cc2nn[nH]c2CN(C)C)[C@H]1c1ccc(F)cc1)c1cc(S(C)=O)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The thioether of Example 76 (155 mg, 0.28 mmol) was dissolved in trifluoroacetic acid (800 μl) cooled to 0° C. and treated with a 2.0M solution of trifluoroperacetic acid in trifluoroacetic acid (153 μl, 0.308 mmol), with stirring for 30 minutes. The reaction mixture was poured into 0.5M sodium bicarbonate solution (50 ml), extracted with dichloromethane (3×15 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude solid (200 mg) was purified by flash silica gel chromatography in 8% methanol:dichioromethane to yield the title compound as unresolved stereoisomers as a white foam (81 mg, 51%). 1H NMR (360 MHz, CDCl3) δ 1.44 and 1.46 (3H total, 2×d, J=6.6 Hz), 2.24 (6H, s), 2.56 (1H, m), 2.59 and 2.62 (3H total, 2×s), 2.88 (1H, d, J=11.9 Hz), 3.23 and 3.26 (1H total, 2×d, J=13.9 Hz), 3.42-3.55 (3H, m), 3.62 (1H, br d, J=11.3 Hz), 3.75 and 3.79 (1H total, 2×d, J=14.4 Hz), 4.22 (1H, m), 4.32 and 4.35 (1H total, 2×d, J=2.7 Hz), 4.89 (1H, m), 6.85 (1/2H, s), 7.04-7.13 (3H, m), 7.24 (1/2H, s), 7.50 (2H, br s), 7.73 and 7.75 (1H total, 2×s); MS (ES+) m/z 570 (M+1, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]2[O:21][C:20]([C@@:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])=[N:19][N:18]=2)=[N:4][C:5]([O:15][CH3:16])=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7]=1[C:8]([CH3:10])=[CH2:9].NC1C(C2OC([C@@](O)(C)C(F)(F)F)=NN=2)=NC(OC)=C(C(F)(F)F)C=1CC>>[NH2:1][C:2]1[C:3]([C:17]2[O:21][C:20]([C@@:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])=[N:19][N:18]=2)=[N:4][C:5]([O:15][CH3:16])=[C:6]([C:11]([F:13])([F:14])[F:12])[C:7]=1[CH:8]([CH3:9])[CH3:10]
Reactant: C=C(C)c1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F
Agent: CCc1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F
Product: COc1nc(-c2nnc([C@](C)(O)C(F)(F)F)o2)c(N)c(C(C)C)c1C(F)(F)F

Procedure:
The title compound was prepared from (S)-2-[5-(3-amino-4-isopropenyl-6-methoxy-5-trifluoromethyl-pyridin-2-yl)-[1,3,4]oxadiazol-2-yl]-1,1,1-trifluoro-propan-2-ol (Ex. 14.1) and prepared analogously to (S)-2-[5-(3-amino-4-ethyl-6-methoxy-5-trifluoromethyl-pyridin-2-yl)-[1,3,4]oxadiazol-2-yl]-1,1,1-trifluoro-propan-2-ol (Ex. 14.0 step 2);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][C:10]([F:16])([F:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: FC1(F)CCNCC1
Reactant: Brc1ccc(Br)nc1
Solvent: O
Product: FC1(F)CCN(c2ccc(Br)cn2)CC1
Reaction time: 8 h
Yield: 46 %

Procedure:
2,5-Dibromopyridine (1.30 g) was heated with 4,4-difluoropiperidine (2 g) in diaethylacetamide (4 ml) at 120° C. for 24 h, then at 150° C. for 8 h. The solution was allowed to cool, then poured into water (30 ml). The aqueous phase was extracted with ether (×3) and the combined extracts washed with water, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography gave the product as, a colourless oil (0.70 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[CH:6][O:7]2>[Pd].CCO.C1COCC1>[O:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([OH:1])[C:3]=2[CH2:4][CH2:5][CH2:6]1
Reactant: O=c1ccoc2cccc(O)c12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1cccc2c1CCCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.8 %

Procedure:
To a solution of 5-hydroxy-chromen-4-one (J. Het. Chem, 13, 1976, 211) (2.5 g, 15.4 mmol) and 1 mL HCl(c) in 75 mL de-gassed EtOH/THF (3:1) was added 0.5 g 10% Pd/C. The reaction mixture was stirred at room temperature for 20 h under an atmosphere of 1 atm H2(g). The Pd/C was then filtered off, the filtrate collected and concentrated in vacuo to give 2.1 g (91%) of the title compound pure enough for subsequent use. 400 MHz 1H NMR (DMSO-d6) δ 9.27 (s, 1H), 6.76 (t, 1H, J=8.1 Hz), 6.26 (d, 1H, J=8.1 Hz), 6.12 (d, 1H, J=8.1 Hz), 3.98 (t, 2H, J=5.0 Hz), 2.46 (m, 2H), 1.80 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])[CH:8]=2)[CH:3]=[CH:2]1.[B]=O.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[CH:27]=[CH:26][C:23]=1[CH:24]=O.N1CCCCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.B(OC(C)C)(OC(C)C)OC(C)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12](=[O:17])[CH2:13][C:14](=[O:16])/[CH:15]=[CH:24]/[C:23]3[CH:26]=[CH:27][C:28]([CH2:30][N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:29][C:22]=3[O:21][CH3:20])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: COc1cc(CN2CCN(C)CC2)ccc1C=O
Reactant: CC(=O)CC(=O)/C=C/c1ccc2cc[nH]c2c1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C([O-])[O-]
Agent: [B]=O
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: COc1cc(CN2CCN(C)CC2)ccc1/C=C/C(=O)CC(=O)/C=C/c1ccc2cc[nH]c2c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To 200 mL of a solution of 7.56 g of (E)-6-(1H-indol-6-yl)hex-5-ene-2,4-dione in AcOEt was added 3.24 g of boron oxide, and the mixture was stirred at 70° C. for 1 hour. To this, 15 mL of a solution of 8.68 g of 2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]benzaldehyde in AcOEt and 18.3 mL of triisopropyl borate were successively added, and the mixture was stirred at the same temperature for 40 minutes. Then, 10 mL of a solution of 0.35 mL of piperidine in AcOEt was added. The mixture was stirred at 70° C. for 3 hours and was allowed to cool back to room temperature. To the reaction mixture, 100 mL of a 10% K2CO3 aqueous solution was added, and the mixture was stirred for 1 hour. The organic layer was separated and concentrated. The residue was purified by amino-silica gel column chromatography (heptane/AcOEt system) to give 7.14 g of the title compound (47% yield).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]3[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:12]3[N:11]=2)=[CH:6][CH:5]=1.[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30].Cl>>[CH3:28][S:29]([C:32]1[CH:33]=[C:34]([NH:38][C:23]([C:22]2[CH:21]=[N:20][N:13]3[C:14]([C:16]([F:18])([F:19])[F:17])=[CH:15][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:27])([F:26])[F:1])=[CH:9][CH:8]=4)=[N:11][C:12]=23)=[O:24])[CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:31]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc12
Agent: Cl
Product: CS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-trifluoromethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.19) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 545.3 [(M+H)+]; mp 245° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[N:13](OCCCC)=[O:14].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:13][OH:14])[CH2:6]2
Reactant: CCCCON=O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)CC(=NO)C2=O
Temperature: 45 °C
Reaction time: 1.75 h
Yield: 62.5 %

Procedure:
To a solution of 5-methoxyindan-1-one (75.8 g; 0.467 mol) in MeOH (1.4 L) at 45° C. is added butyl nitrite (81 mL; 0.693 mol) dropwise over 45 min. Concentrated HCl (45 mL) is then added to the hot solution over 20 min and the reaction was allowed to stir at 45° C. for an additional 1.5-2 h. The reaction suspension is cooled, the precipitate filtered, washed several times with cold MeOH, and dried under vacuo to afford 55.8 g (62%) of 5-methoxyindan-1,2-dione-2-oxime as a beige solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH3:4].[NH2:6][C:7]1[N:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].C(O)C.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl.CO>[CH3:4][C:3]1[N:6]=[C:7]2[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:13][CH:14]=[CH:15][N:16]2[CH:2]=1
Reactant: CC(=O)CBr
Reactant: COC(=O)c1cccnc1N
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccn2cc(C)nc12
Temperature: 25 °C
Yield: 66.7 %

Procedure:
Bromoacetone (6.5 g, 42.7 m moles) and methyl 2-aminonicotinate (4.8 g, 31.5 m moles) were added to ethanol (50 ml), and the mixture was refluxed under heating for 17 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Saturated aqueous solution of sodium bicarbonate (50 ml) was added to the residue, and the mixture was extracted with chloroform (100 ml×3). The extract was washed with water, dried over MgSO4 and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel (eluent:chloroform and then chloroform/methanol=9/1) to give the object compound (4.0 g, yield 85%) as an oily substance.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[Cl:13].C([Li])(C)(C)C.[CH2:19]([C:23]1[N:28]2[N:29]=[C:30]([CH3:33])[C:31](I)=[C:27]2[N:26]=[C:25]([CH3:34])[CH:24]=1)[CH2:20][CH2:21][CH3:22]>[Cl-].[Zn+2].[Cl-].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.C1COCC1>[CH2:19]([C:23]1[N:28]2[N:29]=[C:30]([CH3:33])[C:31]([C:2]3[S:6][C:5]([C:7]4[N:11]([CH3:12])[N:10]=[CH:9][N:8]=4)=[CH:4][C:3]=3[Cl:13])=[C:27]2[N:26]=[C:25]([CH3:34])[CH:24]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Cn1ncnc1-c1cc(Cl)c(Br)s1
Reactant: CCCCc1cc(C)nc2c(I)c(C)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCCc1cc(C)nc2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nn12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 14.7 %

Procedure:
Add 5-(5-bromo-4-chloro-thiophen-2-yl)-1-methyl-1H-[1,2,4]triazole (169 mg, 0.61 mmol) to anhydrous THF (5 mL). Cool to −78° C. Add tert-butyl lithium (0.81 mL, 1.37 mmol, 1.7 M in pentane). Stir for 45 min and then add zinc chloride (1.5 mL, 1.76 mmol, 0.5 M in THF) slowly. Stir for 5 min, then warm to room temperature and stir for 15 min. Add bis(tri-t-butylphosphine)palladium (0) (62 mg, 0.12 mmol) and 7-butyl-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (200 mg, 0.61 mmol). Heat to reflux overnight. Filter the reaction through Celite® and concentrate to dryness. Purify using silica gel column chromatography, eluting with 0-50% ethyl acetate in hexane, to give the title compound (36 mg, 15%). ES/MS m/z (35Cl) 401 (M+1)+.
Reaction SMILES: CN(C)C=O.[C:6]1(=[O:12])[NH:10][C:9](=[O:11])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O>[C:9]1(=[O:11])[N:10]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:6](=[O:12])[CH2:7][CH2:8]1
Reactant: O=C1CCC(=O)N1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCN1C(=O)CCC1=O
Temperature: 25 °C
Yield: 71.8 %

Procedure:
Dimethylformamide (800 ml) was added to a mixture of succinimide (248 g, 2.5 mol), potassium carbonate (346 g, 2.5 mol) and ethyl 5-bromopentanoate (400 g, 1.9 mol). The mixture was heated at 110°-120° C. for 3 h before being cooled to RT. Water (2.5 L) was added and the mixture was extracted with methyl tert-butylether (4×1 L). The combined extracts were washed with water (400 ml), dried (MgSO4) and evaporated in vacuo to provide the title compound (310 g, 71%) as a pale yellow oil.
Reaction SMILES: ClC1C=CC(N)=CC=1.[I-].[K+].[CH2:11]([O:13][C:14]([C@H:16]1[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:17]1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[O:15])[CH3:12]>Cl>[CH2:24]([O:23][C:21]([CH:18]1[CH2:19][CH2:20][CH:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[N:17]1[C:26]1[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)OCC)N1c1ccc(Cl)cc1
Agent: Cl
Agent: Nc1ccc(Cl)cc1
Agent: [I-]
Product: CCOC(=O)C1CCC(C(=O)OCC)N1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Diethyl meso-2,5-dibromo adipate (5.0 g, 13.89 mmol), 4-chloro-aniline (6.2 g, 48.60 mmol), potassium iodide (0.032 g, 0.193 mmol) were combined and heated at 80° C. for 3 h then 90° C. for ½ h. Mix was cooled, diluted with 6N hydrochloric acid (400 mL) and extracted with ethyl acetate (3×400 mL). The combined organic layers were washed with water (5×200 mL), brine (200 mL), dried with magnesium sulfate and concentrated to yield a mixture of cis and trans 1-(4-Chloro-phenyl)-pyrrolidine-2,5-dicarboxylic acid diethyl ester (4.53 g, 100%) as a brown oil. Oil was used without further purification.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][NH:8][CH2:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11]>CO>[OH:5][CH2:4][CH2:3][CH2:2][C:1]([N:8]([CH2:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11])[CH3:7])=[O:6]
Reactant: O=C1CCCO1
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Product: CN(C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)C(=O)CCCO

Procedure:
500 ml (565 g, 6.56 mol) of gamma-butyrolactone are placed in 2.0 l of methanol. 1.28 kg (6.56 mol) of methylglucamine are added to the solution obtained. The mixture is then refluxed for 16 hours. The solution obtained is evaporated to dryness. The colourless syrup so initially obtained crystallises into a white solid after a few days at room temperature. (Melting point 78°-79° C.)
Reaction SMILES: [C:1]1([CH2:6][NH:7][CH2:8][CH:9](O)[C:10]2[C:15]([F:16])=[CH:14][C:13]([O:17][CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=2)[S:5][CH:4]=[CH:3][CH:2]=1.N>>[F:16][C:15]1[C:10]([CH:9]2[CH2:8][NH:7][CH2:6][C:1]3[S:5][CH:4]=[CH:3][C:2]2=3)=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=1
Reactant: COc1cc(F)c(C(O)CNCc2cccs2)cc1OC
Agent: N
Product: COc1cc(F)c(C2CNCc3sccc32)cc1OC
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 106.1 %

Procedure:
##STR61## A mixture of 0.66 g of α-[[(2-thenyl)amino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol and 10 ml of polyphosphoric acid was stirred for 3.5 hours at 60° C. The reaction solution was poured into ice water, and the mixture was basified by addition of 25 ml of conc. aqueous ammonia. The mixture was extracted with chloroform, and the chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and 0.66 g of 4-(6-fluoro-3,4-dimethoxyphenyl)-4,5,6,7-tetrahydrothieno[2,3-c]-pyridine was obtained as a syrupy matter.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[N:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:18][C:15]1[CH:16]=[N:17][C:12]([F:11])=[CH:13][CH:14]=1)[CH:5]=[O:6]
Reactant: Oc1ccc(F)nc1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccc(F)nc2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 3,4-difluorobenzaldehyde and 6-fluoropyridin-3-ol.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH3:13])[C@@:10]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[O:15])[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[C:34]([O:33][C:31](=[O:32])[CH2:30][C@@:10]1([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[O:15])[C@H:11]([CH3:13])[CH2:12][NH:8][CH2:9]1)([CH3:37])([CH3:35])[CH3:36]
Reactant: C[C@@H]1CN(Cc2ccccc2)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNC[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 94.7 %

Procedure:
20% palladium hydroxide (724 mg) was added to a solution of tert-butyl 4-[(3R*,4S*)-1-benzyl-3-[2-(tert-butoxy)-2-oxoethyl]-4-methylpyrrolidin-3-amido]piperidine-1-carboxylate obtained in Example 3a (1.33 g, 2.58 mmol) in methanol (30 ml), which was stirred under a hydrogen atmosphere overnight. The reaction liquid was filtered and concentrated under reduced pressure to give the title compound (1.04 g, yield: 94.7%).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:22])[CH:20]=[CH2:21]>O>[CH2:19]([NH:22][C:7]1[N:6]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=1)[CH:20]=[CH2:21]
Reactant: C=CCN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NCC=C)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.6 %

Procedure:
A mixture of 265 mg (1.00 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 1.52 g (26.65 mmol) of allylamine were stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered out to give 230 mg (yield: 80.6%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:14])=[C:7]2[C:11]([OH:13])=[O:12].C(OCC1CSC2N(C(=O)C2N)C=1C(O)=O)(=O)C.CC1CSC2N(C(=O)C2NC(=O)C(C2C=CC(CCl)=CC=2)N)C=1C(O)=O.C(O[CH2:66][O:67][C:68]([C:70]1N2C(S[CH2:76][C:77]=1C)C(NC(=O)C(C1C=CC(CCl)=CC=1)N)C2=O)=[O:69])(=O)C(C)(C)C>>[C:68]([O:67][CH2:66][O:12][C:11]([C:7]1[N:8]2[CH:3]([S:4][CH2:5][C:6]=1[CH3:14])[CH:2]([NH2:1])[C:9]2=[O:10])=[O:13])(=[O:69])[CH2:70][CH2:77][CH3:76]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(N)c3ccc(CCl)cc3)C2SC1
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Agent: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccc(CCl)cc3)C2SC1
Product: CCCC(=O)OCOC(=O)C1=C(C)CSC2C(N)C(=O)N12

Procedure:
When in the procedure of Example 16 an appropriate amount of 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid or the corresponding pivalyloxymethyl ester is substituted for 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3-methyl-7-[[2-[4-(chloromethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 3-methyl-7-[[2-[4-(chloromethyl)phenyl]-2-aminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid pivalyloxymethyl ester are obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[H][H]>[Ni]>[F:1][C:2]([F:13])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][NH2:12])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Agent: [Ni]
Product: NCCc1ccc(OC(F)(F)F)cc1

Procedure:
reducing the (4-trifluoromethoxyphenyl)acetonitrile using hydrogen in the presence of a nickel catalyst to form 2-(4-trifluoromethoxyphenyl)ethylamine.
Reaction SMILES: [CH3:1][N:2]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:3](=[O:31])[C:4]([CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]C(OC(C)(C)C)=O)=[CH:19][CH:18]=1)=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:3](=[O:31])[C:4]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=1)=[CH:5][C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1
Reactant: CCCCCCCCCCCCCCCCCCN(C)C(=O)C(=Cc1ccc([N+](=O)[O-])cc1)COc1ccc(NC(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCN(C)C(=O)C(=Cc1ccc([N+](=O)[O-])cc1)COc1ccc(N)cc1
Temperature: 0 °C
Reaction time: 10 h

Procedure:
10 g of N-methyl-N-octadecyl-α-(4-t-butoxycarbonylaminophenoxy)methyl-4-nitrocinnamic acid amide was dissolved in 50 ml of chloroform. The mixture was then cooled to a temperature of 0° C. or lower. 12 ml of trifluoroacetic acid wa gradually added dropwise to the mixture. The mixture was then stirred at room temperature for 10 hours. After the reaction was completed, the reaction mixture was neutralized with an aqueous solution of sodium bicarbonate. The neutralized mixture was then extracted with ethyl acetate. The extract was subjected to silica gel flash column chromatography. The desired substance was then obtained from a fraction extracted from a 1:1 mixture of ethyl acetate and hexane. (Yield: 5.4 g (63%))