Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:17](=[O:39])[NH:18][C@H:19]([C:28](=[O:38])[NH:29][C:30]1[S:31][CH:32]=[C:33]([C:35](=[O:37])[CH3:36])[N:34]=1)[C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:35]([C:33]1[N:34]=[C:30]([NH:29][C:28](=[O:38])[C@@H:19]([NH:18][C:17](=[O:39])[C@H:8]([NH2:7])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@H:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:21])[S:31][CH:32]=1)(=[O:37])[CH3:36]
Reactant: COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)Nc2nc(C(C)=O)cs2)[C@@H](C)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc([C@@H](N)C(=O)N[C@H](C(=O)Nc2nc(C(C)=O)cs2)[C@@H](C)c2ccccc2)cc1
Reaction time: 1 h
Yield: 111.3 %

Procedure:
[(R)-[(1S,2S)-1-(4-Acetyl-thiazol-2-ylcarbamoyl)-2-phenyl-propylcarbamoyl]-(4-methoxy-phenyl)-methyl]-carbamic acid tert-butyl ester (3.1 g, 5.2 mmol) was stirred in dichloromethane (50 mL) in an ice-bath. Trifluoroacetic acid (50 mL) was added and the solution was stirred for 1 hour. The reaction mixture was evaporated and the residue was precipitated with hexanes/ether. The mixture was stirred vigorously for 10 minutes and then filtered. The solid was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was separated and the aqueous layer extracted with dichloromethane. The combined organic extracts were washed with brine and dried (sodium sulfate). Evaporation of the solvents gave (2S,3S)-N-(4-acetyl-thiazol-2-yl)-2-[(R)-2-amino-2-(4-methoxy-phenyl)-acetylamino]-3-phenyl-butyramide (2.7 g, 90% pure) as a white solid.
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]([NH2:12])=[N:11][C:6]2=[CH:5][CH:4]=1.[BrH:13]>C(O)(=O)C>[BrH:13].[BrH:13].[NH2:12][C:10]1[S:9][C:7]2[C:6]([N:11]=1)=[CH:5][CH:4]=[C:3]([OH:2])[N:8]=2
Reactant: COc1ccc2nc(N)sc2n1
Agent: Br
Solvent: CC(=O)O
Product: Nc1nc2ccc(O)nc2s1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
5-Methoxy[1,3]thiazolo[5,4-b]pyridin-2-amine (5.0 g, 27.6 mmol) was dissolved in 30% hydrogen bromide in acetic acid (50 ml). The mixture was stirred at 130° C. for 3 hours and cooled to room temperature, and then the solvents were removed in vacuo and the residue was solidified with diethyl ether to give 2-amino[1,3]thiazolo[5,4-b]pyridin-5-ol dihydrobromide (9.11 g, quantitatively) as colorless crystals.
Reaction SMILES: C(O)=O.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[C:12]1[C:16]([CH2:17][O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([C:35]([O:37]C(C)(C)C)=[O:36])=[CH:30][N:31]4[CH3:34])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[C:15]([CH:42]2[CH2:44][CH2:43]2)[O:14][N:13]=1>O>[CH:42]1([C:15]2[O:14][N:13]=[C:12]([C:6]3[C:5]([Cl:4])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])[C:16]=2[CH2:17][O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([C:35]([OH:37])=[O:36])=[CH:30][N:31]4[CH3:34])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH2:43][CH2:44]1
Reactant: Cn1cc(C(=O)OC(C)(C)C)c2ccc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc21
Solvent: O
Solvent: O=CO
Product: Cn1cc(C(=O)O)c2ccc(N3CCC(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CC4)CC3)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
To formic acid (116.5 Kg), add tert-butyl 6-(4-{[3-(2,6-dichlorophenyl)-5-cyclopropylisoxazol-4-yl]methoxy}piperidyl)-1-methylindole-3-carboxylate (19.102 Kg, 34.45 mol) under a nitrogen atmosphere. Stir the mixture at 20-30° C. for 24-72 hours. Follow by HPLC until no starting material is observed. Add water (286.5 Kg) and stir for at least 1 hour. Add water (133.7 Kg) and stir for at least 30 minutes, repeat with a further addition of water (133.7 Kg) with stirring for at least 30 minutes. Collect the solids by filtration and rinse the filter cake with water (3×30 Kg). Add the wet solids to methanol (75.5 Kg) and stir the suspension for at least 12 hours. Cool the suspension to 0-5° C. and stir for at least 1 hour. Collect the solids by filtration. Wash the solids with a solution of methanol (9.1 Kg) and water (1.1 Kg) cooled to 0-5° C. and repeat. Dry solids at 50-55° C. for 12-72 hours under vacuum. Add the solids to formic acid (28.5 Kg) and water (2.3 Kg) and stir for 10-20 minutes. Filter the mixture. Add water (49.7 Kg) and stir for 30-60 minutes. Add water (2×36.6 Kg) and stir for at least 30 minutes. Collect solids by filtration and rinse with water (3×15.9 Kg). Add collected solids to methanol (58.2 Kg). Stir for at least 12 hours, cool to 0-5° C. and stir for at least 1 hour. Collect solids by filtration. Wash solids with a solution of methanol (8.1 Kg) and water (1.1 Kg) cooled to 0-5° C., repeat once. Add the collected solids to a solution of methanol (115.6 Kg) and water (14.6 Kg). Heat the suspension to reflux for 2-3 hours, cool to 0-5° C. and stir 1 hour. Collect the solids by filtration. Wash the solids with a solution of methanol (17.3 Kg) and water (2.2 Kg) cooled to 0-5° C., repeat once. Dry collected solids at 60-65° C. for 12-72 hours under vacuum to give 13.584 Kg (73%) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([O:18][CH3:19])=[O:17])[CH3:14].[CH2:24]=[O:25].[Cl-].[NH4+]>C1COCC1>[CH3:19][O:18][C:16](=[O:17])[C:15]([CH2:13][CH3:14])([CH2:24][OH:25])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C=O
Reactant: CCCCC(CC)C(=O)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCC(CC)(CO)C(=O)OC
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
5.2 ml (0.037 mol) of diisopropylamine are added dropwise at 20° C. to a solution of 12.9 ml (0.035 mol) of n-butyllithium (2.7 M in heptane) in 17 ml of THF, and the mixture is stirred at 20° C. for 15 min. Within approx. 10 min, 5 g (0.032 mol) of methyl 2-ethylhexanoate are added dropwise at 20° C., and the mixture is stirred at 20° C. for a further 30 min and subsequently admixed with 2.9 g (0.097 mol) of paraformaldehyde. After stirring at 20° C. for 2 hours, a saturated aqueous solution of ammonium chloride (20 ml) is added and the mixture is stirred at RT for 2 h. The organic phase is removed, the aqueous phase is re-extracted 1× with 20 ml of MTBE and the combined organic phases are concentrated on a rotary evaporator. The yield of pure product is 77% (GC).
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:13](O)[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1.O>CCCCCCC>[CH3:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:13][C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)=[O:10])[CH3:12]
Reactant: COc1cc(CO)ccc1O
Reactant: CC(C)CCCCCCC(=O)O
Solvent: O
Solvent: CCCCCCC
Product: COc1cc(COC(=O)CCCCCCC(C)C)ccc1O
Temperature: 55 °C
Reaction time: 45 h
Yield: 91.3 %

Procedure:
8-Methylnonanoic acid (1.50 g, 8.70 mmol), vanillyl alcohol (1.34 g, 8.70 mmol), and lipase PS “Amano” (375 mg) were measured and placed in a flask (25 ml). The mixture in the flask free of a plug was heated with stirring in an oil bath at 55° C. for 45 hours. After 2 to 3 hours of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, heptane (10 ml) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Lipase PS “Amano” and a small amount of precipitated vanillyl alcohol were removed by filtration. The filtrate was concentrated under reduced pressure and the obtained oil (2.48 g) was analyzed by HPLC to find that dihydrocapsiate was contained in 94.0 area %. The mixture was partitioned with heptane (15 ml) and 10% aqueous citric acid solution (15 ml), and the aqueous layer was further extracted with heptane (15 ml). The combined heptane layer was washed with saturated brine (15 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give a mixture (2.45 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 80.9%, and the purity was 97.4 area % by HPLC. The mixture contained 12.6 wt % of 8-methylnonanoic acid relative to dihydrocapsiate.
Reaction SMILES: [NH2:1][C@@H:2]1[C:18](=[O:19])[N:4]2[C:5]([P:14]([O-:17])(=[O:16])[O-:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12.[Na+].[Na+].C([O-])(O)=O.[Na+].[C:27]1([CH:33]([C:37]([O:39][CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CCOC(C)=O.O.CC(C)=O>[C:11]([O:10][CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[C@H:2]([NH:1][C:34](=[O:35])[CH:33]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:37]([O:39][CH:40]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[O:38])[C:18](=[O:19])[N:4]2[C:5]=1[P:14]([OH:17])(=[O:15])[OH:16])(=[O:13])[CH3:12]
Reactant: CC(=O)OCC1=C(P(=O)([O-])[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)C(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)OCC1=C(P(=O)(O)O)N2C(=O)[C@@H](NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)[C@H]2SC1

Procedure:
To a solution of 10 mmoles of disodium 7β-amino-3-acetoxymethyl-3-cephem-4-phosphonate in 100 ml. water and 100 ml. acetone containing 5 g. NaHCO3 is added 20 mmoles of 2-phenyl-2-benzhydryloxycarbonylacetyl chloride in 40 ml. acetone at 0° C. After 1 hour stirring at 0° and 2 hours at 25° acetone is pumped off in vacuo and the aqueous solution added to 100 ml. water and 200 ml EtOAc. The pH is adjusted to 2 with HCl and the ethyl acetate layer separated, dried with MgSO4, filtered and evaporated, affording the product, 3-acetoxymethyl-7β-(2-phenyl-2-benzhydryloxycarbonylacetamido)-3-cephem-4-phosphonic acid.
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:20])([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH3:10])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:2][N:3]1[CH2:4][CH:5]=[C:6]([C:9]([CH3:20])([C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH3:10])[CH2:7][CH2:8]1
Reactant: C[n+]1ccc(C(C)(C)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CN1CC=C(C(C)(C)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Methyl-4-[1-methyl-1-(4-nitro-phenyl)-ethyl]-pyridinium (Step A) was treated with DEA (100 mL) in MeOH (300 mL) for 2 h. NaBH4 (19 g, 500 mmol) was added in small portions. The resulting mixture was stirred for 30 min at RT, then partitioned between CH2Cl2/H2O (500 mL/500 mL). The organic layer was collected and the upper layer was washed with CH2Cl2 (300 mL×3). The combined organic layer was washed with brine then concentrated in vacuo. The residue was purified on a silica washed-column (7% TEA in EtOAc). The desired fractions were combined and concentrated under vacuum to give the desired compound as a dark gray solid. (MS: M+1=261).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.[N+:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=1)([O-:41])=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(Cl)Cl>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:17]3[N:18]=[C:19]4[C:11]([C:9]([NH:8][CH:6]([C@H:4]5[CH2:3][C@H:2]([O:1][C:46](=[O:47])[C:45]6[CH:44]=[CH:43][C:42]([N+:39]([O-:41])=[O:40])=[CH:50][CH:49]=6)[CH2:5]5)[CH3:7])=[O:10])=[CH:12][N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:14]4=[N:15][CH:16]=3)=[N:21][N:22]2[CH3:30])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide (200 mg, 0.37 mmol) in THF (4 mL) was added 4-nitrobenzoic acid (124 mg, 0.74 mmol) and triphenylphosphine (204 mg, 0.78 mmol). Then the reaction mixture was cooled to 0° C. and diethyl azodicarboxylate (123 μL, 0.78 mmol) was added dropwise. The reaction was stirred at room temperature overnight then diluted with CH2Cl2 (25 mL) and washed with 1.0 M aqueous NaOH. The aqueous phase was back-extracted with CH2Cl2 then the combined organics were dried over MgSO4 and concentrated. The residue was absorbed onto SiO2 and purified via chromatography with 20% to 80% EtOAc/hexanes to provide 250 mg (98%) of 4-nitrobenzoic acid trans-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][S:14](O)(=[O:16])=[O:15].[Cl-].[NH4+]>C(Cl)Cl>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc(C2CCCCC2)cc1
Reactant: O=S(=O)(O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(C2CCCCC2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 10.6 ml of phenylcyclohexane in 100 ml of methylene chloride was added at 5° C. within 30 minutes to 13.8 ml of chlorosulfonic acid. The mixture was stirred at 5° C. for 1 hour, poured into 400 ml of a 20% ammonium chloride solution and extracted twice with 300 ml of methylene chloride each time. The organic phases were combined, dried with magnesium sulphate and the solvent was removed on a rotary evaporator. 13.6 g of 4-cyclohexyl-benzenesulfonyl chloride separated as a reddish oil, which was used without further purification.
Reaction SMILES: [N:1]1([CH2:6][C:7]#[CH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[C:14]1(=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>O1CCCC1>[N:1]1([CH2:6][C:7]#[C:8][C:14]2([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: C#CCN1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(C#CCN2CCCC2)CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(pyrrolidin-1-yl)-prop-2-yne (prepared by the method of Biel and DiPierro J. Am. Chem. Soc. 1958, 80, 4609) (0.545 g) in dry tetrahydrofuran (15 ml) was treated at -78° C. with a solution of n-butyl lithium in hexanes (2.5 M, 2.2 ml) and the mixture was allowed to stir at -78° C. for 30 minutes and them permitted to warm to room temperature over the course of one hour. Upon recooling to -78° C. this mixture was treated with a solution of cyclohexanone (0.61 g) in tetrahydrofuran (1 ml). The reaction was permitted to warm to room temperature over the course of two hours, and was then partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the pooled organic phase was washed with water, brine, and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give a crude product, which was purified by column chromatography over silica gel (5% methanol in dichloromethane was used as the eluant) to afford the product as a white solid. MS(+ES), m/z: 208 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][N:5]1[C:17](=[O:28])[CH:18]([NH2:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:2]=[CH2:3].[C:29]([N:36]1[CH:45]([C:46](O)=[O:47])[CH2:44][CH:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH2:42]2)[CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:32]([O:31][C:29]([N:36]1[CH:45]([C:46](=[O:47])[NH:27][CH:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:17]([N:5]2[CH2:6][CH:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:8][CH:4]2[CH2:1][CH:2]=[CH2:3])=[O:28])[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(N)Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC2=CC=CCC2CC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C=CCC1CC(OCc2ccccc2)CN1C(=O)C(Cc1ccc(F)cc1)NC(=O)C1Cc2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To solution of 1-(2-allyl-4-benzyloxy-pyrrolidin-1-yl)-2-amino-3-(4-fluorophenyl)-propan-1-one, 54, (1.4 mmol) is dissolved in DMF (10 mL) are added N-Boc-tetrahydroisoquinoline-3-carboxylic acid (0.47 g, 1.5 mmol), 1-hydroxybenzotriazole (0.43 g, 2.8 mmol), N-methylmorpholine (0.84 g, 8.3 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide (0.32 g, 1.7 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 1 hour and then warmed to room temperature and stirred an additional 1.5 hour. The reaction is quenched with saturated NH4Cl solution and then extracted 3 times with EtOAc (70 mL). The organic layers are combined, washed with saturated NaCl solution, dried over Na2SO4, and the solvent is removed in vacuo. The crude product is purified over silica to afford 0.69 g (77% yield) of the desired product as a white solid. 1H NMR (300 MHz, MeOD, Rotamers) δ 6.90–7.41 (m, 13H), 5.55–5.81 (m, 1H), 4.32–5.12 (m, 8H), 3.94–4.18 (m, 2H), 2.75–3.89 (m, 6H), 2.39–2.64 (m, 1H), 1.78–2.29 (m, 2H), 1.20–1.64 (m, 10H); MS (ESMS) m/z 642.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[Cl:21][C:22]1[C:23]([C:29](O)=[O:30])=[N:24][CH:25]=[C:26]([Cl:28])[CH:27]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:23]3[C:22]([Cl:21])=[CH:27][C:26]([Cl:28])=[CH:25][N:24]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 3,5-dichloro-pyridine-2-carboxylic acid following procedure I yielded the 3,5-dichloro-pyridine-2-carboxylic acid [3-((R)-2-amino-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-amide which, after treatment with hydrochloric acid in dioxane (4N), evaporation and trituration with diethylether, gave the title compound as a white solid. MS (ISP): m/z=461.2 [M+H]+, 463.1 [M+2+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)=[O:3].[CH:11]([Sn](CCCC)(CCCC)CCCC)=[CH2:12].CCOC(C)=O>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[CH:11]([C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)=[CH2:12]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1ccc(C(C)=O)cc1
Temperature: 25 °C
Yield: 101.8 %

Procedure:
To a stirred mixture of 4-iodoacetophenone (1.0 g, 4.1 mmol), Pd2(dba)3 (186 mg, 0.2 mmol), P(2-furyl)3 (94 mg, 0.4 mmol), and CuI (77 mg, 0.4 mmol) in 20 mL of anhydrous DMF under N2 atmosphere was added vinyltributyltin (1.43 mL, 4.9 mmol) via syringe. An exothermic reaction was observed. After stirred for over night at r.t., the reaction mixture was poured into EtOAc (20 mL), washed with sat. aq. CsF solution, and brine. The organic layer was dried over Na2SO4, evaporated. The titled compound (610 mg, 100%) was isolated after silica gel MPLC eluting with 0–15% EtOAC in hexanes.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>N1C=CC=CC=1>[S:30]([O:11][CH2:10][CH2:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC(=C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
The reaction is performed under dry conditions. 30.0 g of 1,1,2-triphenyl-1-buten-4-ol are dissolved in 100 ml of dry pyridine. Then with stirring and cooling the mixture on ice, 57.0 g of 4-toluenesulfonic acid chloride in 50 ml of dry pyridine are added dropwise to the mixture. The mixture is stirred for 6 h at 0° C. Then 250 ml of ice-cold water and 750 ml of cold 2 M hydrochloric acid are added. The precipitate is collected by filtration and washed with water. Finally the product is recrystallized from ethanol. The yield is 36.8 g (81%) of a product having m.p. 137°-9° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.[C:12]1([S:18]([CH2:21][C:22]#[N:23])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:21]([S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:19])=[O:20])[C:22]#[N:23])[CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: N#CCS(=O)(=O)c1ccccc1
Product: Cc1cc(C=C(C#N)S(=O)(=O)c2ccccc2)cc(C)c1O

Procedure:
M31 was prepared with 3,5-dimethyl-4-hydroxybenzaldehyde and phenylsulfonly acetonitrile under similar conditions as decribed for M26.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(ccn2Cc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
5-Nitroindole (0.49, 3 mmol) was treated with sodium hydride (0.198 g, 6.6 mmol) in dry dimethylformamide (20 ml). After 15 min at room temperature, 3-picolyl chloride hydrochloride (0.49 g, 3 mmol) was added and the mixture was stirred at room temperature for 24 h, then poured into water. The precipitate was filtered off, washed with water and dried to give the tide compound (0.67 g, 88%), m.p. 131-4° C.