Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][CH2:3][CH2:4]OC.Cl.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([NH:17][C:18]2[N:23]=[C:22]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[CH:21]=[C:20]([C:31]3C=C[N:34]=[C:33](F)[CH:32]=3)[N:19]=2)[CH3:16])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([NH:17][C:18]2[N:19]=[C:20]([C:31]3[CH:32]=[CH:33][N:34]=[C:3]([OH:2])[CH:4]=3)[CH:21]=[C:22]([NH:24][C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[N:23]=2)[CH3:16])=[CH:13][CH:14]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccnc(F)c2)n1)c1ccc(F)cc1
Reactant: COCCOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2ccnc(O)c2)n1)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
1 ml of 1,2-dimethoxyethane and 10% hydrochloric acid were added to 80 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-6-(2-fluoropyridin-4-yl)-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, and the mixture was stirred at 85° C. for 2 hours. 0.5 ml of 10% hydrochloric acid was added thereto, and the mixture was further stirred for 2 hours. The reaction solution was diluted with ethyl acetate and alkalified with a saturated aqueous solution of sodium bicarbonate. The mixture was subjected to extraction, and the obtained organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained solid was washed with diethyl ether and filtrated, and then dried under reduced pressure to obtain 54 mg of the objective compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][C:3]=1[NH:17][C:18](=[O:33])[C@H:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C@@H:20]([CH3:25])[C:21]([F:24])([F:23])[F:22].S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:17][C:18](=[O:33])[C@H:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C@@H:20]([CH3:25])[C:21]([F:24])([F:23])[F:22]
Reactant: CCCC(CC(=O)OC)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCCC(CC(=O)O)c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
1.50 g (2.97 mmol) of methyl 3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)hexanoate (diastereomer mixture) were dissolved in 5 ml of acetic acid, 5 ml of 30% strength sulphuric acid were added and the mixture was heated at reflux (bath temperature about 140° C.). After 1.5 h, a further 2.5 ml of acetic acid were added, and the reaction mixture was stirred under reflux for another 2.5 h. After cooling, the mixture was allowed to stand at RT overnight, then added to water and extracted three times with ethyl acetate. The combined organic phases were washed with 5% strength sodium bicarbonate solution and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure, and the residue was dried under high vacuum. This gave 1.44 g of the target product (98.8% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[N:10][NH:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: NNC(=O)c1cc(N)ccc1Oc1ccccc1
Product: Nc1ccc(Oc2ccccc2)c(C(=O)NN=Cc2cccc(C(F)(F)F)c2)c1

Procedure:
A mixture of phenol (5.64 g, 60 mmol) and potassium t-butoxide (6.74 g, 60 mmol) in 50 mL 1,4-dioxane was stirred at room temperature for 0.5 h. To the mixture was added 2-chloro-5-nitro-benzoic acid methyl ester (10.78 g, 50 mmol) and the mixture was refluxed overnight. The solvent was evaporated and the residue was purified by chromatography with EtOAc:hexanes, 1:4, as eluant, yielding (11.739 g, 86%) 5-nitro-2-phenoxy-benzoic acid methyl ester. A mixture of 5-nitro-2-phenoxy-benzoic acid methyl ester (2.0 g, 7.32 mmol) in 30 mL ethanol and Pd/C (200 mg) were hydrogenated at 40 psi overnight to yield 5-amino-2-phenoxy-benzoic acid methyl ester (1.672 g, 94%). A mixture of 5-amino-2-phenoxy-benzoic acid methyl ester (0.95 g, 3.9 mmol) and hydrazine (4 mL, 80%) was refluxed for 4 h to yield 5-amino-2-phenoxy-benzoic acid hydrazide (0.722 g, 76%). The title compound was prepared from 5-amino-2-phenoxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (CDCl3): 10.81 (s, 1H), 8.15 (s, 1H), 8.0 (s, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.40 (m, 2H), 7.19 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.8, 2H), 6.80 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl[C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[CH:24][N:23]=1>CN(C=O)C>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:22]2[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ncn1
Temperature: 60 °C

Procedure:
18.6 mL triethylamine and piperazine-1-carboxylic acid tert-butyl ester were added to 9.7 g 4-chloro-6-methoxy-pyrimidine in 50 mL DMF. The reaction was stirred over night at 60° C. The reaction was cooled and the precipitate was filtered. The filtrate was evaporated. The residue was dissolved in DCM, extracted with water and washed with sodium chloride solution. The solvent was evaporated and the residue was crystallized with a mixture of petrolether and diethylether (8:2) to yield 8.7 g of the desired compound.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(O)=[O:2].O1CCCC1.[NH3:16]>CCOCC>[C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(=[O:2])[NH2:16]
Reactant: N
Reactant: O=C(O)Cn1nnnc1S
Solvent: C1CCOC1
Solvent: CCOCC
Product: NC(=O)Cn1nnnc1S
Reaction time: 2.5 h

Procedure:
1-Carboxymethyltetrazole-5-thiol and 1,1-carbonyldiimidazole were reacted as described in Example 4. To the reaction mixture was added tetrahydrofuran saturated with dry ammonia gas. The resulting suspension was stirred for 2.5 hours and the solid which formed was collected by filtration, washed with tetrahydrofuran and dissolved in methanol. Amberlite IR-120 ion-exchange resin (50 g.) was added and the suspension was stirred for 15 minutes. The resin was then removed and washed with absolute methanol. The methanol solution was concentrated to give a residue which was dissolved in ether and triturated with acetone to give 1-carbamoylmethyltetrazole-5-thiol, m.p. 200° (dec.).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:10](O)=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH:28](Cl)[C@H:29]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32].Cl>C1COCC1>[NH:4]([C:1]([CH3:2])=[O:3])[C@H:5]([C:10]([NH:28][C@H:29]([C:34]([O:36][CH3:37])=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:11])[CH2:6][CH:7]([CH3:8])[CH3:9]
Reactant: COC(=O)[C@H](CC(C)C)NCl
Reactant: CC(=O)N[C@@H](CC(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(C)=O
Reaction time: 0.33 h

Procedure:
Acetyl-Leucine (5.0 g) was dissolved in 150 mL of distilled THF under argon and the resulting solution was cooled to -15°. Next one equivalent of N-methyl morpholine followed by one equivalent of isobutyl chloroformate was added and the reaction was allowed to activate 20 minutes and then another equivalent of N-methyl morpholine followed by HCl-LeuOMe (5.25 g). The reaction is allowed to slowly come to room temperature and stir overnight. The reaction was then poured into 150 mL of 1N HCl and extracted with ethyl acetate (2×150 mL). The combined organic fractions were washed with 1N HCl (15 mL), brine (50 mL), and dried over MgSO4, filtered and the solvent was removed under reduced pressure and then high vacuum. TLC (silica gel, CHCl3 /isopropanol:95:5) showed the product Ac-Leu-Leu-OCH3 to be a single spot Rf 0.36. NMR (100 MHz) δ 0.95 (d, 12H), 1.5 (bs, 6H), 2.0 (s, 3H), 3.7 (s, 3H), 4.5 (q, 2H), 6.6 (d, 1H), 6.8 (d, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:11]([O-])(=O)=O.[K+].ClCCl>Cl.O>[Cl:11][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:10]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cccc(O)c1Cl
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
73 g (0.52 mol) of 3-nitrophenol are dissolved in 2 liters-of 6N hydrochloric acid while heating. The mixture is cooled in an ice bath to 28°-30° C. 32 g (0.26 mol) of potassium chlorate in 500 ml of water are added over 1.5 hours and then, at the end of the addition, the mixture is left stirring for 30 minutes at 28°-30° C. The mixture is cooled to 15° C. and 1 liter of dichloromethane is added. The layers are separated and the organic phase is washed with water. The organic phase is dried and evaporated. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane/methanol (80/20) mixture. Recrystallization is carried out from toluene. 29 g of product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])[CH:3]=1
Reactant: C[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@H](Nc1cc(Br)ccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitro-benzene (22 g, 100 mmol), L-alanine (8.9 g, 100 mmol), and potassium carbonate (17.5 g, 125 mmol) in ethanol (250 ml), and water (200 ml) was heated to reflux for 5 hours. After cooling to room temperature, the mixture was diluted with water, and acidified with 1N hydrochloric acid. The precipitate was collected on a funnel and dried to afford N-(5-bromo-2-nitrophenyl)-alanine (28.9 g, 100%). A sample was recrystallized from ethanol: m.p. 183-187° C.; 1H-NMR (DMSO-d6) δ 1.44 (d, J=6.9 Hz, 3H), 4.56 (m, 1H), 6.87 (d, J=6 Hz, 1H), 7.21 (d, J=1.7 Hz, 1H), 7.99 (d, J=7 Hz, 1H), 8.36 (d, J=7 Hz, 1H), 13.27 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][OH:7].[CH3:19][S:20](Cl)(=[O:22])=[O:21].CCN(CC)CC>C(Cl)Cl>[CH3:19][S:20]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:22])=[O:21]
Reactant: COc1cc(CO)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(COS(C)(=O)=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(methoxy)-4-(benzyloxy)benzyl alcohol (0.244 g, 1.00 mmol) in CH2Cl2 (2.0 mL) was treated with methanesulfonylchloride (0.085 mL, 1.10 mmol) and Et3N (0.160 mL, 1.15 mmol). After stirring 1 h at ambient temperature, the reaction mixture was filtered through a short plug of silica gel using CH2Cl2 as the eluant. The solution was concentrated in vacuo and taken on without purification. MS (ES+) m/e 323 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.S([O-])([O-])(=O)=O.[Mg+2].[Cl-].[C:18]([O:22][C:23](=[O:26])[CH2:24][Zn+])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.C(OCC)(=O)C>[CH2:18]([O:22][C:23](=[O:26])[CH:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)[CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH3:19]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 65 %

Procedure:
To a solution/suspension of 5-aminoindazole (1.01 g, 7.6 mmol) in tetrahydrofuran (20 mL) was added ethyl glyoxlate solution (ca. 50% in toluene, 1.7 mL, 1.1 equiv) in one portion followed by magnesium sulfate (4.6 g). The mixture was stirred at room temperature overnight (23 h) and then filtered and concentrated in vacuo. The resulting crude imine intermediate (1.3 g, 6 mmol) was dried by azeotroping with anhydrous benzene and further dried under high vacuum. The residue was then dissolved in tetrahydrofuran (20 mL) and cooled at 0° C. A solution of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in ether, 24 mL, 2 equiv) was then slowly added. After stirring at 0° C. for 1 h, the mixture was stored at 4° C. overnight. The mixture was then diluted with ethyl acetate and quenched with half-saturated ammonium chloride solution along with a minimum amount of 0.5 N HCl to dissolve the precipitated solids. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with 10% methanol in methylene chloride, to afford the desired product (1.3 g, 65%) as a tan oil. 1H-NMR (400 MHz, CDCl3) δ 7.89 (1H, s), 7.40–7.27 (1H, m), 6.98–6.77 (2H, m), 4.42–4.35 (1H, m), 4.30–4.12 (3H, m), 2.80 (2H, d, J=4.4 Hz ), 1.43 (9H, s), 1.27–1.17 (4H, m). Mass spec.: 356.24 (M+Na)+, 278.23 (M−tBu)+, tR=1.287 min.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=O)[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:22][NH2:23]>>[Cl:17][C:12]1[CH:11]=[C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:19]([CH3:20])=[N:22][N:23]=[C:1]3[CH3:2])=[C:6]2[CH3:18])[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(Cl)c2)c1C
Reactant: NN
Product: Cc1nnc(C)c2c(C)n(-c3ccc(O)c(Cl)c3)c(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (340 mg, 1.0 mmol) was added hydrazine (50 μL). After stirring at rt for 1 h, the reaction mixture was poured into ice water (25 mL). The resulting precipitate was filtered, washed with diethyl ether (20 mL), and then dried under vacuum to afford 2-chloro-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol as a pale yellow solid: 1H NMR (CD3OD, 500 MHz) δ 7.34 (br s, 1H), 7.08 (m, 2H), 2.83 (s, 6H), 2.52 (s, 6); MS (ESI) 302 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[C:9]1([CH3:17])[CH:14]=[CH:13][C:12]([Mg]Br)=[CH:11][CH:10]=1>>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:12]1[CH:13]=[CH:14][C:9]([CH3:17])=[CH:10][CH:11]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: Fc1ccccc1Br
Product: Cc1ccc(-c2ccccc2F)cc1
Yield: 57 %

Procedure:
6.0 g (57% yield) was prepared as an oil by the method of Example 19A from 10 g 2-bromofluorobenzene, 250 mg bis(diphenylphosphinylethane)nickel dichloride and 89 ml 0.73M 4-toluylmagnesium bromide. The product was used without further purification. NMR (CDCl3, 60 MHz): 7.5-6.9 (m, 8H), 2.3 (s, 3H).
Reaction SMILES: N[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.S(=O)(=O)(O)O>O>[CH:8]1[CH:7]=[CH:6][C:5]2[CH2:4][CH2:3][N:2]3[C:10]=2[C:9]=1[C:11]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=13
Reactant: NN1CCc2ccccc21
Reactant: O=C1CCCCCC1
Agent: O=S(=O)(O)O
Solvent: O
Product: c1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 29.9 %

Procedure:
Following the procedure of Example 1, step 1, indoline (20 g, 170 mmol), sodium nitrite (14 g, 200 mmol), concentrated hydrochloric acid (30 mL) in water (70 mL) and ether (120 mL) provided 1-nitroindoline (31 g), which was reduced with zinc dust (˜50 g) in acetic acid (500 mL) to provide 1-aminoindoline (29 g). A mixture of 1-aminoindoline (17 g, 130 mmol), cycloheptanone (15 mL, 130 mmol), and concentrated sulfuric acid (20 mL) in water (180 mL) provided 8.2 g of 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole. MS (ESI) m/z 212.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:8]2([NH:16][S:17]([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:19])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C[O:34]C1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:30][CH2:29][CH:28]([O:31][CH3:32])[CH2:27][CH2:26]3)[C:8]2([NH:16][S:17]([CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:18])=[O:19])[C:11]([O:13][CH2:14][CH3:15])=[O:34])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C=C(OCC)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Yield: 62.6 %

Procedure:
To a solution of compound 9 (90 mg, 0.19 mmol) in anhydrous toluene (10 mL) was added Lawesson's reagent (84 mg, 0.20 mmol) under a nitrogen atmosphere, the mixture was heated to reflux for 12 h. After cooling down, the solvent was removed by evaporation in vacuo and the resulting residue was purified by column chromatography on silica gel eluting with petroleum ether:EtOAc (3:1) to give compound 10 (65 mg, 70%) as a white solid. LC-MS tR=1.503 min in 2 min chromatography, MS (ESI) m/z 483.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([OH:13])[C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:21]([O:23][CH3:24])=[O:22]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([O:13][C:21]([O:23][CH3:24])=[O:22])[C:9]([NH:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CNC(=O)N(O)c1ccc(Cl)cc1
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CNC(=O)N(OC(=O)OC)c1ccc(Cl)cc1

Procedure:
A solution of 1-(4-chlorophenyl)-1-hydroxy-3-methylurea (10 grams; 0.05 mol) in isopropyl alcohol (40 ml), and pyridine (6 ml) were charged into a glass reaction flask equipped with a mechanical stirrer. Methyl chloroformate (5 ml; 0.06 mol) was added to the flask with stirring, at a temperature of about 10° to 15°C. After the addition was completed the reaction mixture was stirred for an additional one-half hour resulting in the formation of a precipitate. After this time, the reaction mixture was poured onto ice and the precipitate was recovered by filtration and dried. The dried precipitate was then recrystallized from a methyl alcohol-water mixture to yield 1-(4-chlorophenyl)-1-methoxycarbonyloxy-3-methylurea having a melting point of 145° to 146°C and having the following elemental analysis as calculated for C10H11ClN2O4 :
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[OH:17].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([NH:10][C:11](=[O:16])[C:12]([CH3:14])([CH3:13])[CH3:15])=[CH:4][C:3]=1[O:17][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][O:18]1
Reactant: CC(C)(C)C(=O)Nc1cc(O)c(F)c(F)c1F
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(OC2CCCCO2)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
1.19 g (4.82 mmol) of the above 2,3,4-trifluoro-5-pivaloylaminophenol was dissolved in 50 mL of dichloromethane, 0.88 mL (9.6 mmol) of 3,4-dihydro-2 H-pyran and 22 mg (0.095 mmol) of dl-camphorsulfonic acid were added and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 100 mL of a 10% aqueous solution of potassium carbonate and the mixture was extracted once with chloroform. The organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was triturated with n-hexane to give 1.25 g of 2,3,4-trifluoro-5-pivaloylamino-O-tetrahydropyranylphenol (yield: 78%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[I-].[K+].CC(C)([O-])C.[K+].[CH3:18][O:19][CH2:20][CH2:21]Cl>CN(C=O)C>[CH3:18][O:19][CH2:20][CH2:21][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
146.5 g (1.2 mol) of 4-hydroxybenzaldehyde are dissolved in DMF, and 20 g (0.12 mol) of potassium iodide, 134.6 g (1.2 mol) of potassium tert-butoxide and 170.2 g (1.8 mol) of 2-chloroethyl methyl ether are added. The reaction mixture is stirred at 80° C. for 16 h. For work-up, the reaction mixture is concentrated under reduced pressure. The residue is taken up in 1 l of ethyl acetate and extracted with 0.5 l of 1N aqueous sodium hydroxide solution. The ethyl acetate phase is dried using magnesium sulphate and concentrated under reduced pressure. The residue obtained after concentration is distilled under high vacuum (b.p.=100° C. at 0.45 mbar). This gives 184.2 g (85% of theory) of product.
Reaction SMILES: [C:1]([O:20][CH:21]([CH2:35][O:36][C:37](=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:22][NH:23][C:24](=[O:34])[CH2:25][NH:26]C(OC(C)(C)C)=O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:1]([O:20][CH:21]([CH2:35][O:36][C:37](=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]/[CH:45]=[CH:46]\[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:22][NH:23][C:24](=[O:34])[CH2:25][NH2:26])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CNC(=O)CNC(=O)OC(C)(C)C)OC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(CNC(=O)CN)OC(=O)CCCCCCC/C=C\CCCCCCCC
Reaction time: 0.5 h

Procedure:
15.20 g (19.56 mmol) 20 was taken up in 200 ml CH2Cl2 /TFA (3:1 v/v) and stirred for 30 min. Afterwards the solution was diluted with 200 ml CH2Cl2 and shaken out with 200 ml sat. NaHCO3 solution. The organic phase was dried over MgSO4 and rotary evaporated. Yield: 11.64 g (88%) 21 as an oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]([OH:22])[C:19](O)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]([O:33][NH2:34])([CH3:32])[CH3:31]>>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH:18]([OH:22])[C:19]([NH:34][O:33][CH:30]([CH3:32])[CH3:31])=[O:20])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)ON
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Product: CC(C)ONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1

Procedure:
The reaction can be carried out in analogy to reaction step 20.3 by reacting 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-isopropylhydroxylamine.