Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:24]([O:26][CH3:27])=[O:25])[CH2:3][S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(NCC)C>C(#N)C>[NH2:1][C@H:2]([C:24]([O:26][CH3:27])=[O:25])[CH2:3][S:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CC#N
Solvent: CCNCC
Product: COC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of Fmoc-L-Cys(Trt)-OMe (2.58 g, 4.30 mmol) in acetonitrile (20.0 mL) was added diethylamine (20.0 mL). After 30 minutes, the mixture was concentrated in vacuo. The residue was dissolved in acetonitrile (3×10 mL) and concentrated in vacuo to afford L-Cys(Trt)-OMe as crude product which was used without purification.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]([F:19])=[C:4]([F:20])[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:22]>C1COCC1.CO>[CH3:22][O:9][C:8](=[O:10])[C:7]1[C:2]([Br:1])=[CH:3][C:4]([F:20])=[C:5]([F:19])[C:6]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a solution of 6-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (3.18 g, 8.77 mmol) in THF-MeOH (16 mL/5 mL) was added TMSCHN2 (5.30 mL, 10.6 mmol, 2 M solution in hexanes) at room temperature. The resulting mixture was stirred for 1 hour, quenched with AcOH, and diluted with EtOAc. The organic layer was washed with water, saturated NaHCO3 (2×), and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product (3.31 g, 100%) that was used directly without further purification.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH3:7])[N:5]=[N:4][N:3]=1.[CH3:8][C:9]1[CH2:16][S:15][CH:14]2[N:11]([C:12](=[O:27])[CH:13]2[NH:17][C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]=1[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].[Cl-].[Ca+2].[Cl-]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:7][N:6]1[C:2]([S:1][S:15][CH:14]2[N:11]([CH:10]([C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:33])[Cl:34])=[O:29])[C:9]([CH3:16])=[CH2:8])[C:12](=[O:27])[CH:13]2[NH:17][C:18](=[O:26])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:3][N:4]=[N:5]1
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)C2SC1
Reactant: Cn1nnnc1S
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(C)C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)Cc2ccccc2)C1SSc1nnnn1C

Procedure:
A solution of trichloroethyl 6β-phenylacetamido-penicillanate 1β-oxide (28.86 g) and 5-mercapto-1-methyl-tetrazole (6.96 g) in toluene (800 cc.) is heated under reflux for 3 hours, and the water formed during the reaction is removed as it is formed by passing the condensate over calcium chloride before reintroducing it into the reaction mixture. The solvent is evaporated under reduced pressure (12 mm Hg) at 40°C; the residue obtained is dissolved in chloroform (50 cc.) and the solution obtained is chromatographed on a column of silica (400 g) (0.06-0.20 mm, pH neutral; diameter of the column: 4.8 cm., height: 55 cm.). Elution is carried out using chloroform, collecting 250 cc. fractions. Fractions 10 to 17 are combined and concentrated to dryness under reduced pressure (12 mm Hg) at 40°C. 4-(1-Methyl-5-tetrazolyl-dithio)-3-phenylacetamido-1-(1-trichloroethoxycarbonyl-2-methyl-prop-2-en-1-yl)-2-azetidinone (17.4 g.) is obtained in the form of a colourless pastelike product, the characteristics of which are as follows: Rf = 0.50 [silica gel; chloroform/ethyl acetate (50/50 by volume)].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.O[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:35])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: O=C(NCCCO)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)OCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of 2-acetoxybenzoic acid (2.0 g, 11.1 mmol) and triethylamine (1.8 mL, 11.1 mmol) in CH2Cl2 (40 mL) at 0° C. was slowly added CICO2Et (1.1 mL, 167 mmol). The reaction mixture was stirred (0° C., 2 h) and filtered. The filtrate was added to a solution of benzyl 3-hydroxypropylcarbamate (2.1 g, 10.0 mmol) and triethylamine (15 mL) in CH2Cl2 (40 mL). The reaction mixture was stirred (RT, 4 h) and quenched with H2O (50 mL). The organic layer was washed with 1 M HCl, saturated Na2CO3 (30 mL) and H2O (50 mL). The organic solution was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica chromatography, (PE-EtOAc, 5:1) to afford 3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g, 54%) as a colorless oil. Mass calculated for C20H21NO64=371.38. found: [M+H]+=372.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:25](=[O:26])[C:24]([CH3:29])([CH3:28])[CH3:23])[C@H:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(Cc2ccccc2)CCC1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2ccccc2)CC[C@H]1OC(=O)C(C)(C)C

Procedure:
To a cis/trans mixture of 1-benzyl-3-methyl-piperidin-4-ol (50 g, 243 mmol, prepared as described in Can. J. Chem. (1972) 50, 803) in THF is added triethylamine (51 ml, 365 mmol) followed by 2,2-dimethyl-propionyl chloride (45 ml, 365 mmol). The reaction is exothermic and a precipitate is formed. The mixture is heated under reflux for 18 hours, cooled, filtered and washed with ether. The organic layers are washed with 1N—NaOH and brine, dried and evaporated. The crude is purified by chromatography on silicagel using hexane and EtOAc (5%) to give pure trans-isomer as a colourless oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.C(Cl)(Cl)Cl.P(Br)(Br)[Br:19]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][Br:19])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Temperature: -5 °C
Yield: 42.5 %

Procedure:
A 500-mL three-necked round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was purged with nitrogen and charged with 124b (37.0 g, 148 mmol) and chloroform (160 mL). The reaction was cooled to −5° C. using an ice/acetone bath and phosphorous tribromide (40.0 g, 148 mmol) was added portionwise. The cooling bath was removed and the reaction stirred at reflux for 2 h. After this time, the reaction was cooled to −5° C. and saturated aqueous sodium bicarbonate (250 mL) was added until a pH of 8.5 was reached. The mixture was extracted with ethyl acetate (3×150 mL) and the combined organic layers were washed with saturated aqueous sodium carbonate (2×50 mL), brine (75 mL), dried over sodium sulfate and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford a yellow residue that was dissolved with gentle heating in methylene chloride (60 mL). Hexanes (approximately 20 mL) was added and the solution became cloudy. The mixture was heated until a solid precipitate formed, methylene chloride (9 mL) was added and the solution became clear. The solution was left to cool to room temperature and after 4 h the resulting crystals were collected by vacuum filtration. The filter cake was washed with an ice-cold 1:2 mixture of methylene chloride:hexanes (2×20 mL) to afford 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (19.7 g). The combined filtrates were evaporated and the procedure was performed again to afford an additional 9.70 g of 1-(2-bromoethyl)-5-(bromo-methyl)-3-nitro-1H-pyrazole. The solids were combined and dried under high vacuum for 18 h to afford a 57% yield (26.0 g) of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 124c as white crystals: mp 95-97° C.; 1H NMR (300 MHz, CDCl3) δ 6.93 (s, 1H), 4.63 (t, 2H, J=6.0 Hz), 4.54 (s, 2H), 3.86 (t, 2H, J=6.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:25])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[Cl:24])[CH:5]=[CH:6][C:7]=1[CH2:8]Cl.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:25])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[Cl:24])[CH:5]=[CH:6][C:7]=1[CH2:8][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27]
Reactant: CCNCC
Reactant: O=C(COc1ccc(C(F)(F)F)cc1Cl)Nc1ccc(CCl)c(Cl)c1
Product: CCN(CC)Cc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl

Procedure:
Prepared analogously to Example 170 starting from N-(3-chloro-4-chloromethyl-phenyl)-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (Z32b) and diethylamine. The crude product was recrystallised from petroleum ether.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:17]>>[Cl:17][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: COc1ccc(CO)cc1OC1CCCC1
Reactant: Cl
Product: COc1ccc(CCl)cc1OC1CCCC1
Temperature: 23 °C
Reaction time: 0.67 h

Procedure:
The toluene solution from Example 2 was cooled to 20° C. and concentrated hydrochloric acid (37.5%; 9.80 g) was added keeping the temperature between 20 and 22.7° C. A sample was taken 40 minutes after the addition was complete and analysed (GC) and the reaction was deemed to be complete. The phases were allowed to separate and the lower, aqueous phase discarded. Sodium bicarbonate (1.20 g) was charged to the reactor to neutralize the remaining hydrochloric acid. After stirring for 15 minutes the mixture was cooled to 23° C. and filtered to remove the solid (sodium bicarbonate, sodium chloride). A part of the toluene (17.07 g) was removed by distillation in vacuo (end of distillation: 28° C., 7 mbar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1N.F[B-](F)(F)F.N#[O+].[C-:18]#[N:19].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:18]#[N:19]
Reactant: [C-]#N
Reactant: Nc1c(F)cc(Cl)cc1Br
Agent: F[B-](F)(F)F
Agent: N#[O+]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1c(F)cc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a solution of 2-bromo-4-chloro-6-fluoro-phenylamine (10 g, 44.5 mmol) in anhydrous DCM (100 ml) was added nitrosonium tetrafluoroborate (5.72 g, 49.01 mmol) and the mixture was stirred at 25° C. for 1 h. The reaction mixture was then cooled to 0° C. prior to addition of KCN (5.8 g, 89.1 mmol) followed by a dropwise addition of an aqueous solution (50 ml) of cupric sulfate hexahydrate (22.24 g, 89.1 mmol). After stirring for 40 minutes at 0° C. the reaction mixture was allowed to warm to 25° C. and stirring was continued for 1 h. The reaction mixture was diluted with DCM (100 ml) and slowly quenched by the addition of aqueous saturated solution of NaHCO3 until gas evolution is no longer observed. The resulting heterogeneous mixture was then filtered through a pad of celite and the organic layer was separated, washed twice with brine, dried with Na2SO4 and evaporated. The crude residue thus obtained was purified by chromatography (silica gel; hexane/EtOAc 90:10) to obtain the title compound as reddish solid (4 g, 38%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:35][C:36]1([F:40])[CH2:39][NH:38][CH2:37]1.C(N(CC)CC)C>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22]([N:38]4[CH2:39][C:36]([F:40])([F:35])[CH2:37]4)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(S(C)(=O)=O)ncc1Br
Reactant: FC1(F)CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ncc1Br

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (1.4428 g, 2.57 mmol) from Step A, 3,3-difluoroazetidine hydrochloride (0.997 g, 7.70 mmol), triethylamine (1.788 ml, 12.83 mmol) and THF (25 mL) were heated in a 63° C. oil bath overnight. The reaction crude was purified by flash chromatography (SiO2, Isolute Flash Si; 100 g prepacked cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Related fractions were pooled and evaporated to afford a light yellow solid foam as the titled compound. LCMS calc.=574.03. found=575.09 (M+H)+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][N:6]1[CH2:10][CH2:9][C:8](=[O:11])[C:7]1=[O:12]>O>[CH3:5][N:6]1[CH2:10][C:9](=[N:1][OH:3])[C:8](=[O:11])[C:7]1=[O:12]
Reactant: CN1CCC(=O)C1=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN1CC(=NO)C(=O)C1=O
Reaction time: 2 h
Yield: 56.3 %

Procedure:
10.5 g (0.15 mol) of sodium nitrite in 50 ml of water are added dropwise at 0° C. to a solution of 17.0 g (0.15 mol) of 1-methyl-2,3-pyrrolidinedione (H. Rapoport et al., J. Org. Chem. 40 (1975) 1264). The mixture is stirred for a further 2 hours, the deposited product is filtered off and 12.0 g (58%) of 1-methyl-2,3,4-pyrrolidinetrione-4-oxime are obtained.
Reaction SMILES: C(N=[CH:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[CH:9][C:8]=1[CH:21]1[CH2:23][CH2:22]1)CCC.Cl.[OH2:25]>>[CH:21]1([C:8]2[CH:9]=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:11]=[C:12]([C:13]([F:16])([F:15])[F:14])[C:7]=2[CH:6]=[O:25])[CH2:23][CH2:22]1
Reactant: O
Reactant: CCCCN=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F
Agent: Cl
Product: O=Cc1c(C2CC2)cc(C(F)(F)F)cc1C(F)(F)F

Procedure:
Crude butyl-[1-(2-cyclopropyl-4,6-bis-trifluoromethyl-phenyl)-methylidene]-amine (intermediate AL, 3.54 g, 10.5 mmol) was dissolved in 8 mL water. Hydrochloric acid (25%, 0.49 mL) was added and the mixture was refluxed for 2 h. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude material, brown oil (1.01 g, 34%) was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: CCC1(CCCCCl)C(=O)Nc2cc(F)ccc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2cc(F)ccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-(4-chloro-phenyl)-piperazine.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.C(O[C:32]1(O[Si](C)(C)C)[CH2:34][CH2:33]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][N:19]1[CH:32]1[CH2:34][CH2:33]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCC1CCNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)CC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCC1CCC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(C2CC2)CC1
Yield: 59 %

Procedure:
5-propyl-azepane-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide prepared as described in example 47 (68 mg, 0.16 mmol) in MeOH (2 mL), acetic acid (0.1 mL) was added, followed by 1-[(ethyoxycyclopropyl)oxy]trimethylsilane (0.2 mL, 0.96 mmol), sodium cyanoborohydride (41 mg, 0.64 mmol), and 3 Å molecular sieves, heated to reflux for 3 h. Molecular sieves were filtered out and the reaction solvent was removed to obtain the crude material. Purification was carried by silica gel column chromatography (10% MeOH/DCM) and HPLC to provide the title compound (44 mg, 59%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H]([C@@H]([C@@H](CO)O)O)O)O.COC([C@@H](NC([C@@H](N)CC(O)=O)=O)CC1C=CC=CC=1)=O.[C:34]12([CH3:44])[C:40]([CH3:42])([CH3:41])[CH:37]([CH2:38][CH2:39]1)[CH2:36][CH:35]2[OH:43].C[C@H]1C[C@@H](O)[C@H](C(C)C)CC1>C(O)C.OCC(CO)O>[C:34]12([CH3:44])[C:40]([CH3:41])([CH3:42])[CH:37]([CH2:38][CH2:39]1)[CH2:36][C:35]2([CH2:3][CH2:2][OH:1])[OH:43]
Reactant: CC1(C)C2CCC1(C)C(O)C2
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Solvent: CCO
Solvent: OCC(O)CO
Product: CC1(C)C2CCC1(C)C(O)(CCO)C2
Reaction time: 1 h

Procedure:
Thereafter, the warm aqueous mixture is filtered by using 100 mesh sieve and residues from the first filtration are extracted with. 20 l of water at a temperature of 80°-100° C. for 1 hour and condensed and under the reduced. Pressure to produce about 15 l of a natural substance extract. After 76.7 g of Bezoar bovis and 63.3 g of Moschus are dried on a silicagel desiccator for 24 hours and ground into microparticle size in a grinder to form a microparticle mixture by using 140 mesh sieve to make a Bezoar bovis powder and a Moschus powder, respectively. 5 Kg of conc-glycerin, 5 Kg of sugar and 35 Kg of d-sorbitol or 35 Kg of "ASPARTAME" and 10 Kg of Mel are solved with 10 l of distilled warm water for 15 minutes to make a sweetening solution. 5 l of distilled water is added to 110.0 g of genus Gelatin and the aqueous mixture is heated to produce a Gelatin solution. And 63.3 g of Borneol, and 0.5 l of L-menthol are solved with 3.5 l of ethanol to produce a Borneol-ethanol solution.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])[CH3:2].C(OCC)C.[CH:19]1([Mg]Cl)[CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)([OH:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccccc1
Reactant: Cl[Mg]C1CCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(c1ccccc1)C1CCCC1
Reaction time: 0.5 h

Procedure:
Into a solution of 23.5 g of phenylglyoxylic acid ethyl ester in 200 ml of tetrahydrofuran, a diethyl ether solution of cyclopentyl magnesium chloride was added dropwise under ice cooling, followed by 30 minutes' stirring at the same temperature. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction product was extracted with ethyl acetate, washed with saturated saline solution, and dried over anhydrous magnesium sulfate. Distilling the solvent off, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1 to 20/1). Thus 11 g of 2-cyclopentyl-2-hydroxy-2-phenylacetic acid ethyl ester was obtained, which was dissolved in 40 ml of methanol. To the solution 20 ml of 4N sodium hydroxide solution was added at room temperature, followed by 2 hours' stirring at the same temperature, and 1 hour's stirring at 50° C. Distilling the methanol off under reduced pressure, the aqueous layer was rendered weakly acidic with 4N hydrochloric acid and then extracted with ethyl acetate. The extract was washed with saturated saline solution, dried over anhydrous sodium sulfate and removed of the solvent by distillation. The resulting solid was washed with diethyl ether/hexane=1/1, and 8.7 g of 2-cyclopentyl-2-hydroxy-2-phenylacetic acid was obtained, which was dissolved, together with 11.6 g of cinchonidine, in 1.5 liters of toluene under heating, and the solution was cooled off to room temperature consuming about 4 hours. The white needles whereby precipitated were once again dissolved in 900 ml of toluene and cooled off to room temperature consuming about 4 hours. Recovering the precipitated white, acicular crystals by filtration, 8.0 g of (2R)-2-cyclopentyl-2-hydroxy-2-phenylacetic acid cinchonidine salt was obtained. The salt was dissolved in a mixture of diethyl ether and 1N hydrochloric acid, and the organic layer was washed with water and then with saturated saline solution, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, 3.0 g of the title compound was obtained as a white solid
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.[CH:19]1([CH:22]=O)[CH2:21][CH2:20]1.CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][N:10]([CH2:22][CH:19]3[CH2:21][CH2:20]3)[CH2:9][C:7]=2[N:8]=1
Reactant: O=CC1CC1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(CC1CC1)C2
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 94.9 %

Procedure:
To a stirring solution of (S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride (intermediate 6) (870 mg, 3.01 mmol) in dichloroethane, was added cyclopropanecarboxaldehyde (450 uL, 6.02 mmol) and Et3N (840 uL, 6.02 mmol). The reaction mixture was stirred at room temperature (20° C.) for 45 minutes, before adding sodium triacetoxy borohydride (1.28 g, 6.02 mmol). The reaction mixture was then stirred for a further 2 h at room temperature (20° C.) before partitioning between saturated NaHCO3 solution and DCM. The organic layer was recovered, dried over MgSO4, filtered and the solvent removed in vacuo, affording the title compound as a colourless oil (882 mg, 92% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([CH3:10])[C:6]([NH:8][CH3:9])=[O:7])=[O:4].[CH2:11]=O.Cl>>[O:7]=[C:6]1[N:5]([CH3:10])[C:3](=[O:4])[N:2]([CH3:11])[CH2:1][N:8]1[CH3:9]
Reactant: CNC(=O)N(C)C(=O)NC
Reactant: C=O
Agent: Cl
Product: CN1CN(C)C(=O)N(C)C1=O

Procedure:
145 g (1 mol) of 1,3,5-trimethyl-biuret and 30 g of paraformaldehyde are heated together with 5 ml of concentrated hydrochloric acid to 70° C for 5 hours. The liquid contents of the flask are then poured onto a dry metal sheet and, after solidification, recrystallised from cyclohexane. This gives 154 g (98%) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-s-triazine of melting point 88° C to 90° C.