Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12]O)=[N:10][CH:11]=1.C(=O)(O)[O-].[Na+].[ClH:19]>C(Cl)Cl>[ClH:3].[Cl:19][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:11][N:10]=1
Reactant: OCc1ccc(F)cn1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(CCl)nc1

Procedure:
Add thionyl chloride (320 μL, 4.30 mmol) slowly to a 0° C. solution of (5-fluoro-pyridin-2-yl)-methanol (420 mg, 3.31 mmol) in methylene chloride (15 mL). Stir the reaction at 0° C. for 3 h and quench with isopropyl alcohol. Dilute the reaction contents with methylene chloride (50 mL) and then saturated aqueous sodium bicarbonate (20 mL). Separate the organic phase, dry(magnesium sulfate), filter and concentrate in vacuo to give an oil. The oil is treated with hydrochloric acid (10 mL, 3 M solution in dioxane) at room temperature for 30 min. The resultant solid is collected by filtration and washed with a minimal amount of cold diethyl ether to give 200 mg (33%) as a yellow solid. MS (APCI): m/z 146 [C6H5ClFN+H]+; 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 7.56-7.37 (m, 2H), 4.67 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCO
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(C#N)cc1
Reaction time: 48 h

Procedure:
A suspension of 4-cyanophenylacetic acid (31.2 g, prepared as described in J. C. S. 744, (1941)), concentrated sulphuric acid (5 ml) and absolute ethanol (300 ml) was boiled under reflux with stirring for 48 hours. The solvent was removed under reduced pressure and dilute aqueous sodium hydroxide solution was added to neutralise the sulphuric acid. Dichloromethane was added. The mixture was filtered and extracted with further dichloromethane. The organic extracts were dried and evaporated to give ethyl 4-cyanophenylacetate, m.p. 94-95° C.
Reaction SMILES: N#N.[CH2:3]1[CH2:13][CH2:12][N:11]2[C:6](=NCC[CH2:10]2)[CH2:5][CH2:4]1.BrCCCC#[N:19]>CCOCC>[N:11]1([CH2:12][CH2:13][CH2:3][CH2:4][NH2:19])[CH2:10][CH2:5][CH2:6]1
Reactant: N#CCCCBr
Reactant: C1CCC2=NCCCN2CC1
Agent: N#N
Solvent: CCOCC
Product: NCCCCN1CCC1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of trimethylene imine (300 mg, 5.25 mmol) and DBU (0.79 mL, 5.23 mmol) in dry Et2O (4 mL) was added 4-bromobutyronitrile (0.54 mL, 5.27 mmol) at 0° C. The reaction mixture was stirred at rt until completion of the reaction. The mixture was filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (4 mL) and treated with LiALH4 (230 mg, 6.06 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Aq. 1N NaOH (2 mL) was then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 4-(azetidin-1-yl)butan-1-amine as a pale yellow oil. GC-MS-conditions 01: tR=1.35 min; [M+H]+=129.00.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.C1COCC1.[Br:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21](O)=[O:22].[BH4-].[Na+]>CCOC(C)=O.C([O-])(O)=O.[Na+].O>[Br:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[CH2:21][OH:22]
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1cc(F)c(F)cc1Br
Temperature: 25 °C

Procedure:
Solid CDI (4.3 g, 26.4 mmol) was added to a THF solution (130 mL) of 2-bromo-4,5-difluorobenzoic acid and the solution was refluxed. After 3 h the resulting mixture was cooled to room temperature and a water solution (26 mL) of NaBH4 (666 mg, 17.6 mmol) was added. After 10 min the resulting mixture was diluted with EtOAc and 10% aqueous NaHCO3 and the layers were separated. The organic layer was washed with water and brine, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([NH:10][CH3:11])[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:3]=1[C:4]#[N:5].[F:15][C:16]([F:24])([F:23])[CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].[NH4+].[OH-]>CN(C=O)C>[CH3:11][NH:10][C:8]1[C:7]([N+:12]([O-:14])=[O:13])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:20]2[CH2:21][CH2:22][CH:17]([C:16]([F:24])([F:23])[F:15])[CH2:18][CH2:19]2)[CH:9]=1
Reactant: CNc1cc(Cl)c(C#N)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C#N)cc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A mixture of 2-chloro-4-(methylamino)-5-nitrobenzonitrile (3.07 g, 14.5 mmol), 4-trifluoromethylpiperidine (3.33 g, 21.7 mmol), K2CO3 (5.01 g, 36.2 mmol) and DMF (16 mL) was heated at 60° C. for 6 h under Ar atmosphere. The mixture was poured into aqueous NH4OH and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. Crystallization from EtOAc/PE gave the sub-title compound.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl:61][CH2:62][C:63](=[O:69])[CH2:64][C:65]([O:67][CH3:68])=[O:66].[OH-].[Na+]>>[Cl:61][CH2:62][C@@H:63]([OH:69])[CH2:64][C:65]([O:67][CH3:68])=[O:66]
Reactant: COC(=O)CC(=O)CCl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Product: COC(=O)C[C@H](O)CCl
Temperature: 30 °C
Reaction time: 13 h
Yield: 95 %

Procedure:
The recombinant E. coli HB101 (pNTS1G) obtained in Example 10 was inoculated in 100 ml of a 2×YT medium sterilized in a 500 ml Sakaguchi flask, and cultured with agitation at 37° C. for 13 hours. Glucose, 7.2 g, 3.2 mg of NADP, and then 4 g of methyl 4-chloroacetoacetate were added to 50 ml of the resultant culture. The culture was stirred at 30° C. while being adjusted at pH 6.5 with a 5 M sodium hydroxide solution to allow for reaction for 24 hours. After the reaction, the reaction solution was subjected to extraction using ethyl acetate, the solvent was removed under decompression, and the concentrate was purified by silica gel column chromatography, to obtain 3.85 g of methyl (S)-4-chloro-3-hydroxybutyrate. The optical purity of the methyl (S)-4-chloro-3-hydroxybutyrate was analyzed as follows and found to be 100% e.e. That is, the sample was converted to a carbamate using phenyl isocyanate under the presence of pyridine and measuring the optical purity of the carbamate by an HPLC method. 1H-NMR(CDCl3) δ (ppm): 2.65(2H,m), 3.20(1H,br), 3.63(2H,m), 3.73(3H,s), 4.28(1H,m); Column: Chiralcel OJ (0.46×25 cm) manufactured by Daicel Chemical Industries, Co., Ltd.; Column temperature: 25° C.; Eluent: n-hexane/2-propanol of 8/2; Flow rate: 1 ml/min.; Detection: 254 nm; Elution time: 19.2 minutes for (S), 22.6 minutes for (R).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8](=[O:49])[CH:9]([CH2:34][C:35]1[CH:36]=[N:37][C:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:39][CH:40]=1)[CH:10]([S:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18]CC)=[O:17])([CH3:6])([CH3:5])[CH3:4]>C(O)C.C(OCC)C.O.C1(C)C=CC=CC=1>[C:3]([O:7][C:8](=[O:49])[CH:9]([CH2:34][C:35]1[CH:36]=[N:37][C:38]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:39][CH:40]=1)[CH:10]([S:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([OH:18])=[O:17])([CH3:5])([CH3:6])[CH3:4]
Reactant: CCOC(=O)c1cccc(CCC(SCc2ccc(OC)cc2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CSC(CCc2cccc(C(=O)O)c2)C(Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
KOH (5 mL of a 1M solution in ethanol) was added to a solution of ethyl 3-{5-tert-butoxy-4-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]-5-oxopentyl}benzoate (0.27 g, 0.406 mmol, synthesised according to the procedure for Example 1) in ethanol (2 mL), and the mixture was stirred at room temperature for 2 h and then at 50° C. for 2 h. The reaction mixture was then diluted with diethyl ether and water. The organic phase was extracted with 0.1M aqueous KOH and the combined aqueous phase was acidified (pH 5) using 3M aqueous HCl. The aqueous phase was then extracted with diethyl ether and the organic phase was washed with brine, dried and concentrated. Purification of the residue by reversed-phase HPLC (C-8 column, linear gradient 40%→100% of MeCN in 5% aqueous MeCN containing 0.1 M ammonium acetate) gave a residue that was dissolved in toluene and water and concentrated to give 3-{5-tert-butoxy-4-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-[(4-methoxybenzyl)thio]-5-oxopentyl}benzoic acid (0.12 g, 54%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[CH:16]([C:24]([O:26]C)=O)[C:17](=O)[CH2:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1.C(=O)(OC)OC.ClC1C=CC(S(N2C3CCCC2CC(=O)C3)(=O)=O)=CC=1>>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:19]3[CH2:20][CH2:21][CH2:22][CH:15]2[C:16]2[C:17]([CH2:18]3)=[N:3][N:2]([CH3:1])[C:24]=2[OH:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: COC(=O)C1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CNN
Agent: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Solvent: COC(=O)OC
Product: Cn1nc2c(c1O)C1CCCC(C2)N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example using methylhydrazine and methyl 9-(4-chlorophenylsulfonyl)-3-oxo-9-azabicyclo[3.3.1]nonane-2-carboxylate, which was prepared as described in Example 12 using dimethyl carbonate and 9-(4-chlorophenylsulfonyl)-9-azabicyclo[3.3.1]nonan-3-one. See also: Bonjoch, Josep; Linares, Ana; Guardia, Manel; Bosch, Joan. Heterocycles 1987, 26(8), 2165-74.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[C:6]1[CH:11]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[Cl:21])[C:10]([C:22](=O)[CH2:23][S:24](=[O:30])(=[O:29])[NH:25][CH:26]([CH3:28])[CH3:27])=[C:9]([CH3:32])[NH:8][C:7]=1[CH3:33])([CH3:3])[CH3:2].[BH4-].[Na+].C(Cl)Cl.C(OCC)(=O)C>C(O)(C)C.COCCOC>[CH:1]([O:4][C:5](=[O:34])[C:6]1[CH:11]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=2[Cl:21])[C:10](/[CH:22]=[CH:23]/[S:24](=[O:29])(=[O:30])[NH:25][CH:26]([CH3:27])[CH3:28])=[C:9]([CH3:32])[NH:8][C:7]=1[CH3:33])([CH3:3])[CH3:2]
Reactant: CC1=C(C(=O)CS(=O)(=O)NC(C)C)C(c2cc([N+](=O)[O-])ccc2Cl)C(C(=O)OC(C)C)=C(C)N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: CC1=C(/C=C/S(=O)(=O)NC(C)C)C(c2cc([N+](=O)[O-])ccc2Cl)C(C(=O)OC(C)C)=C(C)N1
Yield: 70.8 %

Procedure:
Analogously to Example 18, 1.02 g of 4-(2-chloro-5-nitrophenyl)-1,4-dihydro-5-[(isopropylsulfamoyl)acetyl]-2,6-dimethylnicotinic acid isopropyl ester were treated with 0.08 g of sodium borohydride in a mixture of 10 ml of isopropanol and 2 ml of 1,2-dimethoxyethane. After chromatography with methylene chloride/ethyl acetate (4:1) as the elution agent there was obtained 0.70 g of 4-(2-chloro-5-nitrophenyl)-1,4-dihydro-5-[(E)-2-(isopropylsulfamoyl)vinyl]-2,6-dimethylnicotinic acid isopropyl ester in the form of yellow crystals, m.p. 199°-201°.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7]CC[CH2:4]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[OH:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13].COCCl>C(OCC)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH2:4][O:3][CH3:7])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1ccc(O)c(Br)c1
Reactant: C1CCOC1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OCOC)c(Br)c1
Reaction time: 0.5 h

Procedure:
5.5 g of sodium hydride was added to a tetrahydrofuran (300 ml) solution of 20.5 g of ethyl 3-bromo-4-hydroxybenzoate produced according to the method described in Monatsh. Chem.; 22; 1901; 437, with cooling with ice, and the reaction liquid was stirred for 30 minutes, and then, at the same temperature, 10 ml of chloromethyl methyl ether was added to the reaction liquid, and the reaction liquid was stirred overnight at room temperature. The reaction liquid was diluted with ethyl acetate, and washed with water, and the aqueous layer was extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting solid was suspended in hexane and then taken out through filtration to obtain the entitled compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[O:11][C:10]2([CH3:21])[CH3:20])[CH:7]=[N:6][CH:5]=1)([CH3:3])=[CH2:2]>CO.[Pd]>[CH:1]([C:4]1[N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[O:11][C:10]2([CH3:21])[CH3:20])[CH:7]=[N:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cncn1C1c2ccccc2C(=O)OC1(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cncn1C1c2ccccc2C(=O)OC1(C)C
Reaction time: 72 h
Yield: 92.7 %

Procedure:
To a solution of 4-(5-isopropenyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.225 g, 0.797 mmol) (Example 4) in methanol (5 mL) is added Pd/C (0.250 g). The reaction vessel is flushed with hydrogen gas and stirred under balloon pressure for 72 h. The mixture is filtered and the filtrate concentrated in vacuo to give a 4-(5-isopropyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one(0.210 g) as yellow solid (ESI) m/z 285.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.24 (s, 3 H), 1.41 (d, J=6.6 Hz, 3 H), 1.45 (d, J=6.8 Hz, 3 H), 1.56 (s, 3H), 3.23 (br. s, 1 H), 5.60 (br. s, 1 H), 6.88 (br. s, 1 H), 7.15 (br. s, 1 H), 7.44 (d, J=7.3 Hz, 1H), 7.68 (td, J=7.6, 1.1 Hz, 1 H), 7.79 (td, J=7.6, 1.3 Hz, 1 H), 8.25 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:15])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].[OH:16]O>[NH4+].[OH-]>[CH3:15][C:4]1[C:3]([C:1]([NH2:2])=[O:16])=[C:7]([NH:8][C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[S:6][N:5]=1
Reactant: OO
Reactant: Cc1nsc(NC(=O)CC(C)C)c1C#N
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nsc(NC(=O)CC(C)C)c1C(N)=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of N-(4-cyano-3-methyl-isothiazol-5-yl)-3-methyl-butyramide (method 24) (8 g, 35.8 mmol) in 30% aqueous NH4OH (200 mL), was added dropwise 100 mL of hydrogen peroxide at r.t. After the completion of the addition the reaction mixture was stirred at 60° C. overnight after which the TLC showed the complete disappearance of SM. The reaction mixture was concentrated to 40 mL and extracted with chloroform (3×100 mL). The organic layer was dried (Na2SO4) and concentrated to obtain 3-methyl-5-(3-methyl-butyrylamino)-isothiazole-4-carboxylic acid amide (6.1 g, 71%) as a light yellow solid. 1H NMR (300 MHz) δ 1.03 (d, 6H), 2.24 (m, 1H), 2.43 (d, 2H), 2.69 (s, 3H), 5.98 (bs, 2H), 11.77 (bs, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:13])[C:9]([O:11]C)=[O:10].[OH-].[Na+].C(O)(=O)C>C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:13])[C:9]([OH:11])=[O:10]
Reactant: COC(=O)[C@@H](C)OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@@H](OC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
In ethanol (510 ml) was dissolved methyl (2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionate (42.7 g), to which was added, under ice-cooling, a 2N solution of sodium hydroxide (170 ml), followed by stirring for one hour at room temperature. The reaction mixture was cooled with ice, to which was added a 26% aqueous solution of acetic acid (120 ml), followed by extraction with dichloromethane (200 ml) three times. Dichloromethane layers were combined, washed with a saturated aqueous sodium chloride solution (100 ml) twice, and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure to leave (2R)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionic acid (32 g) as a colorless waxy product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][C:31]4[CH:36]=CC=C[CH:32]=4)=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=CC=1)=N)(C)(C)C.C(=O)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C@H:20]2[N:24]3[C:25](=[O:37])[C:26]([NH:29][CH2:30][CH:31]([CH3:32])[CH3:36])=[CH:27][N:28]=[C:23]3[CH2:22][CH2:21]2)=[O:19])=[CH:12][CH:11]=1)=[NH:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Agent: CC(C)C=O
Product: CC(C)CNc1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OC(C)(C)C)cc1)CC2
Yield: 79 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, intermediate 1j (97.1 mg, 0.228 mmol), isobutyraldehyde (32.8 mg, 0.455 mmol) and NaBH(OAc)3 (135.1 mg, 0.638 mmol) yielded 87.4 mg (79%) of intermediate 7a. MS (ESI) 483.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[C:17]4[CH:24]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([O:31]CC6C=CC=CC=6)=[CH:27][CH:26]=5)[N:22](COCC[Si](C)(C)C)[C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].O.C(=O)(O)O.C(OCC)(=O)C.O1CCCC1>FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[C:17]4[CH:24]=[C:23]([C:25]5[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=5)[NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)n1ccc2cc(Oc3ncnc4c3cc(-c3ccc(OCc5ccccc5)cc3)n4COCC[Si](C)(C)C)ccc21
Agent: O=C(O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)n1ccc2cc(Oc3ncnc4[nH]c(-c5ccc(O)cc5)cc34)ccc21
Temperature: 52.5 °C
Yield: 25.6 %

Procedure:
After dissolving 30 mg of 5-[6-(4-benzyloxyphenyl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]indole-1-carboxylic ethylamide in 1 ml of trifluoroacetic acid and 0.1 ml of thioanisole, the mixture was stirred at 50-55° C. The mixture was then returned to room temperature, saturated bicarbonate water was added to alkalinity, and liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran (5:1) mixed solvent. The organic layer was concentrated, 1 ml of tetrahydrofuran and 1 ml of 2N aqueous sodium hydroxide were added to the residue, and the mixture was stirred at room temperature for 5 minutes. After neutralization with 1N hydrochloric acid, liquid separation and extraction were performed with an ethyl acetate-tetrahydrofuran (5:1) mixed solvent. The organic layer was concentrated and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to obtain 5 mg of the title compound.
Reaction SMILES: C(OC([N:11]1[C@@H:16]([CH3:17])[C:15](=[O:18])[N:14]2[C@@H:19]([CH2:22][CH2:23][N:24]3[CH2:31][CH2:30][C:27]4([CH2:29][CH2:28]4)[C@H:26]([OH:32])[CH2:25]3)[CH2:20][O:21][CH:13]2[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[OH:32][C@@H:26]1[CH2:25][N:24]([CH2:23][CH2:22][C@@H:19]2[N:14]3[C:15](=[O:18])[C@H:16]([CH3:17])[NH:11][CH2:12][CH:13]3[O:21][CH2:20]2)[CH2:31][CH2:30][C:27]21[CH2:29][CH2:28]2
Reactant: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OC[C@@H]2CCN1CCC2(CC2)[C@H](O)C1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1NCC2OC[C@H](CCN3CCC4(CC4)[C@H](O)C3)N2C1=O
Yield: 93.4 %

Procedure:
A solution of (3S,6S)-3-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid benzyl ester (200 mg, 0.45 mmol) in EtOH (2 mL) was stirred for 3½ h at room temperature under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on activated charcoal, 96 mg), then insoluble material was removed by filtration through diatomaceous earth. The filtrate was concentrated to afford (3S,6S)-3-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-hexahydro-oxazolo[3,2-a]pyrazin-5-one (130 mg). This was redissolved in DCM (2 mL), then 3,4-dichlorophenyl isocyanate (88 mg, 0.45 mmol) was added at 0° C. The ice bath was removed, then after 30 min diethylamine (16 mg, 0.23 mmol) was added and the reaction mixture was evaporated. Chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) produced (3S,6S,8aS)-3-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid (3,4-dichloro-phenyl)-amide [example 1; 17 mg, 8%; white solid, MS 497.3 (M+H)+] and (3S,6S,8aR)-3-[2-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-ethyl]-6-methyl-5-oxo-hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid (3,4-dichloro-phenyl)-amide (example 2; 127 mg, 57%; white foam, MS 497.3 (M+H)+].
Reaction SMILES: [O-]CC.[Na+].[C:5]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6].Cl[CH2:21][C:22]1[C:23]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:24]([O:28][CH3:29])[CH:25]=[CH:26][CH:27]=1.O>C(O)C.C(O)(=O)C>[C:5]([NH:8][C:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: COc1cccc(CCl)c1OCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(Cc1cccc(OC)c1OCc1ccccc1)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Yield: 66.4 %

Procedure:
A quantity of 136.20 g (0.42 mole) of 21 wt.% sodium ethoxide in ethanol is added to a stirred solution of 90.14 g (0.415 mole) of diethyl acetamidomalonate (Aldrich) in 800 mL of absolute ethanol. A solution of the benzyl chloride derivative of Example 38 in 500 mL of absolute ethanol is added and the mixture is heated at reflux for 2 hours. The cooled mixture is poured into 4 L of ice and water containing 20.0 g of glacial acetic acid. The supernatant is decanted from the separated gum. The gum is dissolved in 2 L of ether, the solution dried (magnesium sulfate), and concentrated to ca 300 mL volume. Petroleum ether (100 mL) is added to precipitate 107.1 g (66.4% yield) of pure crystalline product; mp 94°-96° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([N:11]=[C:12]=[O:13])=[N:8][C:7]=2[CH:14]=1.[Br:17][CH2:18][CH2:19][NH:20][CH2:21][CH:22]=[O:23]>C1C=CC=CC=1>[Br:17][CH2:18][CH2:19][N:20]([CH2:21][CH:22]=[O:23])[C:12]([NH:11][C:9]1[S:10][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:14][C:7]=2[N:8]=1)=[O:13]
Reactant: O=C=Nc1nc2cc(C(F)(F)F)ccc2s1
Reactant: O=CCNCCBr
Solvent: c1ccccc1
Product: O=CCN(CCBr)C(=O)Nc1nc2cc(C(F)(F)F)ccc2s1
Reaction time: 1 h

Procedure:
5-Trifluoromethylbenzothiazol-2-yl isocyanate dimer (0.1 mole), the dimethyl acetal of 2-β-bromoethylaminoacetaldehyde (0.2 mole) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at ambient temperatures for a period of about 1 hour. After this time the reaction mixture is filtered, and the filtrate is stripped of solvent to yield the desired product the dimethyl acetal of 2-[1-β-bromoethyl-3-(5-trifluoromethylbenzothiazol-2-yl)ureido]acetaldehyde as the residue.