Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:23][CH3:24])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[OH:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[C:4]([O:23][CH3:24])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(OC)nc2nc(C(O)c3ccc(OC)cc3)cn2c1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCc1c(OC)nc2nc(C(=O)c3ccc(OC)cc3)cn2c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
10 g of activated manganese dioxide were added to a solution of 2.2 g (6.7 mmol) of (6-ethyl-7-methoxy-5-methyl imidazo[1,2-a]pyrimidin-2-yl)(4-methoxyphenyl)methanol in 100 ml of chloroform and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite and evaporation of the filtrate gave a solid product. Purification on a 100 g silica gel column using chloroform-methanol (98 to 2) as the eluant gave 1.3 g (59% yield) of pure (6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)(4-methoxyphenyl)methanone as a white crystalline solid melting at 196°-7° C. Overall yield from ester was 37%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:35])[NH:10][CH:11]([C:18]([N:20]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:35])[NH:10][CH:11]([C:18]([N:20]([CH2:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(NC(=O)Nc1cccc(C)c1)C(=O)N(CC(=O)OC(C)(C)C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(NC(=O)NC(CCC(=O)O)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc2)c1
Yield: 31.8 %

Procedure:
The procedure is as in Example 3, but starting with methyl (RS)-4-[3-(3-methylphenyl)ureido]-N-(tert-butoxycarbonylmethyl)-N-phenylglutaramate (4.7 g) and normal sodium hydroxide (9.7 cc). The product obtained is purified by chromatography on silica (0.063-0.200 mm) (60 g) contained in a column 2.4 cm in diameter [eluent: methylene chloride/methanol (99: 1 by volume) (1000 cc), then methylene chloride/methanol (97:3 by volume)], collecting 25-cc fractions. Fractions 42 to 105 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After crystallisation in diethyl ether, (RS)-4-[3-(3-methylphenyl) ureido]-N-(tertbutoxycarbonylmethyl)-N-phenylglutaramic acid (1.45 g), m.p. 191° C., is obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].C(N(CC)CC)C.Br[CH2:46][C:47]([O:49][CH3:50])=[O:48].C(OCC)(=O)C>CN(C=O)C>[CH3:50][O:49][C:47](=[O:48])[CH2:46][NH:1][C@H:2]([C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)CBr
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CN[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (product of example 8) (0.023 g, 0.044 mmol) in DMF (0.7 mL) was added triethylamine (12.0 μL, 0.087 mmol) and methyl bromoacetate (4.0 μL, 0.054 mmol). The mixture was stirred to room temperature for 1 h. Ethyl acetate was added and the organic layer was washed with a saturated solution of NaHCO3, then dried with MgSO4 and concentrated. The residue was purified by flash chromatography eluting with a mixture of hexane/EtOAc. The yield obtained was 47%.
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.Cl.ClC1C=CN=CC=1.[NH2:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[C:21]([O:28][CH3:29])[N:20]=1>O1CCOCC1>[CH3:29][O:28][C:21]1[N:20]=[C:19]([N:18]2[CH:3]=[CH:7][CH:6]=[CH:5]2)[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=1
Reactant: COC1CCC(OC)O1
Reactant: COc1ccc([N+](=O)[O-])c(N)n1
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Product: COc1ccc([N+](=O)[O-])c(-n2cccc2)n1

Procedure:
10.45 g (0.0791 mol; 1.2 eq) of 2,5-dimethoxy-tetrahydrofuran and 12.00 g (0.0791 mol; 1.2 eq) of 4chloropyridine hydrochloride are stirred for 10 minutes in 300 cm3 of dioxane. 11.15 g (0.0659 mol) of 2-amino-6methoxy-3-nitropyridine are added and the solution is brought to reflux for 4 h. The dioxane is evaporated under reduced pressure.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:16](O)=[O:17])[C:12](=[O:14])[CH:13]=1.[NH2:31][C:32]1[CH:36]=[CH:35][N:34]([CH2:37][C:38]([CH3:41])([OH:40])[CH3:39])[N:33]=1>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]([NH:31][C:32]2[CH:36]=[CH:35][N:34]([CH2:37][C:38]([OH:40])([CH3:41])[CH3:39])[N:33]=2)=[O:17])[C:12](=[O:14])[CH:13]=1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2-c2ccccc2)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3-c3ccccc3)cc2=O)n1
Yield: 50 %

Procedure:
Using the method described in Example 17, 2-[4-(biphenyl-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid (Intermediate 37) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(biphenyl-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.74 g, 50%); ES+-HRMS m/e calcd for C31H35N5O4 [M+H+] 542.2762 found 542.2759. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.02 (m, 1H), 1.04 (s, 3H), 1.05 (s, 3H), 1.26 (m, 1H), 1.36-1.66 (m, 7H), 1.88 (m, 1H), 2.15 (m, 1H), 3.88 (s, 2H), 4.66 (s, 1H), 5.37 (dd, J=4.4, J=11.0 Hz, 1H), 5.62 (d, J=2.9 Hz, 1H), 6.37 (d, J=2.3 Hz, 1H), 7.29-7.36 (m, 1H), 7.37-7.43 (m, 3H), 7.44-7.60 (m, 6H), 7.97 (d, J=2.9 Hz, 1H), 10.73 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[N:7]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:14]=2)[CH2:8][C:9](=O)[N:10]=1)[CH2:2][CH2:3][CH3:4].B.C1COCC1.Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH2:1]([CH:5]1[NH:10][CH2:9][CH2:8][N:7]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:14]=[C:6]12)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=NC(=O)Cn2cc(-c3ccccc3OC)nc21
Agent: B
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCCCC1NCCn2cc(-c3ccccc3OC)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
The product from Step 1.e. (6.13 g, 20.5 mmol) (compound vi where R3 is n-butyl, R4 is 2-methoxyphenyl, and R5 and R6 are H) was dissolved in THF (100 ml) and treated with 1M BH3/THF (82.0 ml, 82.0 mmol) at room temperature for about 2 hours and then refluxed for about 3 hours. The mixture was cooled to room temperature and 4N HCl (50 ml) was added dropwise. The mixture was stirred at room temperature for about 2 hours then made basic by careful portionwise addition of solid K2CO3. Product was extracted with EtOAc (3×50 ml). The EtOAc layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (about 50 ml), concentrated HCl (1.75 ml) was added and the solution was again concentrated under reduced pressure. The product was crystallized from MeOH/Et2O to yield 6.76 g (92%) of the desired product. Mass spec. 286.3 MH′, NMR (300 MHz, DMSO-d6, 30° C.) 10.0-11.5 (2H, s broad), 8.05-8.15 (1H, d,d), 8.0-8.1 (1H, s), 7.35-7.5 (1H, t), 7.15-7.3 (1H, d), 7.0-7.15 (1H, t), 4.8-4.95 (1H, m), 4.4-4.65 (2H, m), 3.9-4.0 (3H, s), 3.65-3.8 (1H, m), 3.5-3.65 (1H, m), 2.45-2.65 (1H, m), 2.1-2.35 (1H, m), 1.5-1.7 (2H, m), 1.25-1.5 (2H, m), 0.85-1.0 (3H, t).
Reaction SMILES: C(O)(=O)C.[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:10]#[C:11][CH2:12][OH:13].N(C([O-])=O)=NC([O-])=O.[K+].[K+]>N1C=CC=CC=1>[S:5]1[CH:9]=[CH:8][N:7]=[C:6]1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCC#Cc1nccs1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: OCCCc1nccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Glacial acetic acid (16 ml) was added dropwise during 0.25 h to a stirred solution of 3-(2-thiazolyl)-2-propynol (2.4 g) and dipotassium azodicarboxylate (50 g) in pyridine (200 ml). The mixture was stirred at room temperature for 1 h and additional glacial acetic acid (40 ml) added during 0.5 h. The mixture was stirred at room temperature for 2 days. The solvent was removed by azeotropic distillation with toluene (2×100 ml) and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined extracts dried and evaporated to leave a brown oil. This was purified by FCC eluting with toluene:ethyl acetate:triethylamine (50:50:1) to give the title compound as an orange oil (1.45 g), t.l.c. (toluene:ethyl acetate:triethylamine 50:50:1) Rf 0.15.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH3:43])[CH2:3][O:4][C:5](=[O:42])[N:6]=[C:7]([NH2:41])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH2:37][CH2:38][OH:39])[C:29]=2[F:40])[C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:17]=2)=[CH:10][CH:9]=1.[Cl:45][CH2:46]Cl.C(=O)([O-])O.[Na+].S(Cl)(OCCl)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.C1COCC1.O.C1COCC1.C(OCC)(=O)C.C1COCC1>[CH3:1][C:2]([CH3:44])([CH3:43])[CH2:3][O:4][C:5](=[O:42])[N:6]=[C:7]([NH2:41])[C:8]1[CH:9]=[CH:10][C:11]([NH:14][CH:15]([C:16]2[N:20]=[C:19]([O:21][CH2:46][Cl:45])[N:18]([C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)[N:17]=2)[C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH2:37][CH2:38][OH:39])[C:29]=2[F:40])=[CH:12][CH:13]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: ClCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)(Cl)OCCl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCCl)n(-c3ncccn3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of [1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]carbamic acid 2,2-dimethylpropyl ester (4 g) and dichloromethane (80 mL), sodium hydrogen carbonate (6.63 g) and tetrabutylammonium hydrogen sulfate (447 mg) were added at low temperature (−10° C.˜5° C.). To the resulting mixture, THF (80 mL) and water (80 mL) were added. To the resulting mixture, chloromethyl chlorosulfate (3.26 g) in dichloromethane/THF (1:1) mixture (10 mL) was added dropwise at −5° C., and the resulting mixture was stirred overnight at room temperature. Under ice-cooling, THF/ethyl acetate (1:4) mixture (500 mL) was added to the mixture, and the resulting mixture was filtered. To the filtrate obtained, water (300 mL) was added, and the resulting mixture was shaken, after which the organic layer was collected. The organic layer was washed with saturated aqueous sodium chloride solution (150 mL). An aqueous layer was extracted with THF/ethyl acetate (1:4) mixture (250 mL, twice). The organic layers were combined and washed with saturated aqueous sodium chloride solution (150 mL). All the organic layers were combined and dried over anhydrous sodium sulfate and anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (1.56 g).
Reaction SMILES: [F:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH:23]([CH2:26][NH:27]C(=O)OC(C)(C)C)[CH2:22][CH2:21]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:19])[C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O>[NH2:27][CH2:26][CH:23]1[CH2:22][CH2:21][N:20]([C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]([CH3:19])[C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=3)[N:4]=2)[CH2:25][CH2:24]1
Reactant: CC(=O)N(C)c1ccc(Nc2ncc(F)c(N3CCC(CNC(=O)OC(C)(C)C)CC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(C)c1ccc(Nc2ncc(F)c(N3CCC(CN)CC3)n2)cc1
Yield: 51.6 %

Procedure:
A solution of tert-butyl (1-(5-fluoro-2-(4-(N-methylacetamido)phenylamino)pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (60 mg, 0.13 mmol) in TFA (2 mL) was stirred at room temperature for 60 min. TFA was removed in vacuo. The residue was purified by HPLC to give N-(4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)-N-methylacetamide (25 mg). MS 373.3 (M+H); UV 201.8, 266.8 nm.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH:5]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClC1C=CC=CC=1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:5]1([N:11]=[C:1]=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: NC1CCCCC1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: O=C=NC1CCCCC1
Temperature: 79 °C
Yield: 142.5 %

Procedure:
500 g of chlorobenzene and 7 g of triphenylphosphine oxide (0.025 mol) were placed in the glass vessel and 47 g of gaseous phosgene was introduced at room temperature. The reaction mixture was subsequently heated to 78° C., with vigorous phosgene reflux being established. While stirring vigorously at 78-80° C., a total of 99.2 g of cyclohexylamine (1 mol) dissolved in 200 g of chlorobenzene and at the same time a further 116 g of phosgene were introduced over a period of 3 hours. After addition was complete, the system was maintained at 78-80° C. for a further one hour without introduction of phosgene to allow further reaction to occur and the residual unreacted phosgene was subsequently stripped out at 40° C. by means of nitrogen. The reaction mixture obtained was a fluid suspension from which the solid obtained was separated by filtration. 1.9 g of solid were able to be isolated in this way. The filtered crude product was worked up by distillation. Removal of the solvent and fractional distillation gave 84.6 g of cyclohexyl isocyanate (0.677 mol). This corresponds to 67.7% of the theoretical yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[O:7][C:6](=[O:8])[CH:5]([C:9](=O)[C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:4](=[O:31])[O:3]1.C(O)(=O)C.[BH4-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:32])[O:3][C:4](=[O:31])[CH:5]([CH2:9][C@@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=2)[C:6](=[O:8])[O:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)C1C(=O)OC(C)(C)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CC1C(=O)OC(C)(C)OC1=O
Reaction time: 0.67 h

Procedure:
(S)-tert-Butyl 1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (22.0 g, 48 mmol) in 200 mL DCM was cooled to −5° C. Acetic acid (32 g, 527 mmol) was added in one portion and sodium tetrahydroborate (4.5 g, 120 mmol) as a solid was added portion wise over about 40 minutes. The reaction mixture was stirred for another 40 minutes and the reaction mixture was stored in the freezer overnight and was then washed with brine (3×150 mL) and water (2×100 mL). The organic layer was dried over MgSO4. The desired product was obtained as a white amorphous solid (21.0 g, 98%). No further purification was performed and the reaction was carried on to the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:11]=[C:10]([Cl:12])[NH:9][N:8]=1)=[O:6].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[N:11]=[C:10]([Cl:12])[N:9]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[N:8]=1)=[O:6]
Reactant: COC(=O)c1n[nH]c(Cl)n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)n(COCC[Si](C)(C)C)n1
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a suspension of NaH (60% dispersion, 53.9 mg, 1.34 mmol) in DMF (5 mL) at 0° C., a solution of 5-chloro-1H-[1,2,4]-triazole-3-carboxylic acid methyl ester (Bull. Pharm. Sci., 20(1): 47-61, (1997), 218 mg, 1.35 mmol) in DMF (10 mL) was added dropwise. The resulting suspension was stirred at the same temperature for 30 min and then treated with SEMCl (0.24 mL, 1.4 mmol). The resulting solution was stirred at RT for 30 min and poured onto ice. The mixture was extracted with ether (3×20 mL) and the ether layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue obtained was chromatographed on silica (10% EtOAc/hexane) to obtain the title compound (227 mg, 58%). Mass spectrum (ESI, m/z): Calcd. for C10H18ClN3O3Si, 292.0 and 294.0 (M+H), found 291.5 and 293.6.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl>[C:21]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1Cc2cc(-c3ccccc3)ccc2N1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
5-Bromo-2-oxindole (5 g, 23.5 mmol) was dissolved in 110 mL toluene and 110 mL ethanol with stirring and a little heat. Tetrakis(triphenylphosphine)palladium(0) (1.9 g, 1.6 mmol) was added followed by 40 mL (80 mmol) 2M aqueous sodium carbonate. To this mixture was added benzene boronic acid (3.7 g, 30.6 mmol) and the mixture was heated in a 100° C. oil bath for 12 hours. The reaction was cooled, diluted with ethyl acetate (500 mL), washed with saturated sodium bicarbonate (200 mL), water (200 mL), 1N HCl (200 mL) and brine (200 mL). The organic layer was dried over magnesium sulfate and concentrated to afford a brown solid. Trituration with dichloromethane afforded 3.8 g (77%) of 5-phenyl-2-oxindole as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH3:9][Mg+].[Br-]>C1COCC1.CCOCC>[Cl:1][C:2]1[S:3][C:4]([C:7](=[O:8])[CH3:9])=[CH:5][N:6]=1
Reactant: O=Cc1cnc(Cl)s1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cnc(Cl)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
2-Chloro-thiazole-5-carbaldehyde (1.00 g., 6.77 mmol) was dissolved in THF (10 mL) and cooled to −78° C. MeMgBr (2.26 mL of a 3.0 M solution in Et2O, 6.78 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and then allowed to slowly warm to −20° C. over a further 30 min. The reaction was quenched by the addition of EtOAc (2 mL), allowed to warm to 20° C., and 2 M hydrochloric acid (20 mL) was added. The mixture was poured into water (200 mL) and extracted into DCM (200 mL), dried (Na2SO4) and concentrated. The residue was dissolved in reagent grade acetone (20 mL), cooled in an ice bath, and Jones' reagent (3.0 mL of a 2.67 M solution) was added dropwise. The mixture was stirred for 16 h, allowing to warm to 20° C., and then quenched with IPA (5 mL), poured into saturated aqueous NaHCO3 (200 mL) and extracted with EtOAc (2×100 mL). The EtOAc extracts were dried (Na2SO4) and concentrated to give pure product (800 mg, 73%) as a somewhat volatile white solid.
Reaction SMILES: CC1(C)[N:6]2[C:7](=[O:13])[C:8](=[C:10]([CH3:12])[CH3:11])[CH2:9][C@@H:5]2[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:3][CH2:4][C@@H:5]1[NH:6][C:7](=[O:13])[C:8](=[C:10]([CH3:12])[CH3:11])[CH2:9]1
Reactant: CC(C)=C1C[C@@H]2COC(C)(C)N2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)=C1C[C@H](CO)NC1=O
Temperature: 60 °C
Yield: 60.3 %

Procedure:
To a solution of (R)-3,3-dimethyl-6-(propan-2-ylidene)tetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (4.63 g, 23.73 mmol) in MeOH (50 mL) at room temperature was added p-toluenesulfonic acid monohydrate (0.451 g, 2.373 mmol) and then heated at 60° C. for 45 min. The solvent was evaporated and the crude material was absorbed onto a plug of silica gel and was purified by chromatography through a REDISEP™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 10% MeOH in DCM to give (R)-5-(hydroxymethyl)-3-(propan-2-ylidene)pyrrolidin-2-one (2.223 g, 14.32 mmol, 60.4% yield) as an yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.60 (br. s., 1H), 3.74 (td, J=8.0, 3.9 Hz, 1H), 3.67 (dd, J=11.1, 3.6 Hz, 1H), 3.44 (dd, J=11.1, 7.3 Hz, 1H), 2.75-2.86 (m, 1H), 2.81 (dd, J=16.5, 8.7 Hz, 1H), 2.33-2.43 (m, 1H), 2.23 (s, 3H), 1.77 (s, 3H). m/z (ESI, +ve) 156 (M+H).
Reaction SMILES: [H-].[K+].[CH3:3][C:4]1([CH3:22])[O:8][CH:7]2[CH2:9][C:10]([CH3:21])([CH3:20])[C:11]([CH2:15][Si](C)(C)C)(O)[C:12]([CH3:13])=[C:6]2[O:5]1.O>O1CCCC1>[CH3:3][C:4]1([CH3:22])[O:8][CH:7]2[CH2:9][C:10]([CH3:21])([CH3:20])[C:11](=[CH2:15])[C:12]([CH3:13])=[C:6]2[O:5]1
Reactant: CC1=C2OC(C)(C)OC2CC(C)(C)C1(O)C[Si](C)(C)C
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C1C(C)=C2OC(C)(C)OC2CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 171.8 %

Procedure:
23 ml of a 20% suspension of potassium hydride in oil (containing about 3.7 g/92 mmol KH) were pipetted into a 500 ml round flask provided with a magnetic stirrer and dropping funnel having a fitted argon bubble counter and washed three times with 10 ml of hexane each time. Then, 120 ml of tetrahydrofuran were added thereto and a solution of 25.0 g (83 mmol) of 2,2,4,6,6-pentamethyl-5,6,7,7a-tetrahydro-5-trimethylsilylmethyl-1,3-benzodioxol-5-ol in 220 ml of tetrahydrofuran was added dropwise thereto at room temperature and the mixture was stirred at room temperature for 30 minutes (GC control: educt no longer present). Then, the mixture was cooled to 0° C. and 50 ml of water were slowly added dropwise. An analogous working up to that in (i) gave 29.7 g of crude 2,2,4,6,6-pentamethyl-5,6,7,7a-tetrahydro-5-methylidene-1,3-benzodioxol as a yellowish oil. A distillation on a very short Vigreux column gave at a boiling temperature of 50° C./0.02 mbar (2 Pa) 15.6 g (90% yield) of pure product as a colorless oil. 1H-NMR (CDCl3, 250 MHz): inter alia 1.12 and 1.23 (2s, in each case 3H, C(6)-(CH3)2), 1.50 and 1.53 (2s, in each case 3H, C(2)(CH3)2), 1.73 (s, 3H, C(4)-CH3), 4.55 (m, 1H, CH—O—), 4.79 (d, J=6 Hz, ═CH2); IR (film): 1693, 1112 cm−1; mass spectrum: 208 (M+, 40), 107(100);