Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].ClCC=CC1C=CC=CC=1.C(N(CC)CC)C.[F:28][C:29]([F:48])([C:33]([F:47])([F:46])[C:34]([F:45])([F:44])[C:35]([F:43])([F:42])[C:36]([F:41])([F:40])[CH:37]([F:39])[F:38])[C:30](Cl)=[O:31]>C(OCC)C>[CH:1]([CH:3]([O:10][C:30](=[O:31])[C:29]([F:28])([F:48])[C:33]([F:46])([F:47])[C:34]([F:44])([F:45])[C:35]([F:42])([F:43])[C:36]([F:40])([F:41])[CH:37]([F:38])[F:39])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: C=CC(O)c1ccccc1
Agent: ClCC=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(OC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F)c1ccccc1
Temperature: 0 °C
Yield: 44 %

Procedure:
100 ml of diethyl ether, 40.2 g (0.3 mol) of vinylbenzylalcohol (synthesized by the method described in "Polymer", 14 330 (1973) from chloromethylstyrene (meta: para=about 6: about 4); b.p.=69° to 73° C./0.4 mm Hg), 30.3 g (0.3 mol) of triethylamine, and 0.5 g of 2,6-di-tbutylphenol were charged into a 300-ml three-necked flask equipped with a stirrer, a reflux condenser, and a calcium chloride tube, and the mixture was then cooled with ice-water. 109.4 g (0.3 mol) of the 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-n-heptanoic acid chloride synthesized above was cooled with ice and was added to the mixture dropwise, with stirring. Next the mixture was stirred for 2 hours at room temperature, after which it was stirred for 1 hour under reflux. Then, after cooling, the deposited triethylamine hydrochloride was filtered off, the filtrate was washed twice with water, then with an aqueous sodium carbonate solution, and then it was dried over anhydrous sodium carbonate. Distillation was carried out twice to purify the dried filtrate, thus giving 61.0 g (yield: 44.0%; b.p.: 106 to 116° C./0.9 mm Hg; d: 1.47) of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-n-heptanoic acid vinylbenzyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13](=[O:15])[CH2:12][S:11](=[O:17])(=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O.[NH2:28]/[C:29](/[CH3:37])=[CH:30]\[C:31]([O:33][CH2:34][CH2:35][OH:36])=[O:32]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2([OH:15])[NH:28][C:29]([CH3:37])=[C:30]([C:31]([O:33][CH2:34][CH2:35][OH:36])=[O:32])[CH:21]([C:20]3[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:19]=3[Cl:18])[CH:12]2[S:11](=[O:16])(=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC(=O)C1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: C/C(N)=C/C(=O)OCCO
Solvent: CCO
Product: CC1=C(C(=O)OCCO)C(c2cccc(Cl)c2Cl)C2C(O)(CN(C(=O)OC(C)(C)C)CCS2(=O)=O)N1
Yield: 34.6 %

Procedure:
A mixture of 4-N-(t-butyloxycarbonyl)-1,1-dioxo -2,3,4,5,6,7-hexahydro-1,4-thiazepine-6-one (9.06 g, 34.5 mmole) from Example 6, 2,3-dichlorobenzaldehyde (6.03 g, 34.5 mmole) and 2-hydroxyethyl 3-aminocrotonate (5.00 g, 34.5 mmole) was heated to reflux in 200 mL of ethanol for 24 hours. The ethanol was removed under reduced pressure and the residue was heated in refluxing toluene for 2 hours. After cooling a precipitate was filtered to give 6.75 g of the title compound. Evaporation of the filtrate and chromatography (2.5:1, ethyl acetate:hexane) produced 3.78 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: NS(=O)(=O)Oc1ccc(Cl)c(Cl)c1
Yield: 82.2 %

Procedure:
A solution of 16.3 g (0.1 mole) of 3,4-dichlorophenol in 100 ml of toluene was heated at reflux utilizing a Dean-Stark trap to remove any water that may have been present. The solution was cooled in an ice bath, treated with 9.1 ml (14.8 g, 0.105 mole) of chlorosulfonyl isocyanate, and heated at reflux overnight. The solution was cooled in an ice bath, vigorously stirred, and treated dropwise with water until gas evolution ceased. The solid which precipitated was collected by filtration, washed with water and benzene, dried, and recrystallized from benzene to yield 19.9 g (82%) of a white solid, mp 121°-123° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH3:25])=[CH:17][CH:16]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(F)cc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1c2cc(F)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
A solution of 80 mg (0.33 mmol) of 6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid, 66 mg (0.40 mmol) of 7-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline, 63 mg (0.33 mmol) of EDC and 50 mg (0.12 mmol) of HOBt in 2 mL of DMF is stirred at room temperature for 24 h. The mixture is concentrated in vacuo and the solid residue is partitioned between methylene chloride (3 mL) and saturated aqueous sodium hydrocarbonate solution (3 mL). The organic layer is separated, washed with 0.5 N HCl, water and brine and concentrated in vacuo.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:22])[CH3:21])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
Amine preparation: a mixture of BOC-piperazine (1.87 g), ethyl 2-bromoisobutyrate (5.90 g) and potassium carbonate (1.53 g) in MeCN (20 mL) was heated in a sealed tube at 80° C. for 3 days. The reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash column chromatography to yield 4-(1-ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (2.97 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.Cl.[C:19]1(=[O:29])[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([N:7]2[C:3]([CH2:2][N:26]3[CH2:27][CH2:28][C:23]4([C:19](=[O:29])[NH:20][CH2:21][CH2:22]4)[CH2:24][CH2:25]3)=[N:4][N:5]=[N:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Reactant: O=C1NCCC12CCNCC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1NCCC12CCN(Cc1nnnn1-c1cccc(C(F)(F)F)c1)CC2
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (200 mg, 0.762 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (4 mL) was added 2,8-diazaspiro[4.5]decan-1-one hydrochloride (290 mg, 1.52 mmol, Tyger Scientific, Ewing, USA) and triethylamine (0.318 mL, 2.29 mmol). The reaction mixture was heated at 120° C. for 20 minutes in a microwave reactor. The reaction mixture was then cooled and the solvent removed under vacuum. The residue was purified by MDAP. Fractions containing the desired product were combined and the solvent removed. The product was partitioned between DCM (6 mL) and saturated aqueous NaHCO3 (3 mL) and the organic layer collected via a hydrophobic frit. The solvent was removed under a stream of argon to yield the title compound as a solid (0.161 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][Cl:18]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH2:16][CH2:17][Cl:18])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCl)cn1
Temperature: 25 °C

Procedure:
The solution of 13.8 g of 5-hydroxy-2-pyridinecarboxylic acid methyl ester in 200 ml of dimethylformamide is added over a period of 45 minutes to a suspension of 4.3 g of sodium hydride in (57% mineral oil dispersion) 50 ml of dimethylformamide with stirring at room temperature. The mixture is stirred at room temperature for one hour and then is cooled to 5°-10°. To this cooled mixture is added a solution of 19.3 g of 1-bromo-3-chloropropane in 100 ml of dimethylformamide. The mixture is heated to 45°-50° and stirred at 45°-50° for 4 hours and 30 minutes. After that, the mixture is cooled, filtered and the filtrate evaporated to a residue. The residue is partitioned between methylene chloride and water and the layers are separated. The methylene chloride layer is washed with water and dried over anhydrous sodium sulfate. The methylene chloride solution is filtered and the filtrate evaporated to yield 5-(3-chloropropoxy)-2 -pyridinecarboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:5]C(OC(OC(C)(C)C)=O)=O)(C)(C)C.[CH2:16]([NH:19][C:20]1[N:21]=[C:22]([NH2:30])[C:23]2[S:28][CH:27]=[C:26]([CH3:29])[C:24]=2[N:25]=1)[CH:17]=[CH2:18].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].C(OCC)(=O)C.CCCCCC>C(#N)C>[CH2:16]([NH:19][C:20]1[N:21]=[C:22]([NH:30][C:1](=[O:5])[NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])[C:23]2[S:28][CH:27]=[C:26]([CH3:29])[C:24]=2[N:25]=1)[CH:17]=[CH2:18]
Reactant: C=CCNc1nc(N)c2scc(C)c2n1
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCNc1nc(NC(=O)NC(C)(C)C)c2scc(C)c2n1
Reaction time: 0.33 h
Yield: 50.4 %

Procedure:
To a solution of 306 mg (1.4 mmol) of di-t-butyldicarbonate in acetonitrile was added 122 mg (1.0 mmol) of N,N-dimethylaminopiridine at room temperature, followed by stirring for 20 minutes. 220 mg (1.0 mmol) of 2-allylamino-4-amino-7-methylthieno[3,2-d]pyrimidine was added to the reaction solution, followed by stirring at room temperature for 2 hours. Further, after 102 mg (1.4 mmol) of t-butylamine was added to the mixture, the reaction mixture was subjected to heating under reflux for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/23 to give 161 mg (yield: 50.5%) of the title compound.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[NH2:6][C:7]1[C:12]2=CC(C#N)=C[N:11]2[N:10]=[CH:9][N:8]=1.[H-].C([Al+]CC(C)C)C(C)C>CCOC(C)=O>[NH2:6][C:7]1[C:5]2=[CH:1][C:2]([CH:3]=[O:4])=[CH:12][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: C1CCOC1
Reactant: N#Cc1cc2c(N)ncnn2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOC(C)=O
Product: Nc1ncnn2cc(C=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of THF (200 mL) was added 4-aminopyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile (1.00 g, 6.28 mmol). The solution was heated until all starting material was in solution and was then cooled in an ice-water bath. 1 M Diisobutylaluminum hydride in THF (50.3 mL, 50.3 mmol) was then added to the solution which was stirred for 1 h. EtOAc was added to the solution and it was then allowed to warm to rt. Wet silica gel was carefully pipetted into the solution, and the reaction mixture was heated to 50° C. for 30 min, filtered through Celite, and washed with excess EtOAc. The solution was transferred to a separatory funnel and washed with water. The organic layer was collected, dried (MgSO4), filtered, and concentrated to dryness yielding 0.92 g of yellow solid (5.69 mmol, yield 91%). 1H-NMR (DMSO-d6) δ 9.91 (s, 1H) 7.92 (d, J=1.7 Hz, 1H), 8.14 (d, J=35.3 Hz, 2H), 7.89 (s, 1H), 7.30 (d, J=1.8 Hz, 1H); MS [M+H]+=163.3; LCMS RT=1.07 min.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[C:12]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>CCOCC>[Si:16]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Brc1nccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)c1nccs1
Temperature: -70 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
A solution of 2-bromothiazole (57.4 g) in ether (70 ml) was added slowly to a solution of n-butyllithium (1.6M solution in hexane, 241 ml) in ether (700 ml) under an atmosphere of argon, maintaining the temperature below -60° C. After stirring for 1 hour at -70° C., a solution of tert-butylchlorodimethylsilane (63.0 g) in ether (70 ml) was added slowly dropwise. The reaction mixture was then allowed to warm to ambient temperature and stirred for 16 hours. Saturated aqueous sodium bicarbonate solution was added, the layers were separated, and the aqueous phase extracted twice with ether. The combined organic phases were dried (MgSO4), concentrated, and the residue was purified by column chromatography, eluting with 25% ethyl acetate/hexane (v/v), and subsequent distillation to give 2-tert-butyldimethylsilylthiazole (Q) (46 g, 58% yield) as an oil (b.p. 88°-96° C. at 10 mm of mercury); NMR: 0.38(6H,s), 0.97(9H,s), 7.51 (1H,d). 8.12(1H,d).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH:20]=[CH:19][C:18]=1SC)[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[S:32]([O-:37])(O[O-])(=O)=O.[K+].[K+].S(=O)(=O)(O)[O-].[Na+].[CH3:46]C(C)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:16][C:17]1[CH:18]([CH3:19])[C:46](=[S:32]=[O:37])[CH:20]=[C:21]([O:23][CH2:24][C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)[CH:22]=1)[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC(C)=O
Reactant: O=S(=O)([O-])O[O-]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1SC)c1ccccc1C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Product: CCOC(=O)CCC(OC1=CC(OCc2ccsc2)=CC(=S=O)C1C)c1ccccc1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of ethyl (RS)-4-(2-methylphenyl)-4-[2-methylthio-5-(3-thienylmethoxy)phenoxy]butanoate in acetone (20 mL), at 0° C. is treated dropwise with a solution of potassium peroxymonosulphate (1.01 g of commercial 2KHSO5:KHSO4:K2SO4). The reaction mixture is stirred at 0° C. for 20 minutes, then treated with saturated aqueous sodium bisulphate solution (20 mL), and extracted with dichloromethane (2×50 mL). The combined organic extracts are dried over magnesium sulphate, filtered and concentrated in vacuo, to give ethyl (RS,RS)-4-(2-methylphenyl)-4-[2-methyl-sulphinyl-5-(3-thienylmethoxy)phenoxy)-butanoate (0.75 g) in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[C:5]([CH3:19])[N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>CC#N>[C:35]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([O:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)=[C:5]([CH3:19])[N:6]2[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])(=[O:37])[CH3:36]
Reactant: Cc1c(Oc2ccc(Cl)cc2)c2c(N)cccc2n1CC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1cccc2c1c(Oc1ccc(Cl)cc1)c(C)n2CC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of the product from example 3 step (iv) (70 mg) in MeCN (1 ml) was added triethylamine (50 μl) and acetyl chloride (17 μl) and the reaction stirred at 50° C. for 3 h. The residue was partitioned between diethylether/water, the organics were separated, washed with aq potassium hydrogensulfate solution, brine, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 5-30% ethylacetate/iso-hexane.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)[CH2:3][OH:4].[N:17]#[C:18]Br>>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2([CH2:6][CH2:5][C@H:2]3[CH2:3][O:4][C:18]([NH2:17])=[N:1]3)[CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: N#CBr
Reactant: N[C@H](CO)CCC1(c2ccc(Cl)cc2)CC1
Product: NC1=N[C@@H](CCC2(c3ccc(Cl)cc3)CC2)CO1

Procedure:
In analogy to example 1d (S)-2-amino-4-[1-(4-chloro-phenyl)-cyclopropyl]-butan-1-ol was reacted with cyanogen bromide to give (S)-4-{2-[1-(4-chloro-phenyl)-cyclopropyl]-ethyl}-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 265.1 ([M+H]+))
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[CH:23]1[CH:28]=CC=[CH:25][CH:24]=1>>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[C:23]([CH3:28])[C:24](=[O:6])[CH3:25])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Reactant: c1ccccc1
Agent: CC(C)(C)C(=O)O
Product: C=S1[C@@H]2C(=C(C)C(C)=O)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 7.8 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 200 ml of benzene is treated at room temperature with 10 g of triphenylphosphinemethylacetylmethylene. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (6:4). There is obtained methylene-(2S,5R)-3,3-dimethyl-6-(1-methyl-2-oxopropylidene)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as white crystals of melting point 59°-60° [Rf: 0.30; cyclohexane/ethyl acetate (6:4)].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[CH3:28])[C:24](=[O:29])[N:23]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH:22]=[CH:21]2.O>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][C:27]=2[CH3:28])[C:24](=[O:29])[N:23]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[CH:22]=[CH:21]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(Cn2ccc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)c(C)cc3c2=O)cc1
Temperature: 80 °C
Yield: 88.6 %

Procedure:
A solution of 3.2 g (15.9 mmol) 1-tert-butoxycarbonyl-4-hydroxypiperidine in 110 mL dimethylacetamide was stirred with 1.36 g (45.4 mmol) of 80-% sodium hydride for 1 h at room temperature. Then a suspension of 4.5 g (15.1 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one in dimethylacetamide was added. The reaction mixture was heated to 80° C. for 2 h during which time a clear solution was obtained. The reaction mixture was slowly added to 160 mL water and after 1 h of stirring the product was isolated by filtration and dried over night in vacuum. 6.4 g of 4-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-piperidine-1-carboxylic acid tert-butyl ester were obtained.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[O:9][N:8]=1)(=O)=O.[Br-:18].[Li+].O>CC(C)=O>[Br:18][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[O:9][N:8]=1
Reactant: [Br-]
Reactant: CS(=O)(=O)OCc1cc(-c2ncccn2)on1
Agent: [Li+]
Solvent: O
Solvent: CC(C)=O
Product: BrCc1cc(-c2ncccn2)on1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(3-methanesulfonyloxymethyl-isoxazol-5-yl)-pyrimidine (19 gm), lithium bromide (13 gm) in acetone (190 ml) was stirred at 30° C. temperature over a period of 2 h. The reaction was monitored by TLC. The reaction mixture was evaporated under vacuum to provide a crude mass which upon stirring with water (150 ml) provided suspension. Filtration of suspension under suction afforded the title compound in 15.2 gm quantity (75.3%) as a solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][C@@H:10]([NH2:14])[CH2:11]2)=[CH:6][CH:5]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:14][C@@H:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[CH2:11]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc2c(c1)C[C@H](N)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc2c(c1)C[C@H](NC1CCN(C(=O)OC(C)(C)C)CC1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.8 %

Procedure:
To a solution of (R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride (6.0g, 28.1 mmol)(prepared as described in the French patent FR 2,653,765 or available commercially) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.7g, 33.7 mmol, 1.2 eq.) in dichloroethane (200 mL) under an inert atmosphere was added sodium triacetoxyborohydride (14.9 g, 70.2 mmol, 2.5 eq). The reaction was stirred at room temperature for 24 h then concentrated in vacuo. The residue was partitioned between EtOAc (200 mL) and 5% KOH (150 mL). The aqueous layer was extracted twice more with EtOAc (2×75 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated to afford 4-((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (9.7 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:3]1.Cl[CH2:44][C:45]1[CH:46]=[C:47]([O:55][CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[C:48]2[C:53]([CH:54]=1)=[CH:52][CH:51]=[CH:50][CH:49]=2>>[CH3:61][Si:60]([CH3:62])([CH3:63])[CH2:59][CH2:58][O:57][CH2:56][O:55][C:47]1[C:48]2[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:54]=[C:45]([CH2:44][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:3]2)[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(O)C1
Reactant: C[Si](C)(C)CCOCOc1cc(CCl)cc2ccccc12
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2cc(OCOCC[Si](C)(C)C)c3ccccc3c2)C1

Procedure:
(α) In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(2-trityloxy-ethyl)-phenyl]-piperidine-1-carboxylate [Example 29(t)] with 3-chloromethyl-1-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene [Example 5(c)] there was obtained tert-butyl (3RS,4RS)-3-[4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]-4-[4-(2-trityloxy-ethyl)-phenyl]-piperidine-1-carboxylate.