Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.C([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][CH2:21][C:22]([C:35]#[N:36])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1.[OH-].[Na+]>C(OCC)(=O)C>[C:35]([C:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][CH2:20][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][NH:14]1)#[N:36]
Reactant: N#CC(CCC1CCCCN1Cc1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: N#CC(CCC1CCCCN1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 87.6 %

Procedure:
1-Benzyl-2-(3-cyano-3,3-diphenylpropyl)piperidine oxalate (3.70 g, 7.5 mmol--see Example 25) was partitioned between ethyl acetate and 0.5M aqueous sodium hydroxide solution and the organic layer was dried over magnesium sulphate and evaporated. The residue was dissolved in a mixture of acetic acid (5 ml), ethanol (5 ml) and water (2 ml) and the solution treated with sodium acetate (100 mg), palladium dichloride (100 mg) and charcoal. The mixture was stirred under 4 atmospheres of hydrogen at room temperature for 26 hours, filtered and evaporated. The residue was partitioned between ethyl acetate and 10% aqueous sodium carbonate solution and the organic layer was washed with water, dried over magnesium sulphate and evaporated to give the title compound (2.0 g, 88%) as a colourless oil which was characterised by its 1H-NMR spectrum.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>O1CCCC1>[CH3:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][N:5]=1
Reactant: Cc1nccc(Cl)n1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: Cc1nccc(N2CCNCC2)n1

Procedure:
13 g of 4-chloro-2-methyl-pyrimidine were dissolved in 200 ml of tetrahydrofuran, and 17.5 g of piperazine were added. The reaction mixture was refluxed for 24 h. The precipitated piperazine hydrochloride was filtered off with suction and washed with tetrahydrofuran. Concentration of the solution in vacuo resulted in 19 g of 2-methyl-4-piperazino-pyrimidine, which was reacted without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]1([CH3:10])[CH3:9].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[N:12][OH:13])[C:3]1([CH3:10])[CH3:9]
Reactant: NO
Reactant: CC1(C)C(=O)CCCC1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)C(=NO)CCCC1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.8 %

Procedure:
A mixture of 3-hydroxy-2,2-dimethylcyclohexanone (1.6 g, crude), hydroxylamine hydrochloride (2.98 g, 42.9 mmol) and sodium carbonate (4.54 g, 42.9 mmol) in EtOH (30 mL) and water (3 mL) was stirred at 25° C. for 6 h. After removal of EtOH, the residue was extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford the title compound (1.8 g, crude). MS (ESI) m/z 158.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:11]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[N-:47]=[C:48]=[O:49].[K+]>O.C(O)(=O)C>[CH3:9][O:8][C:7]1[C:2]([NH:1][C:48]([NH2:47])=[O:49])=[CH:3][C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:11]=2)=[CH:5][N:6]=1
Reactant: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1N
Reactant: [N-]=C=O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ncc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)cc1NC(N)=O
Yield: 53 %

Procedure:
To a suspension of (S)-2-(1-((5-(5-amino-6-methoxypyridin-3-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (92 mg, 0.14 mmol) in water (0.75 mL) and acetic acid (1.2 mL) was added potassium isocyanate (20 mg, 0.25 mmol) according to the method described in Preparation 181. The residue was purified using SP1® Purification System (0% to 5% dichloromethane methanol) to obtain 61 mg (53% yield, 86% purity) of the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@H:18]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[Si:28]([O:27][C@@H:18]1[CH2:17][CH2:16][C@H:15]2[C@H:14]3[C@H:23]([CH2:22][CH2:21][C@:19]12[CH3:20])[C:24]1[CH:25]=[CH:26][C:9]([OH:8])=[CH:10][C:11]=1[CH2:12][CH2:13]3)([C:31]([CH3:34])([CH3:32])[CH3:33])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]12C
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of 3-benzyloxy-17α-tert-butyldimethylsilyloxyestra-1,3,5(10)-triene (50, 1.90 g, 4.0 mmol) in THF (30 mL) was added 10% palladium on carbon (0.500 g). The reaction mixture was stirred for 2 h under a hydrogen atmosphere at room temperature. After the catalyst was filtered, the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:EtOAc (10:1→5:1, v/v) to afford 1.45 g of 51 (94% yield) mp: 161-162° C. (silica gel) using n-hexane:EtOAc (10:1→5:1, v/v) to afford 1.45 g of 51 (94% yield) mp: 161-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.OS(O)(=O)=O.[CH3:16]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
An oven-dried, 500 milliliter (mL) round bottom flask (“RBF”) was charged with 6-chloronicotinic acid (compound 1) (14.4 grams (g), 91.3 millimole (mmol)), in 200 mL of freshly distilled MeOH. H2SO4 (1.22 mL, 22.8 mmol) was added dropwise to this mixture at room temperature. The mixture was stirred for 6 hours at 60° C. The organic phase was separated and extracted with ethyl acetate at pH 8. The organics were then combined and dried over Na2SO4. After filtering the mixture, the solvent was evaporated to obtain the crude product. The resulting crude product was then purified by silica gel column chromatography (eluent: methylene chloride:hexane=1:10 v/v) to yield 10.5 g (73%) of methyl 6-chloronicotinate (Compound 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:26]2[CH2:30][C@H:29]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:28][C:27]2=[O:36])[CH:5]=[C:6]([F:25])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][O:16]CC2C=CC=CC=2)[CH2:10][CH2:9]1>CO>[F:25][C:6]1[CH:5]=[C:4]([N:26]2[CH2:30][C@H:29]([CH2:31][NH:32][C:33](=[O:35])[CH3:34])[O:28][C:27]2=[O:36])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(C(=O)COCc4ccccc4)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 98.2 %

Procedure:
Next, (S)-N-[[3-[3,5-difluoro-4-[4-(benzyloxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (3.84 g, 7.6 mmol) was dissolved in hot 10% EtOac/MeOH (150 mL). After degassing the solution three times with N2, the Pearlman's catalyst (384 mg, 10% by weight) was added. The solution was degassed again and then the atmosphere was replaced with H2. The reaction was stirred at room temperature for 4.5 hours. At this point, the reaction was found to be complete by TLC (10% MeOH/CHCl3, UV short wave). The solution was filtered through celite, washing the cake with EtOAc (250 mL). The filtrate was concentrated under reduced pressure to give a white solid. The material was chromatographed on silica gel (150 g), eluting with a gradient of 1-6, 10% MeOH in 10% CH3CN/CHCl3 to yield 3.078 g (98%) of (S)-N-[[3-[3,5-difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide as a white solid with a melting point of 160.5°-162.5° C.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:21]/[N:22]=[C:23](/[C:54]2[N:55]=[C:56]([NH:59][C:60]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[S:57][CH:58]=2)\[C:24]([NH:26][CH:27]2[C:52](=[O:53])[N:29]3[C:30]([C:36]([O:38][CH:39]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])=[C:31]([CH2:34][Cl:35])[CH2:32][S:33][C@H:28]23)=[O:25])[CH2:20][CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:87])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([O:14][C:15]([C:17]1([O:21]/[N:22]=[C:23](/[C:54]2[N:55]=[C:56]([NH:59][C:60]([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)([C:67]3[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=3)[C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[S:57][CH:58]=2)\[C:24]([NH:26][CH:27]2[C:52](=[O:53])[N:29]3[C:30]([C:36]([O:38][CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[O:37])=[C:31]([CH2:34][Cl:35])[CH2:32][S:33](=[O:87])[C@H:28]23)=[O:25])[CH2:18][CH2:19][CH2:20]1)=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS(=O)[C@@H]2C(NC(=O)/C(=N\OC3(C(=O)OC(c4ccccc4)c4ccccc4)CCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Reaction time: 0.33 h

Procedure:
The residue obtained in (A) was dissolved in 50 ml of methylene chloride, and 620 mg (2.87 mmol) of m-chloroperbenzoic acid (purity: 80%) was added. The mixture was stirred for 20 minutes. To the reaction solution, 30 ml of methylene chloride and a 5% sodium bi-carbonate aqueous solution were added. Then, the organic layer was distributed and washed with water and with a saturated sodium chloride aqueous solution. Then, it was dried over anhydrous sodium sulfate, and concentrated to obtain a residue of the above-identified compound. The residue of the compound thus obtained was employed for the next reaction without purification.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])(=O)=O>>[CH3:22][C:21](=[CH:20][CH2:19][CH2:18][CH:17]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)[CH3:24])[CH3:23]
Reactant: CC(C)=CCCC(C)OS(C)(=O)=O
Reactant: O=Cc1cccc2[nH]ccc12
Product: CC(C)=CCCC(C)n1ccc2c(C=O)cccc21

Procedure:
The same procedures used in Example 1 were repeated except for using 1.02 g of indole-4-carbaldehyde and (2-methyl-2-hepten-6-yl) methanesulfonate instead of the benzyl bromide used in Example 1 to give 1.36 g of 1-(2-methyl-2-hepten-6-yl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 76%.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>>[F:10][C:8]1[CH:9]=[C:2]([C:22]2[N:18]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:19]=[CH:20][CH:21]=2)[CH:3]=[C:4]([F:11])[C:5]=1[C:6]#[N:7]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1c(F)cc(Br)cc1F
Product: N#Cc1c(F)cc(-c2ccnn2C2CCCCO2)cc1F
Yield: 108.8 %

Procedure:
The title compound was prepared from 4-bromo-2,6-difluorobenzonitrile (2.5 g, 11.47 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.51 g, 12.61 mmol) using the method of Example 34(a) producing 3.61 g of title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.52-1.67 (m, 3H), 1.81-1.87 (m, 1H), 1.95-1.99 (m, 1H), 2.33-2.41 (m, 1H), 3.59-3.65 (m, 1H), 3.94-3.98 (m, 1H), 5.36-5.39 (m, 1H), 6.77 (d, 1H), 7.62 (s, 1H), 7.64 (s, 1H), 7.66 (d, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][Br:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1ccccc1OCc1ccccc1
Solvent: ClCCl
Solvent: CSC
Product: BrCc1ccccc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of N-Bromosuccinimide (1.84 g, 10.36 mmol) in 50 mL of CH2Cl2 was cooled in a wet ice/acetone bath. Dimethyl sulfide (0.91 mL, 12.44 mmol) was added and the reaction stirred for 10 minutes. The product from Step L (1.48 g, 6.91 mmol) in 25 mL of CH2Cl2 was added and the reaction was stirred at 0° C. for 4.5 hours. The reaction was poured into water/ice and separated layers. The organic portion was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the benzyl bromide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CO.O1CCCC1.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(N)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
Ethyl 2-(3-methyl-4-nitrophenyl)propanoate (1.2 g, 5.05 mmol) was dissolved in methanol and tetrahydrofuran (1:1, 15 mL). 10% Pd/C (180 mg, 10%) was added to it. The resulting mixture was stirred at room temperature for 3 h under H2. TLC showed complete consumption of starting material. The mixture was filtered through celite bed and the filterate was concentrated under reduced pressure. The crude was purified by column chromatography to give ethyl 2-(4-amino-3-methylphenyl)propanoate (944 mg, 90%).
Reaction SMILES: Cl.C([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20]CC1C=CC=CC=1)[CH2:16][CH2:15][C:14]([C:28]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=3)[CH2:32][CH2:31]1)=[O:29])=[CH:13]2)C1C=CC=CC=1.[BrH:49].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:49].[OH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[OH:20])[CH2:16][CH2:15][C:14]([C:28]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([O:47][CH3:48])[C:40]([O:45][CH3:46])=[C:41]([O:43][CH3:44])[CH:42]=3)[CH2:32][CH2:31]1)=[O:29])=[CH:13]2
Reactant: COc1cc(CN2CCN(C(=O)C3=Cc4cc(OCc5ccccc5)c(OCc5ccccc5)cc4CC3)CC2)cc(OC)c1OC
Agent: Br
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc(CN2CCN(C(=O)C3=Cc4cc(O)c(O)cc4CC3)CC2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
1-(6,7-dibenzyloxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrochloride (0.4 g) is dissolved in acetic acid (8 ml). To the solution is added a 30% solution of hydrogen bromide-acetic acid (4 ml), and the mixture is left standing at room temperature for one hour. To the reaction mixture is added ethyl ether (200 ml), and the mixture is left standing, and then the supernatant is removed by decantation. The precipitates are washed twice with 50 ml each portion of ethyl ether, followed by addition of ethanol (10 ml), whereupon crystallization occurs. The crystals are diluted in ethyl ether (30 ml). The precipitates are collected by filtration to give 1-(6,7-dihydroxy-1,2-dihydro-3-naphthoyl)-4-(3,4,5-trimethoxybenzyl)piperazine hydrobromide (0.25 g) as colorless crystals, m.p. 258°-262° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1>[Pd].CO>[NH:10]1[CH2:11][CH2:12][CH:7]([C@H:5]2[CH2:6][C@H:4]2[CH2:3][CH2:2][OH:1])[CH2:8][CH2:9]1
Reactant: O=C(OCc1ccccc1)N1CCC([C@H]2C[C@H]2CCO)CC1
Agent: [Pd]
Solvent: CO
Product: OCC[C@@H]1C[C@@H]1C1CCNCC1
Yield: 92.6 %

Procedure:
Benzyl 4-((1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (7.50 g, 24.7 mmol) and palladium on activated carbon (10%, wet, 1.00 g) in methanol (130 mL) were stirred under an atmosphere of hydrogen (1 atm) at RT for 48 h. The mixture was filtered through Celite® and the filter cake washed with methanol. The filtrate was concentrated to dryness under reduced pressure to afford the title compound (3.87 g, 93%) as a white solid. 1H NMR (500 MHz, CDCl3) δ 3.74 (m, 2H), 3.15-3.05 (m, 2H), 2.56 (m, 2H), 1.91-1.87 (m, 2H), 1.76-1.72 (m, 3H), 1.36-1.28 (m, 3H), 0.92-0.87 (m, 1H), 0.84-0.76 (m, 1H), 0.67-0.61 (m, 1H), 0.60-0.56 (m, 1H), −0.18 (q, J=4.5 Hz, 1H).
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:20][C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:5][N:1]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:2]1
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To 1-benzyl 3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 13.1 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (16.4 mL, 16.4 mmol) in THF at −78° C., and the reaction was stirred at this temperature for 20 minutes. MeI (1.10 mL, 17.7 mmol) was added, and the reaction was warmed to room temperature. After 2 hours at room temperature, the mixture was poured onto saturated ammonium chloride (20 mL) and extracted with ether, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate 4:1) to give 1-benzyl 3-methyl 3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 75% yield) as an oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:13]([OH:15])=[O:14])[C:3]=1[OH:16].C(O)(=O)C.[Sn].Cl>O>[Br:12][C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[C:3]([OH:16])[C:4]([C:13]([OH:15])=[O:14])=[CH:5]2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2c(Br)c1O
Agent: Cl
Agent: [Sn]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc2cc(Br)ccc2cc1O
Temperature: 125 °C
Yield: 96.5 %

Procedure:
In a 1 L three-necked bottle, 40 g of 4,7-dibromo-3-hydroxy-2-naphthoic acid (0.116 mol) and 500 ml of glacial acetic acid were added, and stirred to make homogenous. 18 g of tin powder (0.153 mol) and 130 ml of concentrated hydrochloric acid were then added to the mixture in order, heated to 125° C., and refluxed under heating for 12 h. 300 ml of water was added to the mixture, stirred to room temperature, filtered, and the filter cake was washed with water (200 ml*2), and dried in an oven to obtain 29.9 g of a solid with a yield of 96.5%.
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH3:10])[CH:9]=1)[CH3:2].C([Li])CCC.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>O1CCCC1.CCCCCC>[CH2:1]([S:3][CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH3:10])[C:9]=1[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)[CH3:2]
Reactant: CCSCc1cnn(C)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCSCc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of 4-[(ethylthio)methyl]-1-methyl-1H-pyrazole (0.81 g, 5.2 mmol) in tetrahydrofuran (3.0 mL) at 0° C. was added 1.6 M n-butyllithium in hexane (6.3 mL, 10. mmol). The solution was stirred at room temperature for 1 h and then cooled down to −78° C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.06 mL, 10.1 mmol). The reaction was continued at −78° C. for 0.5 h, then warmed up to 0° C. (taking about 0.5 h). The reaction mixture was quenched with brine, adjusted to PH=6-7 with 1 N HCl aqueous solution, extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give one oil residue which was purified by combi-flash chromatography eluted with EtOAc/hexane (20-100%). The purification gave 1.2 g (86% yield) of the desired product as yellowish oil. LC-MS found: 283.1 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:11]([O:13][CH3:14])=[O:12].Br[CH2:25][CH2:26][CH2:27][CH2:28]Br>C(O)(C)(C)C>[C:20]([O:19][C:17]([NH:16][CH2:15][C@H:10]([N:9]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:11]([O:13][CH3:14])=[O:12])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: BrCCCCBr
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCCC1
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 53.2 %

Procedure:
10 ml (65 mmol) of triethylamine are added to a solution of 5 g (20 mmol) of commercial methyl(S)-2-amino-3-tert-butoxycarbonylaminopropanoate hydrochloride in 150 ml of tert-butanol. The reaction medium is stirred for 20 min at 40° C. and then filtered in order to remove the triethylammonium salts. 3.8 ml (32 mmol) of 1,4-dibromobutane are added to the filtrate thus obtained, and the reaction medium is heated at 80° C. for 3 days. After the insoluble material has been filtered off, the filtrate is concentrated under vacuum. The residue obtained is purified by chromatography on a silica column, elution being carried out with a 98/2 dichloromethane/methanol mixture. 2.9 g (55%) of methyl(S)-3-tert-butoxycarbonylamino-2-pyrrolidin-1-ylpropanoate are obtained in the form of a yellow oil.