Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:6][CH:5]=1.N1C=CC=CC=1.[H-].[Na+].Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>CN(C=O)C.C(#N)C>[C:48]([O:47][C:45]([CH2:44][N:10]([C:11](=[O:33])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:34])=[CH:5][CH:6]=1)=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: COC(=O)c1ccc(NC(=O)CCCCCCCCCCCCCCC(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)N(CC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-(15-tert-Butoxycarbonylpentadecanoylamino)benzoic acid methyl ester (235 mg, 0.495 mmol) was evaporated twice from dry pyridine and once from dry acetonitrile, dissolved in dry DMF (4 mL) under nitrogen. 60% NaH (14 mg, 0.594 mmol) was added and the mixture was stirred for 20 minutes at room temperature under nitrogen. tert-Butyl bromoacetate (0.11 mL, 0.742 mmol) was added and the mixture was stirred for 1 hour, the reaction was quenched with ice and separated between water (50 mL) and diethylether (75 mL). The organic phase was dried (Na2SO4) and solvent remove in vacuo. The crude material was dissolved in ethanol (4 mL). NaOH (5 N, 0.15 mL) was added and the mixture was stirred for 1 hour. pH was adjusted to pH=5 with acetic acid and the mixture was separated between water and ethyl acetate. The organic phase was dried (Na2SO4) and solvent removed in vacuo to give the crude product which was purified on RP-HPLC, C-18 with acetonitrile/water gradient (75-95%) containing 0.1% TFA. To give pure 4-[tert-Butoxycarbonylmethyl-(15-tert-butoxycarbonylpentadecanoyl)amino]benzoic acid) (53 mg, 19%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>ClCCl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][Br:38])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a cooled (0° C.) solution of 3.00 g 4-benzyloxy phenethyl alcohol (13.1 mmol) in dichloromethane (132 mL) were added subsequently 5.17 g of triphenylphosphine (19.7 mmol) and 6.54 g carbon tetrabromide (19.7 mmol). The resulting mixture was stirred for 2 h at room temperature and was then evaporated. The residue was triturated with diethyl ether at −20° C. for 30 minutes, and then all solids were removed by filtration. and the filtrate was concentrated in vacuo. The residue was subjected to column chromatography on silica gel (1%→10% ethyl acetate in hexane) to give 2.80 g of the target compound (73% yield) as a pale yellow oil crystallizing upon standing.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH2:10][CH2:9]1.[CH3:23][S-:24].[Na+]>CC(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([S:24][CH3:23])[C:11]=2[CH2:10][CH2:9]1
Reactant: Cc1ccccc1N1CCc2c(Cl)nc3c(C)cccc3c21
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(C)O
Product: CSc1nc2c(C)cccc2c2c1CCN2c1ccccc1C
Yield: 49.9 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-methyl-2,3-dihydro pyrrolo-[3,2-c]quinoline (1.54 g, 5 mmol) and sodium methanethiolate (1.40 g, 20 mmol) in 2-propanol (25 ml) were heated at 170° in a pressure vessel for 18 hours. The solvent was evaporated, the residue taken up in dichloromethaneand washed with sodium bicarbonate solution. Chromatography (silica gel, dichloromethane) and crystallisation from methanol gave 1-(2-methylphenyl)-4-methylthio-6-methyl-2,3-dihydropyrrolo-[3,2-c]quinoline (0.8 g), m.p. 111°-113°.
Reaction SMILES: C[O:2][C:3]([CH:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1)[C:6](OC)=[O:7])=O.[Li+].[BH4-].CO>C1COCC1>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:5]([CH2:3][OH:2])[CH2:6][OH:7])=[CH:22][CH:21]=1
Reactant: COC(=O)C(CCCCCCOc1ccc([N+](=O)[O-])cc1)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(OCCCCCCC(CO)CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Compound 17 (1.19 g, 3.4 mmol) was dissolved in dry THF (50 mL). LiBH4 (0.44 g, 20.2 mmol) was added and the mixture was refluxed overnight. The mixture was allowed to cool to r.t. and MeOH (10 mL) was added. The reaction mixture was stirred for 30 min at r.t. The mixture was evaporated to dryness. Saturated aqueous NaHCO3 was added and the mixture was refluxed for one hour. The mixture was allowed to cool to r.t. and then filtered. The precipitate was washed with water and purified on silica gel (10% MeOH/CH2Cl2), yielding 0.60 g (67%) of the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[I-].[K+].[CH2:9](Br)[CH3:10].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[N:32]([CH3:40])[N:33]=[C:34]4[C:39]=3[CH:38]=[CH:37][CH:36]=[CH:35]4)=[O:30])[CH2:25][CH2:24]2)=[CH:15][CH:14]=1.[ClH:41]>C(O)C>[ClH:41].[CH2:9]([N:21]([CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([C:31]2[N:32]([CH3:40])[N:33]=[C:34]3[C:39]=2[CH:38]=[CH:37][CH:36]=[CH:35]3)=[O:30])[CH2:25][CH2:24]1)[CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[CH3:10]
Reactant: CCBr
Reactant: Cn1nc2ccccc2c1C(=O)N1CCC(CNCCc2ccc(F)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Product: CCN(CCc1ccc(F)cc1)CC1CCN(C(=O)c2c3ccccc3nn2C)CC1

Procedure:
K2CO3 (0.71 g; 0.0052 mol), potassium iodide (10 mg; 0.062 mmol) and ethyl bromide (0.54 ml; 0.0072 mol) were added to a solution of 2-(4-fluorophenyl)-N-({1-[(2-methyl-2H-indazol-3-yl)carbonyl]piperidin-4-yl}methyl)ethanamine (10a) (1.7 g; 0.0043 mol) in absolute ethanol (20 ml). The mixture was heated under reflux for 48 h and then the solvent was evaporated at reduced pressure. The residue was taken up in chloroform and was washed with water twice. The organic phase was dried over Na2SO4, filtered and concentrated at reduced pressure. The resultant raw compound (1.5 g) was purified by flash chromatography (ethyl acetate/n-hexane/ammonia=96/4/0.2). The compound obtained (0.5 g) was converted to its hydrochloride by dissolving in absolute ethanol and treatment with an excess of 5N hydrochloric ethanol for 3 h. After evaporation of the solvent at reduced pressure, the solid residue was crystallized from ethanol/ethyl acetate, obtaining 0.15 g of N-ethyl-2-(4-fluorophenyl)-N-({1-[(2-methyl-2H-indazol-3-yl)carbonyl]piperidin-4-yl}methyl)ethanamine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][C:12]#[N:13].[OH-].[Na+].C1COCC1>CN(C=O)C.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: N#CCCCl
Reactant: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCOc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1.43 g (0.013 mol) 1,4-dihydroxybenzene, 1.15 g (0.013 mol) 3-chloropropionitrile and 15 ml (2N, NaOH) in 15 ml DMF anmd 50 ml THF is stirred overnight at 60° C. bath temperature. The reaction mixture is poured into water and extracted with ether. The ether extract is washed with water, dried and concentrated to dryness under reduced pressure. The residue is passed through a silica gel column using hexane/ethylacetate (3:1) as eluent. Evaporation of eluent gives the desired product which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2[Cl:14])=[CH:4][CH:3]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:12][C:13]=2[Cl:14])=[CH:6][C:7]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)cc2)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)c([N+](=O)[O-])c2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
0.2 g (0.62 mmol) of 3-(4-chlorophenyl)-4-chloro-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 2 ml of concentrated sulfuric acid, and 0.04 g (0.64 mmol) of fuming nitric acid was added thereto under cooling with ice, followed by stirring for 1 hour. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium hydrogencarbonate aqueous solution and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained crude crystals were washed with isopropyl ether to obtain 0.21 g (yield: 91%) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:19](=O)[C:20]([N:22]([CH3:24])[CH3:23])=O)=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH2:19][CH2:20][N:22]([CH3:23])[CH3:24])=[CH:12][NH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)C(=O)c1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CN(C)CCc1c[nH]c2ccc(F)c(OCc3ccccc3)c12
Yield: 80 %

Procedure:
A solution of 1-6a (2.26 g, 6.647 mmol) in dry 1,4-dioxane (30 mL) was added dropwise to a slurry of LiAlH4 (2.52 g, 66.47 mmol) in dry 1,4-dioxane (40 mL) at reflux. The mixture was held at reflux for 1 h. The mixture was then cooled, quenched with ice-water (mixed with NaOH), filtered through Celite, and the filter cake was washed with EtOAc. The filtrate and EtOAc washings were combined and extracted three times with EtOAc. The organic layer was washed with 1 N NaOH and brine, dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography on silica gel with CH2Cl2 (100%) to 5% NH4OH in CH2Cl2 as eluent to give the product (1-7a) as a brown oil in 80% yield, 1.67 g. 1H NMR (300 MHz, CDCl3-d) δ (ppm) 2.14 (s, 6H). 2.52-2.57 (m, 2H), 2.91-2.97 (m, 2H), 5.25 (s, 2H), 6.92-6.98 (m, 3H), 7.31-7.40 (m, 3H), 7.49-7.52 (m, 2H), 7.97 (br, 1H). APCI [M+1]: 313.1.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(COC)OC.CCOCC>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Reactant: COC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: COC(=O)COc1ccc(CCNCc2ccccc2)cc1
Reaction time: 8 h
Yield: 125.4 %

Procedure:
The starting material was obtained as follows: N-Benzyltyramine (9.08 g) was added to a stirred solution of potassium t-butoxide (4.5 g) in dimethoxyethane (80 ml). To the clear solution was added methyl bromoacetate (6.2 g) and the mixture was stirred overnight. The mixture was diluted with ether (250 ml) and washed with water (2×25 ml). The ethereal solution was dried (MgSO4) and evaporated, to give methyl 4-[2-(benzylamino)ethyl]phenoxyacetate (15.0 g) as an oil, which was dissolved in isopropanol and teated with phenylglycidyl ether (7.5 g). The solution was heated to reflux for 1 hour, and then evaporated. The residue was dissolved in toluene and volatile material evaporated before being purified by chromatography on K60 silica (220 g) using 1% methanol in dichloromethane. Methyl 4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenoxyacetate was obtained as an oil (9.5 g), NMR: 2.55-2.85[m,6H, CH2NHCH2CH2 ]; 3.65-4.05[m,8H, PhOCH2CHOH and PhCH2 and OCH3 ]; 4.67]s, 2H, OCH2CO]; 6.73-7.40[m, 14H, aromatic H].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][C:22]1([CH3:31])[CH2:27][CH2:26][C:25](B(O)O)=[CH:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[C:14]([Si:11]([CH3:13])([CH3:12])[O:10][CH2:9][C:8]([C:6]1[CH:5]=[CH:4][C:3]([NH2:20])=[C:2]([C:25]2[CH2:26][CH2:27][C:22]([CH3:31])([CH3:21])[CH2:23][CH:24]=2)[CH:7]=1)([CH3:19])[CH3:18])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)c1ccc(N)c(Br)c1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1(C)CC=C(c2cc(C(C)(C)CO[Si](C)(C)C(C)(C)C)ccc2N)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a mixture of 2-bromo-4-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-phenylamine (as prepared in the previous step, 1.50 g, 4.19 mmol), 4,4-dimethylcyclohexen-1-ylboronic acid (1.09 g, 4.61 mmol) and Pd(PPh3)4 (484 mg, 0.419 mmol) in 50 mL of 1,4-dioxane was added aqueous Na2CO3 (16.8 mL, 33.5 mmol, 2.0 M). The resulting mixture was stirred at 90° C. for 16 h under Ar. After cooling to RT, the mixture was treated with 150 mL of EtOAc and washed with H2O (3×30 mL) and brine (30 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5-10% EtOAc/hexane) to afford 1.46 g (90%) of the title compound as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C24H41NOSi, 388.3 (M+H). found 388.3.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15]>N1C=CC=CC=1>[C:1]([C:5]1[CH:9]=[C:8]([S:10][CH3:11])[N:7]([C:14](=[O:15])[N:13]([CH3:17])[CH3:12])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1cc(C(C)(C)C)n[nH]1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CSc1cc(C(C)(C)C)nn1C(=O)N(C)C
Temperature: 115 °C
Yield: 58.8 %

Procedure:
A mixture of 3-t-butyl-5-methylthiopyrazole (6.0 g) and dimethylcarbamoyl chloride (4.3 g) in pyridine (40 ml) were refluxed (at 115° C.) for 16 hours. The pyridine was evaporated, and the residue poured into water and extracted with chloroform. The chloroform layer was washed with 2 N HCl (2×50 ml), then water (50 ml), dried and evaporated to give an oil which soon crystallised. Recrystallisation from 60°-80° petrol at 0° C. gave 5.0 g of 3-t-butyl-1-(dimethylcarbamoyl)-5-(methylthio)pyrazole (59% yield), melting point 56°-8°. Only a single isomer was shown to be present by nuclear magnetic resonance spectroscopy (NMR) and thin layer chromatography.
Reaction SMILES: Br[C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:14]C(N)=O.P(=O)(O)(O)O.[OH-].[K+]>C(O)=O>[NH2:14][C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: NC(N)=O
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: CC12CC3CC(C)(C1)CC(N)(C3)C2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To 100 g of 1-bromo-3,5-dimethyl adamantane and 86 g of urea, adding 80 ml of 80 wt % formic acid, heating to 80° C. and holding for 3 hours. Cooling to the room temperature and adding 75 ml of 85% phosphoric acid to hydrolyze at 80° C. for 1 hour. Adjusting with 10% potassium hydroxide aqueous solution to a pH of 12. Extracting with toluene twice, combining the organic layers and washing with water. Concentrating under reduced pressure to yield a limpid yellow solution as 1-amino-3,5-dimethyl adamantane crude. To the crude, adding 150 ml of ethanol and concentrated hydrochloric acid, heating to dissolve and crystallizing to yield a white solid. Drying the solid and re-crystallizing with ethanol to yield 61.0 g of pure Memantine Hydrochloride. The yield is 68.8% (GC 99.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]([OH:19])[C:16](O)=[O:17])=[O:12].[CH3:31][O:32][NH2:33]>>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH:15]([OH:19])[C:16]([NH:33][O:32][CH3:31])=[O:17])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12]
Reactant: CON
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1Cl
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1Cl

Procedure:
The reaction can be carried out in analogy to reaction step 20.3 by reacting 3-((R)-1-(2-chlorobenzyl)-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-methylhydroxylamine.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[N:10]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]#[N:52])[C:11]2[C:16]([C:17]=1[CH2:18][N:19]1[C:25](=[O:26])[C@@H:24]([NH:27][C:28](=[O:40])[C@@H:29]([N:31](C)[C:32](=O)OC(C)(C)C)[CH3:30])[CH2:23][O:22][C:21]3[CH:41]=[CH:42][CH:43]=[CH:44][C:20]1=3)=[CH:15][CH:14]=[CH:13][CH:12]=2>C(Cl)Cl>[Cl:8][C:9]1[N:10]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]#[N:52])[C:11]2[C:16]([C:17]=1[CH2:18][N:19]1[C:25](=[O:26])[C@@H:24]([NH:27][C:28](=[O:40])[C@@H:29]([NH:31][CH3:32])[CH3:30])[CH2:23][O:22][C:21]3[CH:41]=[CH:42][CH:43]=[CH:44][C:20]1=3)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2N(Cc2c(Cl)n(-c3ccccc3C#N)c3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H]1COc2ccccc2N(Cc2c(Cl)n(-c3ccccc3C#N)c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.7 %

Procedure:
TFA (5 mL) was added to a solution of tert-butyl (S)-1-((S)-5-((2-chloro-1-(2-cyanophenyl)-1H-indol-3-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (130 mg, 207 μmol, Eq: 1.00) in DCM (5 mL). The mixture was stirred at RT for 16 h, then concentrated. Sat. NaHCO3 was added to the residue and the mixture was extracted with DCM. The combined organic extracts were concentrated and the residue purified by preparative TLC to give the title compound (50 mg, 43%) as a white solid. MS m/z 529 (MH+)
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](Cl)=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].Cl.C(OCC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[ClH:23].[N:1]1([CH2:6][C:7]2([C:32](=[O:33])[CH2:31][C:26]3[CH:27]=[CH:28][C:29]([Cl:30])=[C:24]([Cl:23])[CH:25]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][NH:8]2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Reactant: C1=CCN(CC2NCCc3ccccc32)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)C1(CN2CC=CC2)NCCc2ccccc21
Yield: 85.1 %

Procedure:
Prepared as Example No. 1 from 1.44 g (6.73 mmoles) of 1-(3-pyrrolin-1-yl)methyl-1,2,3,4-tetrahydroisoquinoline, 1.8 g (13.05 mmoles) of anhydrous potassium carbonate and 1.8 g (8.05 mmoles) of 3,4-dichlorophenylacetyl chloride in 50 ml of dry chloroform. The work-up of the reaction mixture afforded 1.9 g of the crude product which was dissolved in 60 ml of ethyl acetate and the solution brought to acidic pH with HCl/diethyl ether. The precipitate was filtered, washed and dried, to yield 1.5 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=O)[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[C:15]([S@:19]([NH2:21])=[O:20])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:1]([C:3]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[N:21]/[S:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:20])[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: CCC1(CCCCCC=O)OCCO1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCC1(CCCCC/C=N/S(=O)C(C)(C)C)OCCO1

Procedure:
A solution of 6-(2-ethyl-1,3-dioxolan-2-yl)hexanal (M3) (1.1 eq.), (R)-(+)-tert-butanesulfinamide (1.0 eq.) and anhydrous copper sulfate (2.2 eq.) in DCM was stirred for 70 h at RT. The reaction mixture was filtered through Celite. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography with hexane/ethyl acetate mixture as eluent to yield the desired product as an oil. 1H NMR (300 MHz, CDCl3) δ: 8.05 (1H, t, J=4.6 Hz), 3.91 (4H, s), 2.60-2.40 (2H, m), 1.70-1.50 (6H, m), 1.47-1.28 (4H, m), 1.18 (9H, s), 0.88 (3H, t, J=7.5 Hz). 13C NMR (75 MHz, CDCl3) δ: 169.6, 111.9, 65.0, 56.5, 36.5, 36.0, 29.8, 29.5, 25.5, 23.5, 22.3, 8.1. MS (ES) C15H29NO3S requires: 303, found: 304 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24]C(=O)C)[CH2:21][O:20]C(C)(C)[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O>[NH2:24][C:16]([CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:36][C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[CH:3][C:4]=2[F:28])=[CH:9][CH:10]=1)([CH2:21][OH:20])[CH2:17][OH:18]
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Reactant: Fc1ccc(S)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NC(CO)(CO)CCc1ccc(-c2ccc(Sc3ccc(F)cc3)cc2F)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 11.6 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (225 mg) of Reference Example 10, 4-fluorobenzenethiol (64 mg), diisopropylethylamine (129 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (12.9 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (14.9 mg) in 1,4-dioxane (2 mL) was heated under reflux for 6 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethanol (4 mL). Concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated, aqueous potassium carbonate solution was added to the residue, and the precipitated crystals were collected by filtration. The crude crystals were purified by preparative HPLC to give the title compound (24 mg) as white crystals.