Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH2:11]([CH:16]([CH2:19]O)[CH2:17][OH:18])[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:11]([C@@H:16]1[CH2:17][O:18][C@@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([C:1]#[N:2])[CH2:4][CH2:5]2)[O:10][CH2:19]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N#C[C@H]1CC[C@H](C=O)CC1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCCCC[C@H]1CO[C@H]([C@H]2CC[C@H](C#N)CC2)OC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2.00 g of trans-4-cyanocyclohexanecarboxaldehyde, 2.13 g of 2-pentyl-1,3-propanediol and 65 mg of p-toluenesulphonic acid in 100 ml of benzene was heated to reflux for 3 hours while gassing with argon and with separation of water in a round flask provided with a water separator and a reflux condenser. The mixture was subsequently treated with 3.0 g of potassium carbonate, stirred at room temperature for 16 hours, then filtered and the filtrate was concentrated. Recrystallization of the crystalline residue (4.1 g) from hexane at 0° C. gave 1.47 g (38%) of trans-4-(trans-5-pentyl-m-dioxan-2-yl)cyclohexanecarbonitrile as colourless crystals in a purity of 99.1%. After a further recrystallization from hexane at 0° C., the purity increased to 99.9%; m.p. (C-N) 45.6° C., cl.p. (N-I) 46.7° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[K].[O-]CCCC.[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]2[N:47]=[C:46]([C:48]3[S:52][C:51]([CH:53]=O)=[N:50][CH:49]=3)[CH:45]=[CH:44][CH:43]=2)[CH:36]=1>C1COCC1.O>[CH3:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]2[CH:43]=[CH:44][CH:45]=[C:46]([C:48]3[S:52][C:51](/[CH:53]=[CH:2]/[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[N:50][CH:49]=3)[N:47]=2)[CH:36]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(C=O)s3)n2)c1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[O-]
Agent: [Br-]
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc(Nc2cccc(-c3cnc(/C=C/c4ccccc4)s3)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of benzyltriphenylphosphonium bromide (176 mg, 0.406 mmol) in dry THF cooled at 0° C. under inert atmosphere was added potassium tot-butoxide (1.0M in THF) (675 μL, 675 μmol). The mixture was stirred at 0° C. for 30 mins, then 5-[6-(4-methyl-pyridin-2-ylamino)-pyridin-2-yl]-thiazole-2-carbaldehyde was added in one portion. After stirring at room temperature for 3 hours, the reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 using combiflash Companion®, eluting with cyclohexane/ethyl acetate. The E-isomer was then further purified by preparative chromatography on silica plate, eluting with 5% methanol in dichloromethane to afford the title compound as a yellow solid. 1H NMR (Acetone-d6, 300 MHz): δ=8.41 (s, 1H), 8.16 (d, J=5.1 Hz, 1H), 8.00 (s, 1H), 7.80-7.70 (m, 3H), 7.65-7.55 (m, 2H), 7.53-7.36 (m, 4H), 7.50 (s, 1H), 6.84 (d, J=5.1 Hz, 1H), 2.47 (s, 3H). (APCI+) m/z 371 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:38](O)=[O:39]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:38]([C:29]4[CH:30]=[CH:31][C:32]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:28]=4[O:27][CH3:26])=[O:39])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1c(C(=O)O)ccc2ccccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5ccccc5c4OC)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1-methoxynaphthalene-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from diethyl ether to yield the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[Cl-].[NH4+]>O1CCCC1.C([Mg]Cl)CC1C=CC=CC=1>[CH3:18][N:2]([CH3:1])[C:3]1([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7][C:6]([CH2:11][CH2:10][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([OH:9])[CH2:5][CH2:4]1
Reactant: CN(C)C1(CCc2ccccc2)CCC(=O)CC1
Agent: Cl[Mg]CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C1(CCc2ccccc2)CCC(O)(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.58 g 4-dimethylamino-4-phenethylcyclohexanone were dissolved in 45 ml analytical grade tetrahydrofuran, 43 ml 1.0 molar phenethylmagnesium chloride solution in THF were added under a nitrogen atmosphere, while cooling in an ice-bath, and the mixture was stirred overnight at room temperature. For working up, 43 ml ammonium chloride solution (20 per cent by weight) were added, while cooling with ice, and the mixture was extracted three times with 80 ml diethyl ether each time, the combined organic phases were extracted three times with 70 ml dilute hydrochloric acid (5 per cent by weight) each time, the combined aqueous extracts were washed with 50 ml diethyl ether, adjusted to pH 9 with ammonia solution (25 per cent by weight) and extracted three times with 80 ml methylene chloride each time, the combined methylene chloride extracts were dried over sodium sulfate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. The crude product obtained (9.57 g) was chromatographed over silica gel with diethyl ether/hexane (v/v=1:1). 938 mg of the nonpolar diastereoisomer of 4-dimethylamino-1,4-diphenethylcyclohexanol obtained were dissolved in 7.5 ml 2-butanone, 26 μl water followed by 371 μl trimethylchlorosilane were added at room temperature and the mixture was stirred overnight at room temperature. The white solid which had precipitated out was filtered with suction, washed with diethyl ether and dried in an oil pump vacuum. 1.00 g of the hydrochloride of the nonpolar diastereoisomer of 4-dimethylamino-1,4-diphenethylcyclohexanol were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]#[C:13][Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH3:1])[C:6]([O:8][CH3:9])=[O:7])#[CH:13]
Reactant: COC(=O)c1ccc(C)c(C#C[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cc(C(=O)OC)ccc1C
Reaction time: 0.25 h

Procedure:
To the solution of methyl 4-methyl-3-[(trimethylsilyl)ethynyl]benzoate (2.3 g) in THF (40 ml) was added tetrabutylammonium fluoride (1.0M in THF, 3.2 ml, 11 mmol) at ambient temperature and stirred for 15 minutes, concentrated and the residue purified by flash chromatography on silica gel (elution with 2% ethyl acetate in n-hexane) to provide methyl 3-ethynyl-4-methylbenzoate.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][N:7]=1>C(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:3])=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Product: ClCc1ccc(Cl)nc1

Procedure:
Thionyl chloride (14.6 ml, 0.2 mol) was added extremely carefully in dropwise manner to a rapidly stirred mixture of 2-chloro-5-hydroxymethylpyridine (18.6 g, 0.13 mol) and chloroform (150 ml) at ambient temperature (20° C.). After addition was complete the resulting mixture was heated under reflux for 12 hours. The reaction mixture was then allowed to cool to ambient temperature (20° C.) and chloroform was evaporated off under reduced pressure to give a brown oil. The product, 2-chloro-5-chloromethyl-pyridine was isolated from this brown oil by flash chromatography using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), with dichloromethane as eluent, as a yellow oil which solidified on standing (17.45 g, 82.9%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([N:21]=[N+]=[N-])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]=1[F:20]>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[NH:21][C:11]2[C:6]([CH:5]=1)=[C:7]([F:20])[C:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:10]=2)=[O:24]
Reactant: COC(=O)C(=Cc1cccc(OCc2ccccc2)c1F)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2c(F)c(OCc3ccccc3)ccc2[nH]1
Yield: 84.7 %

Procedure:
A solution of methyl-2-azido-3-(2-fluoro-3-benzyloxyphenyl)propenoate (16.7 g) in xylene (600 ml) was added dropwise with stirring to refluxino xylene (2.4 L) over 1 hour and then stirred for a further 20 minutes. The reaction mixture was concentrated in vacuo and purified by flash column chromatography, using a gradient of 0-100% ethyl acetate/iso-hexane as eluent to give the product as a yellow solid (12.93 g) 1H NMR (DMSO-d6) δ 3.85(s, 3H), 5.15(s, 2H), 7.05-7.45(m, 8H), 12.06(s, 1H); M/z(+) 300.4 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[C:4](/[NH:11]C(OCC1C=CC=CC=1)=O)=[CH:5]/[C@H:6]1[CH2:9][C@H:8]([CH3:10])[CH2:7]1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:22])[CH:4]([NH2:11])[CH2:5][C@H:6]1[CH2:7][C@H:8]([CH3:10])[CH2:9]1
Reactant: COC(=O)/C(=C/[C@H]1C[C@H](C)C1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)C[C@H]1C[C@H](C)C1
Reaction time: 1.5 h
Yield: 87.3 %

Procedure:
In a Parr shaker bottle was placed (Z)-2-benzyloxycarbonylamino-3-(trans-3-methyl-cyclobutyl)-acrylic acid methyl ester (300 mg, 0.99 mmol), methanol (10 mL) and 10% palladium on activated carbon (60 mg). The mixture was placed on the Parr hydrogenator and charged with 40 psi hydrogen pressure and shaken for 1.5 h. After such time, the catalyst was filtered off through a plug of celite and the filterate concentrated in vacuo to afford 2-amino-3-(trans-3-methyl-cyclobutyl)-propionic acid methyl ester (148 mg, 87%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26](O)=[O:27])[CH:20]=[CH:19]2)=[O:15]>C(Cl)Cl.N1C=CC=CC=1>[OH:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:26]([C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:17]=2)[CH:22]=1)=[O:27]
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: COC(=O)c1ccc2cc(C(=O)O)ccc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2cc(C(=O)Nc3cc(C(=O)O)ccc3O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.8 %

Procedure:
A solution of 3-amino-4-hydroxybenzoic acid (0.142 g, 0.927 mmol) and the acyl chloride prepared from acid 74 (in 84% yield) (0.259 g, 1.019 mmol) in DCM (5 ml) and pyridine (6 ml) was stirred at room temperature for under at for 24 h. The solvent was removed under reduced pressure. HCl (aq, 4 M, 6 ml) was added and the precipitate was filtered, washed with water (10 ml) and dried under vacuum. Trituration with methanol (15 ml) and acetone (10 ml) afforded 75 as an off-white solid (0.084 g, 0.230 mml, 25%). 1H NMR (400 MHz, DMSO-d6) δ 3.92 (3H, s), 7.00 (1H, d, J 8.4 Hz), 7.67 (1H, d, J 8.8 Hz), 8.04-8.10 (2H, m), 8.16-8.27 (2H, m), 8.33 (1H, s), 8.70-8.66 (2H, m), 9.80 (1H, s), 10.55 (1H, bs). 13C NMR (100 MHz, DMSO-d6) δ 53.09, 116.18, 122.59, 125.94, 126.45, 126.26, 126.80, 128.45, 128.48, 129.19, 130.35, 130.40, 130.93, 134.13, 134.66, 134.94, 154.61, 165.85, 166.84, 167.73. νmax (solid)/(cm−1) 3059, 1716, 1666, 1592, 1541, 1283, 1247, 1132, 759.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH:6]=[N:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[Cl:19].[BH4-].[Na+]>C(O)C>[Cl:19][C:10]1[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]=1[CH2:8][NH:7][CH2:6][C:5]1[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=[C:3]([C:2]([F:1])([F:27])[F:28])[CH:4]=1
Reactant: FC(F)(F)c1cc(C=NCc2cc(C(F)(F)F)ccc2Cl)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1cc(CNCc2cc(C(F)(F)F)ccc2Cl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound from step A in ethanol was added 4 gm of sodium borohydride and the reaction was allowed to stir overnight at ambient temperature. The reaction was quenched with 50 mL of methanol diluted with 100 mL of water and 100 mL of methyl tert-butyl ether. The layers were separated and the organic layer dried over magnesium sulfate, filtered and concentrated to an oil. 10 gm of desired amine was collected which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) 7.84 (s, 2H), 7.77 (s, 1H), 7.66 (s, 1H), 7.48 (s, 2H), 7.47 (s, 4H), 13C NMR (400 MHz, CDCl3) δ 142.6, 183.3, 130.4, 128.4, 127.1, 127.0, 125.6, 121.4, 52.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9](OC)=[O:10])[CH:7]=1.[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:17][C:9](=[O:10])[CH:8]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1C(=O)Nc2ccc(F)cc21
Yield: 92.9 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer and a gas inlet tube and having an inner volume of 100 ml were charged 3.93 g (14.2 mmol) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate synthesized according to Example 1 with a purity of 98%, 0.5 g (0.12 mmol as a palladium atom) of 5% by weight palladium/carbon (49% hydrated product) and 50 ml of ethyl acetate under argon atmosphere. Then, the inner system was replaced with hydrogen, and the mixture was reacted under a hydrogen pressure of 0.15 MPa at 20° C. for 2 hours. After completion of the reaction, the catalyst was filtered off by filtrating the reaction mixture and then the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: chloroform) to obtain 2.76 g (isolation yield: 92%) of 5-fluoro-3-methoxycarbonyloxindole as white crystals with a purity of 99% (areal percentage by high performance liquid chromatography).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@:9]([C@H:18]1[CH2:22][O:21][CH2:20][C@H:19]1[OH:23])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[CH3:10].[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25]>ClCCl.CN(C)C1C=CN=CC=1>[C:24]([Si:28]([CH3:31])([CH3:30])[O:23][C@@H:19]1[CH2:20][O:21][CH2:22][C@@H:18]1[C@:9]([NH2:8])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[CH3:10])([CH3:27])([CH3:26])[CH3:25]
Reactant: C[C@@](N)(c1ccccc1F)[C@H]1COC[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1COC[C@@H]1[C@](C)(N)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Triethylamine (8.05 g, 79.6 mmol) was added to a solution of rel-(3S,4S)-4-((S)-1-amino-1-(2-fluorophenyl)ethyl)tetrahydrofuran-3-ol (5.6 g, 24.9 mmol) in dichloromethane (100 ml) at 0° C., then 4-dimethylaminopyridine (1.52 g, 12.4 mmol) followed by tert-butyldimethylchlorosilane (7.49 g, 49.7 mmol). The reaction mixture was stirred at room temperature overnight. For the workup, the reaction mixture was extracted with a saturated solution of sodium hydrogencarbonate and brine. The organic layer was dried over sodium sulphate and evaporated. The crude material was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 50:50 as the eluent. The rel-(S)-1-[(3S,4S)-4-(tert-butyl-dimethyl-silanyloxy)-tetrahydro-furan-3-yl]-1-(2-fluoro-phenyl)-ethylamine (8.13 g, 96% yield) was obtained as a colorless oil. MS (ISP): m/z=340.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH2:14])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCOCCN(Cc1ccccc1)Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN(CCOCCN)C(=O)OC(C)(C)C
Yield: 91.3 %

Procedure:
[2-(2-Amino-ethoxy)-ethyl]-methyl-carbamic acid tert-butyl ester (100 mg) was prepared following General Procedure T starting from [2-(2-dibenzylamino-ethoxy)-ethyl]-methyl-carbamic acid tert-butyl ester (200 mg) and Pd—C (40 mg) in methanol (1.5 mL).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([CH3:16])=[N:10]2)=[CH:5][C:4]=1[CH3:17].Br>C(O)(=O)C>[CH3:17][C:4]1[CH:5]=[C:6]([N:9]2[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([CH3:16])=[N:10]2)[CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccc(-n2nc(C)c(C)c2C)cc1C
Agent: Br
Solvent: CC(=O)O
Product: Cc1cc(-n2nc(C)c(C)c2C)ccc1O
Yield: 89 %

Procedure:
A mixture of 1-(4-methoxy-3-methyl-phenyl)-3,4,5-trimethyl-1H-pyrazole (described in Reference Preparation example 33) 7.3 g, 47% hydrobromic acid 50 ml and acetic acid 50 ml was stirred with heating under reflux for thirty hours. The solvent was distilled off and to the resulting residues was added ethyl acetate 400 ml, and the resulting mixture was stirred at room temperature for one hour. The precipitates were filtered and were washed with hexane, and were concentrated under reduced pressure to give 2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenol 6.1 g.
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([O:20]C)=[O:19])[C:15]([OH:22])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[OH-].[Li+].Cl>CO>[O:23]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[C:15]([OH:22])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: COC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-hydroxy-1,6-naphthyridine-7-carboxylate (1.00 g, 2.96 mmol, prepared as described in Example 2 above) in methanol (18 mL) with aqueous lithium hydroxide (17.8 mL, 17.8 mmol, 1N solution) was stirred overnight at 60° C. The suspension was acidified to a pH=4 using 3N HCl (about 6 mL) and the resulting solution was allowed to stir overnight at room temperature. In the morning, the solids that had precipitated out of solution were collected by vacuum filtration to give the desired product as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.ClC(OCC1C=CC=CC=1)=O.[C:22]([N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)(N1C=CN=C1)=O.C(OC(N1CCNCC1)=O)C.Br>C1COCC1.CN(C=O)C.C1COCC1.C(O)(=O)C.N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:29]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Br
Agent: CCOC(=O)N1CCNCC1
Agent: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Nc1ccc(C(=O)N2CCNCC2)cc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
4-aminobenzoic acid (Aldrich 99%) was reacted stoichiometrically with benzyl chloroformate (Aldrich 95%) in THF solvent in the presence of pyridine acid acceptor initially at 2-25° C. for 1 hour then refluxed 75° C. for 2 hours. After evaporation of solvent, washing the solids in water, filtering and drying, the resulting N-CBZ-protected product was obtained in 85% yield. This compound was first reacted with a stoichiometric quantity of 1,1'-carbonyl diimidazole at room temperature for 2 hours in DMF/THF solvent. A stoichiometric amount of ethyl-1-piperazine carboxylate (Lancaster 99%) in THF was then added to this mix, kept at room temperature for 1 hour, then refluxed at 80° C. for 8 hours. The reaction solution was evaporated to a solid residue, washed with water, filtered and finally dried to obtain the solid diprotected product in 90% yield. This solid was deprotected in excess 5N hydrobromic acid in acetic acid at 48° C. for 10 hours. After evaporation of acidic fluids, the solid residue was washed with acetone then ether, filtered and dried as the dihydrobromide salt. Dissolution of this salt in a stirred aqueous suspension of 2× equivalents of strong base anion exchange resin (Amberlite IRA-400-OH) followed by filtration and washing of resin, evaporation of filtrates and azeotropic drying in anhydrous ethanol then in 1,2-dichloroethane, gave dry 4-aminobenzoyl piperazine (4ABP) solid in 50% yield. 3ABP was prepared in the same manner as above but starting with 3-aminobenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28]O)[CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:13]([N:20]1[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][CH2:28][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:25]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To a solution of methyl 3-hydroxyphenylacetate (0.409 g, 2.4 mmol), 3-(N-Boc-piperidin-4-yl)-propan-1-ol (0.50 g, 20.5 mmol) and triphenylphosphine (0.645, 24.6 mmol) in THF, was added diisopropyl azodicarboxylate at 0° C. slowly, then the ice bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in methylene chloride (2 mL) and loaded on a silica gel column. The product was eluted with 20% ethyl acetate in hexane, to afford methyl 3-(3-(N-Boc-piperidin-4-yl)-propoxy)-phenylacetate (0.5 g, 62%). 1H NMR (CDCl3) δ1.1 (m, 2H), 1.4 (m, 2H), 1.46 (s, 9H), 1.66 (d, 2H), 1.78 (m, 2H), 2.67 (t, 2H), 3.58 (s, 2H), 3.68 (s, 3H), 4.05 (m, 2H), 6.75 (m, 3H), 7.18 (dd, 1H).
Reaction SMILES: S(O)(O[CH2:5][CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[CH3:16][O:17][CH2:18][C:19]1([CH2:22][O:23][CH3:24])[CH2:21][O:20]1>O.[OH-].[Na+]>[CH2:8]([N:7]1[CH2:6][CH2:5][O:20][C:19]([CH2:18][O:17][CH3:16])([CH2:22][O:23][CH3:24])[CH2:21]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCC1(COC)CO1
Reactant: O=S(=O)(O)OCCNCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC1(COC)CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 87 h
Yield: 99 %

Procedure:
To a solution of 2-(N-benzylamino)ethyl hydrogen sulfate (28 g) in a mixture of water (36.3 ml) and 40% sodium hydroxide aqueous solution (12.1 ml) was added 2,2-bis(methoxymethyl)oxirane (16.0 g) at room temperature over 30 minutes. After stirring at room temperature for 87 hours, 40% sodium hydroxide aqueous solution (73 ml) was added dropwise to the mixture over 20 minutes. The mixture was stirred at room temperature for 1 hour and at 40° C. for 20 hours, and extracted with ethyl acetate (100 ml×3). The organic layer was extracted with 1N hydrochloric acid (×6). The combined extracts were neutralized with sodium hydroxide, and then added sodium chloride, and extracted with ethyl acetate (100 ml×3). The combined extracts were washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure to give 4-benzyl-2,2-dimethoxymethylmorpholine (31.79 g) as an orange oil.