Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)CCCCCCC/C=C\CCCC.[CH2:16]([OH:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH:27][CH2:28][CH2:29][CH2:30][CH2:31]CCCC.C=CCCCC>C1COCC1>[CH2:16]([OH:36])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCC=CCCCCCCCCCCO
Agent: CCCC/C=C\CCCCCCCCO
Solvent: C1CCOC1
Solvent: C=CCCCC
Product: CCCC/C=C\CCCCCCCCCCO
Yield: 76 %

Procedure:
According to the procedure for compound 3, 11-eicosenol (1.3 g, 4.4 mmol) and 1-hexene (6 mL) in THF (6 mL) were reacted with 1 (0.028 g, 1 mol %) to provide 5 (0.84 g, 76% yield, 86% Z as determined by 1H-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.36 (2H, m), 3.64 (2H, td, J=6.5, 5.3 Hz), 2.02 (4H, m), 1.56 (2H, m), 1.23-1.38 (19H, m), 0.90 (3H, t, J=7.2 Hz); 13C NMR (CDCl3): δ 129.9 (2C), 63.1, 32.8, 32.0, 29.8, 29.6 (2C), 29.5, 29.4, 29.3, 27.2, 26.9, 25.8, 22.4, 14.0; HRMS (FAB): 241.2536, [C16H32O+H]+ requires 241.2531.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]([C:14]2([NH:29]C(=O)OC(C)(C)C)[CH2:19][CH2:18][N:17]([C:20]3[C:21]4[CH:28]=[CH:27][NH:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:9][OH:10])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:29][C:14]1([C:12]([NH:11][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][OH:10])=[O:13])[CH2:15][CH2:16][N:17]([C:20]2[C:21]3[CH:28]=[CH:27][NH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC(CO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(C(=O)NC(CO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
tert-Butyl 4-(1-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 18) (137 mg, 0.27 mmol) was treated with trifluoroacetic acid (2 mL). The solution was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by ion exchange chromatography, using a SCX column. The residue was loaded onto the column in methanol and washed with methanol. The desired product was eluted from the column using 2M ammonia in methanol and pure fractions were evaporated to dryness to afford 4-amino-N-(1-(4-chlorophenyl)-2-hydroxyethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (111 mg, quant.) as a colourless crystalline solid.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CN(C)CCN(C)C.[CH3:17][O:18][C:19](=[O:32])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([Cl:31])[CH:22]=1.I[CH2:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][S:37][CH2:36]1>CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.O1CCCC1>[CH3:17][O:18][C:19](=[O:32])[CH:20]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([Cl:31])[CH:22]=1)[CH2:34][C@H:35]1[CH2:40][CH2:39][CH2:38][S:37][CH2:36]1
Reactant: IC[C@@H]1CCCSC1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)C(C[C@H]1CCCSC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
A 2.0M solution of lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (564.0 [L, 1.128 mmol) and N,N,N′,N′-tetramethylethylenediamine (157.0 μL, 1.040 mmol) in dry tetrahydrofuran (3 mL) cooled to −78° C. under nitrogen was treated with (3-chloro-4-methanesulfonyl-phenyl)-acetic acid methyl ester (269.4 mg, 1.02 mmol). The reaction mixture was stirred at −78° C. for 1 h and then warmed to 0° C. The reaction was then treated with a solution of 3(R)-iodomethyl-tetrahydro-thiopyran (71.00 mg, 0.293 mmol) in dry tetrahydrofuran (1 mL) and allowed to warm to 25° C., where it was stirred for 19 h. The reaction mixture was then quenched with a saturated aqueous ammonium chloride solution (10 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was extracted with ethyl acetate (2×20 mL), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 4/1 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3(R)-(tetrahydro-thiopyran-3-yl)-propionic acid methyl ester (96 mg, 86.9%) as a colorless oil: [α]23589=+10.93° (c=0.76, methanol); EI-HRMS m/e calcd for C16H21ClO4S2 (M+) 376.0570. found 376.0574.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH:17]=[C:16]2[C:21]2[O:22][C:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:25]=2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:26]1([C:24]2[N:25]=[C:21]([C:16]3[CH:15]([CH2:14][C:10]4[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=4)[CH2:20][CH2:19][CH2:18][CH:17]=3)[O:22][C:23]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.6 %

Procedure:
To a solution of {3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}phenyl}carbamic acid tert-butyl ester (2.34 g, 4.62 mmol) in methylene chloride (25 ml) was added trifluoroacetic acid (7 ml) at 5° C. and the mixture was stirred at room temperature for 1.5 hour. After evaporation, the residue was dissolved in EtOAc, and saturated sodium hydrogencarbonate solution was added thereto under ice-cooling. The mixture was extracted with EtOAc, washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 3:1 elution) to give 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-y]methyl}phenylamine (1.74 g, 93%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:32])[CH2:16][N:17](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:11][C:10]=1[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])C1C=CC=CC=1>CO.[Pd]>[NH2:17][CH2:16][CH:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:11]=1)[OH:32]
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Temperature: 25 °C

Procedure:
To a stirred suspension of N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (1.03 g, 2 mmol) and 10% Pd/C (0.4 g) in methanol (100 mL) at room temperature is added anhydrous HCO2NH4 (1.26 g, 20 mmol) under a nitrogen atmosphere. The resulting mixture is refluxed for 2 hours. After cooling to room temperature the catalyst is removed by filtration through a celite pad and washed with methanol. The filtrate is evaporated under reduced pressure to give the titled compound as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 2.62 (dd, J=12.6, 8.7 Hz, 1 H), 2.75 (dd, J=12.6, 3.7 Hz, 1 H), 2.90 (s, 3 H), 4.47 (dd, J=8.7, 3.7Hz, 1 H), 6.84 (d, J=9.1 Hz, 1 H), 6.96 (dd, J=9.1, 2.0Hz, 1 H), 7.16 (d, J=2.1 Hz, 1 H), 8.44 (s, 1 H); MS (ES) m/z: 246.7 (M++H); HRMS Calcd. for C9H14N2O4S(M+): 246.0674. Found: 246.0672.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8](=[O:13])[NH:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:28]=[CH:27][C:21]2[N:22]=[C:23]([S:25][CH3:26])[S:24][C:20]=2[CH:19]=1.O>CN(C=O)C>[CH3:26][S:25][C:23]1[S:24][C:20]2[CH:19]=[C:18]([CH2:17][N:9]3[CH:10]=[CH:11][N:12]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[C:8]3=[O:13])[CH:28]=[CH:27][C:21]=2[N:22]=1
Reactant: CSc1nc2ccc(CCl)cc2s1
Reactant: O=c1[nH]ccnc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3ccnc(N4CCOCC4)c3=O)cc2s1
Reaction time: 0.33 h
Yield: 95.4 %

Procedure:
To a stirred solution of 3-morpholinopyrazin-2(1H)-one (317 mg, 1.75 mmol) in DMF (8 mL) at 0° C. was added NaH (60% in mineral oil, 105 mg, 2.63 mmol). After stirring for 20 min, a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (400 mg, 1.75 mmol) in DMF (2 mL) was added dropwise, and the mixture was stirred at rt for 2 h. The mixture was poured into water and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-morpholinopyrazin-2(1H)-one as a light yellow solid (625 mg, 95.4%). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.36 (d, J=6.6 Hz, 1H), 6.92 (d, J=4.2 Hz, 1H), 6.71 (d, J=4.2 Hz, 1H), 5.10 (s, 2H), 3.81 (s, 8H), 2.80 (s, 3H). LCMS (ESI) m/z 375 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][N:21]=2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CO>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20](/[CH:19]=[CH:18]/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)=[N:21]1
Reactant: CCOC(=O)c1cnc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(Nc2ccccc2/C=C/c2n[nH]c3ccccc23)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
Compound 165 (0.02 g, 0.051 mmol) was dissolved in methanol (1.0 mL) and 1 mol/L aqueous sodium hydroxide solution (1.0 mol) was added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was added with water, washed with ethyl acetate and the aqueous layer was neutralized using 6 mol/L hydrochloric acid. The precipitated solid was triturated in ethyl acetate to obtain Compound 166 (13 mg, 72%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH2:20])=[CH:13][C:12]=2[O:21][CH3:22])[CH2:5][CH2:4]1>[Ni]>[F:1][C:2]([F:24])([F:25])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:20])=[CH:13][C:12]=2[O:21][CH3:22])[CH2:5][CH2:4]1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: [Ni]
Product: COc1cc(N)c(N)cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The sub-title compound was prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-methoxy-4-amino-5-nitro benzoic acid amide with Ra—Ni in analogy to example 59g.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:28][C:29]1[C:34]([Pb+3])=[C:33]([CH3:36])[CH:32]=[C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH3:28][C:29]1[CH:30]=[C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:32]=[C:33]([CH3:36])[C:34]=1[CH:4]1[C:5](=[O:10])[C@H:6]2[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]2)[C:3]1=[O:11]
Reactant: Cc1cc(-c2ccccc2)cc(C)c1[Pb+3]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccccc2)cc(C)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 32 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.20 g, 1.30 mmol) and 4-dimethylaminopyridine (0.792 g, 6.49 mmol) are added to a mixture of chloroform (4 ml) and toluene (1 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 3,5-Dimethylbiphen-4-yllead triacetate (0.805 g, 1.43 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×5 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(3,5-dimethyl-biphenyl-4-yl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (0.139 g).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.CC[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1CCCCC1.C1(O)CCCC1>[C:10]1([CH3:20])[CH:11]=[CH:12][C:13]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:14][CH:15]=1.[CH:23]1([O:8][C:7](=[O:9])[C@@H:2]([NH2:1])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCCCCCC
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OC1CCCC1
Solvent: C1CCCCC1
Product: CC(C)C[C@H](N)C(=O)OC1CCCC1
Yield: 85 %

Procedure:
To a suspension of (S)-leucine (15 g, 0.11 mol) in cyclohexane (400 ml) was added cyclopentanol (103.78 ml, 1.14 mmol) and p-toluene sulfonic acid (23.93 g, 0.13 mol). The suspension was heated at reflux to effect solvation. After refluxing the solution for 16 hours it was cooled to give a white suspension. Heptane (500 ml) was added to the mixture and the suspension was filtered to give the product as a white solid (35 g, 85% yield). 1H NMR (300 MHz, MeOD), δ: 1.01 (6H, t, CH3×2, J=5.8 Hz), 1.54-2.03 (11H, m, 11×CH), 2.39 (3H, s, CH3), 3.96 (1H, t, CH, J=6.5 Hz), 5.26-5.36 (1H, m, CH), 7.25 (2H, d, ArH x 2, J=7.9 Hz), 7.72 (2H, d, ArH×2, J=8.3 Hz).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1)[OH:4].[CH3:11][O:12][CH2:13]Cl.Cl>C1COCC1>[CH3:11][O:12][CH2:13][O:4][C:3]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1
Reactant: COCCl
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(O)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
A mixture of 60% sodium hydride (1.80 g, 45.0 mmol) and dry THF (20 mL) was cooled to −20° C. After addition of a solution of hydroquinone (2.00 g, 18.2 mmol) in THF (30 mL), the mixture was stirred at room temperature for one hour and then cooled again to −20° C. After dropwise addition of chloromethyl methyl ether (1.3 mL, 18.0 mmol), the cooled mixture was slowly warmed to 10° C., stirred at room temperature for one hour, and poured onto ice pieces (500 g). To the resulting mixture was added 3 mol/L aqueous hydrochloric acid until the mixture reached pH 4-5. Subsequently, the mixture was subjected to extraction with dichloromethane (100 mL×2). The extract was washed with water (100 mL×2) and saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), to obtain 581 mg (yield 21%) of the titled compound as pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:30]([C@H:13]1[C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)=[N+:31]=[N-:32]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](N=[N+]=[N-])C1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of trans-tert-butyl 4-(benzyloxycarbonylamino)-3-(methylsulfonyloxy)piperidine-1-carboxylate (6.0 g, 14 mmol) in dimethyl sulfoxide (40 mL) was added sodium azide (9.11 g, 140 mmol), and the reaction mixture was stirred at 90° C. overnight under N2. The solution mixture was cooled to ˜30° C., diluted with ethyl acetate (˜300 mL), and washed with water (700 mL×3) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to the title compound (3.8 g, 72%) as a yellow oil. MS (ES+) C18H25N5O4 requires: 375, found: 276 [M+H−100]+, 373 [M+Na]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24]([NH:31][C@@H:32]([C:36](O)=[O:37])[CH:33]([CH3:35])[CH3:34])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:27]([O:26][C:24](=[O:25])[NH:31][CH:32]([C:36](=[O:37])[NH:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:33]([CH3:34])[CH3:35])([CH3:28])([CH3:30])[CH3:29]
Reactant: Cc1ccc(NCc2ccccc2)c(N)c1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NCc2ccccc2)c(NC(=O)C(NC(=O)OC(C)(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N1-benzyl-4-methyl-benzene-1,2-diamine (1.24 mmol) and triethylamine (0.26 mL, 1.86 mmol) in dry DMF (5 mL), was added boc-D-valine (296 mg, 1.36 mmol) followed by TBTU (400 mg, 1.24 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the filtrated was concentrated in vacuo. The crude material was purified by flash chromatography to yield [1-(2-Benzylamino-5-methyl-phenylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:20][C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[CH:25][CH:24]=4)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C1COCC1>[C:23]1([O:22][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:21])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(Oc4cccc5ccccc45)cc3c(=O)[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3ccc(Oc4cccc5ccccc45)cc3c(=O)[nH]2)c1
Reaction time: 4 h
Yield: 86.2 %

Procedure:
A mixture of 1-[6-(naphthalen-1-yloxy)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.42 g, 0.99 mmol), 1M aq. KOH (5.0 mL) and THF (5.0 mL) was stirred for 4 h. The mixture was concentrated to remove the THF and the aqueous residue was acidified to pH 2 with 1M aq. HCl. The resulting precipitate was collected by filtration to provide the titled compound (0.34 g, 86%). MS (ESI): mass calcd. for C22H14N4O4, 398.1; m/z found, 399.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.99 (s, 1H), 12.86 (s, 1H), 8.94 (s, 1H), 8.24 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.71 (dd, J=8.9, 2.9 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.60-7.54 (m, 2H), 7.38 (s, 1H), 7.24 (d, J=7.4 Hz, 1H).
Reaction SMILES: [CH:1]([CH:3]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([C:19]([OH:21])=[O:20])=[CH:7][CH:8]=2)=[O:2].[BH4-].[Na+]>O.C1COCC1>[OH:2][CH2:1][CH:3]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][C:6]([C:19]([OH:21])=[O:20])=[CH:7][CH:8]=2
Reactant: O=CC1c2cc(C(=O)O)ccc2-c2ccc(C(=O)O)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(CO)c1cc(C(=O)O)ccc1-2

Procedure:
A small sample of 9-formyl-2,7-fluorenedicarboxylic acid (5-10 mg) was dissolved in water with a small amount of THF. An excess amount of sodium borohydride was added and allowed to react for two hours. The reaction was quenched with the careful addition of 1 M HCl until acidic. The product was extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to dryness. 1H-NMR (CD3OD): δ (ppm) 8.4 (s, 2H, Ar); 8.2 (m, 2H, Ar); 8.0 (m, 2H, Ar); 4.2 (t, 1H, CH); 4.0 (d, 2H, CH2).
Reaction SMILES: [OH:1][CH2:2][C:3]([N+:23]([O-])=O)([CH2:21][OH:22])[CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)O.[H][H].[ClH:28]>CO.[C].[Pd]>[CH3:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:5][CH2:4][C:3]([NH2:23])([CH2:2][OH:1])[CH2:21][OH:22])=[CH:8][CH:9]=1.[ClH:28]
Reactant: CCCCCCCCc1ccc(C(O)CC(CO)(CO)[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCCCCCc1ccc(CCC(N)(CO)CO)cc1
Reaction time: 1 h

Procedure:
To 14.1 g (0.04 mol) of 3-(hydroxymethyl)-3-nitro-1-(p-octylphenyl)butane-1,4-diol in 250 ml of methyl alcohol, 30 ml of concentrated hydrochloric acid was added, followed by the catalyst—10% palladium-carbon. The mixture was stirred at 20 kg/cm2 hydrogen pressure for two days at room temperature. The mixture was then filtered, methyl alcohol was distilled off, the residue was dissolved in water, adjusted to pH 8 with saturated sodium bicarbonate, and extracted with ethyl acetate (100 ml×3). The ethyl acetate extracts were dried over magnesium sulfate, filtered, evaporated. The residue was dissolved in ethanol (50 ml) and a 1N hydrochloric acid (50 ml) was added thereto. The mixture was stirred for 1 h, the solvent was distilled off and the resultant solid were recrystallized from ethanol to give Fingolimod hydrochloride.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=1)(=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>>[CH2:17]([O:16][C:14]([NH:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C:1]([CH3:2])=[N:4][CH2:5][CH2:6]2)=[O:15])[CH3:18]
Reactant: CCOC(=O)Nc1cccc(CCNC(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Nc1ccc2c(c1)CCN=C2C

Procedure:
Using N-acetyl-N-(3-ethoxycarbonylaminophenethyl)amine (1.0 g, Production Example 30b), a cyclization reaction was run according to the method described in Heterocycles 31 (2), 341 (1990). After the reaction was completed, the reaction solution was poured into ice and basified with potassium carbonate. Then, the solution was extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound as a brown oil.
Reaction SMILES: [N:1]([CH:4]([C:25]1[O:29][C:28]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=1)[CH2:5][C:6]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[C:8]([Cl:24])[CH:7]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O.C(OCC)(=O)C>[CH2:17]([O:16][C:15]1[C:6]([CH2:5][CH:4]([C:25]2[O:29][C:28]([CH2:30][N:31]([CH3:32])[CH3:33])=[CH:27][CH:26]=2)[NH2:1])=[CH:7][C:8]([Cl:24])=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)Cc1ccc(C(Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)N=[N+]=[N-])o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(C(N)Cc2cc(Cl)c3cccnc3c2OCc2ccccc2)o1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 1-(5-{1-azido-2-[8-(benzyloxy)-5-chloroquinolin-7-yl]ethyl}-2-furyl)-N,N-dimethylmethanamine (0.1.451 mmol) in tetrahydrofuran (5 mL) and water (1.5 mL) in a round bottom flask equipped with a reflux condenser was added triphenylphosphine (1.596 mmol, 1.1 eq.) (CAUTION: vigorous gas evolution, do not seal reaction vessel) and the resulting mixture was then warmed to 70° C. and stirred 2 h. The reaction mixture was then allowed to cool to room temperature, diluted with ethyl acetate (50 mL) and was washed with 1N HCl (3×25 mL). The aqueous layers were combined, backextracted with ethyl acetate (25 mL) and then adjusted to pH=12 by addition of 5N NaOH resulting in a precipitate. The aqueous solution was extracted with ethyl acetate (3×50 mL) and the organic layers were combined, dried (MgSO4), filtered and concentrated a yellow oil that was used directly in the ensuing step. MS (ESI) m/z 436.4; HRMS: calcd for C25H26ClN3O2+H+, 436.17863; found (ESI, [M+H]+ Obs'd), 436.1788.