Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12]([S:18](Cl)(=[O:20])=[O:19])=[CH:13]2.C1(C)C=CC=CC=1.O>N1C=CC=CC=1>[Br:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12]([S:18]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:19])=[O:20])=[CH:13]2
Reactant: CC(C)(C)CO
Reactant: O=S(=O)(Cl)c1ccc2c(Br)cccc2c1
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)COS(=O)(=O)c1ccc2c(Br)cccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Solid neopentyl alcohol (2.7 grams; 30.8 mmol) was added at room temperature to a solution of 5-bromonaphthalene-2-sulfonyl chloride (8.5 grams; 28 mmol) in 40 mL of pyridine. The reaction mixture was stirred at room temperature overnight (about 16 hours). The reaction mixture was co-distilled with toluene (about 100 mL) and the resulting oil poured into water to give a pale yellow solid which was filtered and dried. The solid was further purified by silica gel chromatography (EtOAc: Hexane 1:8). Yield: 8.9 gm (89%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH3:24][CH:25]([CH3:30])[CH2:26][C:27](O)=[O:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:16])([NH:17][C:27](=[O:28])[CH2:26][CH:25]([CH3:30])[CH3:24])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: CC(C)CC(=O)O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)CC(C)C)c2c1N

Procedure:
Prepared as in Example Da from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example Db) and 3-methylbutanoic acid as an off-white solid (100%). MS 402 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](=N)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([N:14]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)C1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](N=C(c2ccccc2)c2ccccc2)[C@H](O)C1
Yield: 87.9 %

Procedure:
tert-butyl-4-amino-3-hydroxypiperidine-1-carboxylate (11.9 g; 55 mmol) and benzophenone imine (10 g; 59 mmol; 1.05 eq.) were dissolved in anhydrous toluene and heated to reflux for 18 hrs. Monitored the reaction by TLC (30% EtOAc/hexanes with 0.1% triethylamine). The crude reaction was concentrated and purified by flash column chromatography. Isolation gave 18.4 g of the title compound in an 86% yield. LC/MS (ES+)[(M+H)+]: 381 for C23H28N2O3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(OCCCCCCCl)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 89.2 %

Procedure:
A mixture of 16.7 g (100 mmol) of 5-hydroxy-2-nitrobenzaldehyde, 32 g (110 mmol) of 6-chlorohexyl-p-toluenesulfonate and 17 g of potassium carbonate in dry 250 ml of DMF was heated to 100° C. under dry nitrogen for 3 h. The reaction was cooled, filtered and evaporated to a dark oil. The crude product was dissolved in 500 ml of ethyl acetate, and the organic layer was washed twice with 300 ml of saturated sodium carbonate, and twice with 300 ml of brine, dried, filtered and evaporated. Filtration through silica gel gave 25.5 g (89.2 mmol, 89%) of 5-(6-chlorohexyl)oxy-2-nitrobenzaldehyde as a green syrup unstable to distillation.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: COc1ccc(-c2c(-c3cc(C#N)ccn3)ncn2C)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-methoxyphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H14N4O, 291. Found, 291.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:20]=[C:19]2[S:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[N:20]=[C:19]2[S:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1nc(Sc2ccccc2)c2cc(N)ccc21
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1nc(Sc2ccccc2)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
2-Methylsulfonyl-N-[3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide can be obtained in the following way: 0.44 g of 2-methylsulfonylbenzenesulfonyl chloride is added to a solution, at a temperature in the region of 0° C. and under argon, of 0.61 g of 5-amino-3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in 10 ml of pyridine. The reaction mixture is then stirred for 1 hour at a temperature in the region of 0° C. and then 2 hours at a temperature in the region of 20° C. After filtration through sintered glass, the filtrate is diluted with a mixture of 45 ml of ethyl acetate and 30 ml of water. After settling out, the organic phase is washed with 2 times 30 ml of water. The organic extracts are pooled, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 25° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa), on a cartridge of 150 g of silica (particle size 20-40 μm), eluting successively with cyclohexane/ethyl acetate (90/10; 85/15; 70/30 by volume) mixtures. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. 0.68 g of 2-methylsulfonyl-N-[3-phenylsulfanyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide is thus obtained in the form of a burgundy-colored paste (Rf=0.35, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (70/30 by volume)).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:7][CH:4]2[CH2:5][CH2:6][CH:2]([CH3:1])[CH2:3]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1CCC(O)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(C)C2)cc1
Yield: 92.5 %

Procedure:
3-Methylcyclopentanol (5.0 g, 49.9 mmol) was reacted with p-toluenesulfonyl chloride in pyridine (50 ml) in the same procedure as in Reference Example 7 to obtain 3-methylcyclopentyl p-toluenesulfonate (11.7 g, 46.2 mmol, 92.5% yield). 1H-NMR Spectrum (CDCl3, TMS, ppm): δ0.93 and 1.00 (total 3H, each d, J=6.0 Hz), 1.20-2.30 (7H, m), 2.48 (3H, s), 4.97 (1H, m), 7.38 (1H, d, J=8.0 Hz), 7.85 (1H, d, J=8.0 Hz).
Reaction SMILES: CC(OC([NH:8][C@@H:9]([CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:20][CH:19]=1)=O)[C:10]([O:12][CH3:13])=[O:11])=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[CH2:15][CH2:14][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[N:8]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)[C@H](CCC(=O)c1ccc(OCc2ccccc2F)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCC(c2ccc(OCc3ccccc3F)cc2)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-5-oxopentanoate (D31, 339 g) in dry DCM (3390 mL), at 0° C., was added trifluoroacetic acid (TFA) (640 mL) dropwise. The mixture was allowed to warm to room temperature and stirred for 2 hrs. Solvent and excess TFA were removed under vacuum and the resulting dark oil was stripped with EtOAc (1700 mL) and left overnight under high vacuum. The title compound was obtained as a red oil (818 g). 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.16 (m, 2H); 7.60 (td, 1H); 7.46 (m, 1H); 7.34 (m, 2H); 7.27 (m, 2H); 5.32 (s, 2H); 5.25 (m, 1H); 3.77 (s, 3H); 3.57 (m, 2H); 2.60 (m, 1H); 2.34 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=[CH:5][CH:4]=1.[CH3:45][Mg]Br.[Cl-].[NH4+].O>C1COCC1.CCOC(C)=O>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:44][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH:21]([OH:22])[CH3:45])[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=3)[N:10]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 82.6 %

Procedure:
5-(4-(Bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (1.0538 g, 1.769 mmol) was suspended in THF (16 mL) and the reaction flask was cooled in an ice water bath. Then, methylmagnesium bromide (3.0 M in diethyl ether, 1.80 mL, 5.40 mmol) was added via syringe, and the reaction was stirred at 0° C. for 25 min. Then, the reaction was treated with saturated ammonium chloride (3 mL, dropwise at first as gas evolution is observed) and water (20 mL). The reaction was diluted with EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; 100:1 DCM/MeOH (to elute non-polar impurities) to 40:1 (to elute product)) to give 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (893.8 mg). 1H NMR (400 MHz, CDCl3) δ 11.86 (s, 1H), 8.83 (d, J=2.35 Hz, 1H), 8.32 (d, J=2.35 Hz, 1H), 8.01 (dd, J=12.13 Hz, 2.15 Hz, 1H), 7.96 (d, J=2.35 Hz, 1H), 7.21 (dd, J=10.76 Hz, 8.61 Hz, 4H), 6.87 (dd, J=12.13 Hz, 8.80 Hz, 4H), 4.94-4.81 (m, 5H), 4.02 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.59 (s, 3H), 1.73 (d, J=3.72 Hz, 1H), 1.53 (d, J=6.46 Hz, 3H). m/z (ESI, pos. ion) 612 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[H-].[Na+].[CH2:13](I)[CH2:14][CH3:15].C(N1C=CC(C2SC=CC=2)=N1)CC>CN(C)C=O.CC(OC)(C)C.O>[CH2:13]([N:7]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:9]=[N:8]1)[CH2:14][CH3:15]
Reactant: CCCI
Reactant: c1csc(-c2cc[nH]n2)c1
Agent: CCCn1ccc(-c2cccs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: CCCn1nccc1-c1cccs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
3-(2-thienyl)-1H-pyrazole (33.3 mmol) was dissolved in 100 mL dry N,N-dimethylformamide and cooled to 0° C. under argon atmosphere. Sodium hydride (39.9 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 15 min. After cooling to 0° C. again, propyl iodide (49.9 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 14 h. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. 6.50 g of a mixture of 1-propyl-3-(2-thienyl)-1H-pyrazole and 1-propyl-5-(2-thienyl)-1H-pyrazole (81:19; 99% yield) were obtained. 1.0 g of this mixture was used as such in the next step. 5.50 g of the mixture were purified again by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 4.35 g of 1-propyl-3-(2-thienyl)-1H-pyrazole and 1-propyl-5-(2-thienyl)-1H-pyrazole (67% yield) and 0.40 g of 1-propyl-5-(2-thienyl)-1H-pyrazole (6% yield).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:50](Cl)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1>O1CCCC1.O>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:50]([C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([O:43][CH3:42])[CH:45]=3)(=[O:52])=[O:51])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2C#N)c1
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-methoxybenzenesulfonyl chloride (310 mg) under ice-cooling and the mixture was stirred for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 477 mg, 95%).
Reaction SMILES: [I-].Cl[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][C@H:7]1[C@@H:11]([OH:12])[CH2:10][N+:9](C)([CH2:13]C2C=CC=CC=2)[CH2:8]1>[Ag]=O.C(O)C>[CH3:13][N:9]1[CH2:8][C@H:7]([O:6][C:5]2[CH:21]=[CH:22][CH:23]=[CH:3][CH:4]=2)[C@H:11]([OH:12])[CH2:10]1
Reactant: C[N+]1(Cc2ccccc2)C[C@H](O)[C@H](Oc2cccc(Cl)c2)C1
Agent: O=[Ag]
Agent: [I-]
Solvent: CCO
Product: CN1C[C@@H](O)[C@@H](Oc2ccccc2)C1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 12.5 g. (28 mmoles) of cis-3-(3-chlorophenoxy)-4-hydroxy-1-methyl-1-phenylmethylpyrrolidinium iodide in 400 ml. of ethanol was stirred at 45° C. with 3.5 g. (15 mmoles) of silver oxide for 1 hr. The solids were removed by filtration and the filtrate was concentrated to 100 ml., treated with 0.5 g. of 10% palladium-on-charcoal catalyst and was shaken under hydrogen at 60° C. for 3 hr. The mixture was cooled and the catalyst was collected by filtration. The filtrate was concentrated and the residue was treated with dilute sodium hydroxide and extracted into methylene chloride. The solution was concentrated and redissolved in hot cyclohexane, treated with charcoal, separated by filtration through Celite and recrystallized from cyclohexane to give 4.6 g. (85%) of white needles (m.p. 78°-81° C.).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH3:15])[CH2:7][N:6]1C(OC)=O)[CH:2]([CH3:4])[CH3:3].C(O)(=O)C.O.[OH-].[Na+]>Cl>[CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH3:15])[CH2:7][NH:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)N1Cc2cccc(C)c2CC1CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c1CC(CC(C)C)NC2
Yield: 83.6 %

Procedure:
A solution of 20 mg of methyl 3-isobutyl-5-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate in hydrochloric acid (0.8 mL)-acetic acid (0.3 mL) was reacted at 90° C. for 48 hours. Under ice-cooling, the reaction liquid was diluted by addition of water, alkalized with 5 N sodium hydroxide, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by PLC (chloroform:ammonia saturated methanol=20:1) to obtain 13 mg (yield 84%) of a title compound as a light yellow oily substance.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[O:7][CH2:8][C@H:9]([OH:12])[CH2:10][CH3:11].[C:13](OC=C)(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]([O:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH3:11]
Reactant: CC[C@@H](O)CO[C@H]1CCCCO1
Reactant: C=COC(=O)CCCCC
Product: CCCCCC(=O)OC(CC)COC1CCCCO1
Temperature: 38 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 23 g of enzyme lipase "Amano" CES (produced by Amano Pharmaceutical Co., Ltd), 40 g of (R,S)-1-tetrahydropyranyloxy-2-butanol and 16.5 g of vinyl caproate was reacted with stirring at 38° C. for eight hours. After the reaction was stopped, the enzyme was removed by filtration, and the enzyme on the filter paper was washed by using n-heptane. n-Heptane was distilled away from the filtrate, the residue was purified with a chromatograph over silical gel, and 21.5 g of optically active 1-tetrahydropyranyloxy-2-butanol and 23 g of 1-tetrahydropyranyloxy-2-caproyloxybutane were obtained.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:34])[N:25]([CH2:31]C=C)[CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[Mn]([O-])(=O)(=O)=O.[K+].I([O-])(=O)(=O)=O.[Na+].[C:48](=O)([OH:50])[O-:49].[Na+]>C(O)(C)(C)C.O.C(O)C>[Cl:23][C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:22]=1)[C:24]([N:25]([CH2:31][C:48]([OH:50])=[O:49])[CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:34]
Reactant: O=C([O-])O
Reactant: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: O
Product: O=C(O)CN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.9 %

Procedure:
To a solution of {2-[3-(allyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.06 g) in tert-butanol (3.2 ml) was added a solution of potassium permanganate (0.006 g), sodium periodate (0.157 g) and sodium bicarbonate (0.051 g) in water (3.2 ml). The purple reaction mixture was stirred at room temperature for 1.5 h and then added to ethanol (25 ml) the precipitate was filtered and the filtrate evaporated in vacuo. The residue was dissolved in a mixture of dichloromethane (5 ml) and trifluoroacetic acid (5 ml) was stored at room temperature for 17 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.021 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:48]1[CH2:52][CH2:51][CH:50]([C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)[CH2:49]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([C:14]([N:48]3[CH2:52][CH2:51][CH:50]([C:53]4[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=4)[CH2:49]3)=[O:16])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: c1cncc(C2CCNC2)c1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CCC(c3cccnc3)C2)cc1
Yield: 85.9 %

Procedure:
A solution of 3-(4-methoxyphenyl)isoxazole-4-carboxylic acid (7 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.09 mmol, 3 equ.) and TBTU (12 mg, 0.036 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 3-pyrrolidin-3-ylpyridine (4 mg, 0.03 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (9 mg). MS (ESI, pos. ion) m/z: calcd for C20H19N3O3: 349.1426, found 349.1427.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][C:7]1[C:2]([C:20]2[CH:21]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:14]([O:13][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:15])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccnc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 62.9 %

Procedure:
2-Bromo-3-methylpyridine (50.0 g, 291 mmol), 3-(tert-butoxycarbonyl)phenyl-boronic acid (68.4 g, 308 mmol), potassium carbonate (96.4 g, 697 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (Pd(dppf)Cl2, 3.19 g, 3.91 mmol) were dissolved in a mixture of 1.5 L of toluene and 350 mL of water. The resulting solution was stirred and heated at 80° C. for 16 hours. The reaction mixture was cooled to 25° C. and then the layers were separated. The organic layer was evaporated to dryness and was then purified on 3 kg of silica gel utilizing a gradient of 0-18.5% ethylacetate in hexanes to yield tert-butyl 3-(3-methylpyridin-2-yl)benzoate as a pale yellow oil (49.3 g, 63%). ESI-MS m/z calc. 269.1. found 270.2 (M+1)+. Retention time 0.93 minutes