Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[N:23][CH:22]=1>>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:27][C:24]2[CH:25]=[CH:26][N:21]=[CH:22][N:23]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: Nc1ccncn1
Product: O=C(Nc1ccncn1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (100 mg, 0.35 mmol) and 4-pyrimidinamine (CAN 591-54-8, 39.5 mg, 0.41 mmol) as starting materials; off white solid (63 mg, 49.7%). MS (ESI): 367.2 (M+H)+.
Reaction SMILES: [Cl:1]Cl.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][C:12]([OH:14])=[O:13].O>C(O)(=O)C>[Cl:1][C:7]1[C:6]([CH3:10])=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[C:4]([CH3:3])=[CH:9][CH:8]=1
Reactant: Cc1cccc(C)c1CC(=O)O
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Cl)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
At 10-15° C., 9.22 g [130 mmol] of chlorine gas are slowly introduced into a solution of 16.4 g [100 mmol] of 2,6-dimethylphenylacetic acid in 100 ml of glacial acetic acid. The reaction mixture is then stirred at room temperature for 16 hours and then poured into 500 ml of water. The precipitated solid is filtered off with suction, washed with water and dried. This gives 18.8 g of a white solid which, according to GC(sil.), has the following composition: 86.4% of 3-chloro-2,6-dimethylphenylacetic acid (corresponds to a yield of 81.8% of theory), 8.8% of dichloro-2,6-dimethylphenylacetic acid (isomer 1), 3.8% of dichloro-2,6-dimethylphenylacetic acid (isomer 2).
Reaction SMILES: C([O-])(=O)C.[K+].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[C:9]2[N:14]([CH3:17])[N:15]=[CH:16][C:8]=12.[C:18]([C:20]1[C:21]([F:29])=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>CN(C=O)C.C(#N)C>[Cl:6][C:7]1[CH:12]=[C:11]([C:22]2[C:21]([F:29])=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:18]#[N:19])[N:10]=[C:9]2[N:14]([CH3:17])[N:15]=[CH:16][C:8]=12
Reactant: N#Cc1cccc(B(O)O)c1F
Reactant: Cn1ncc2c(Cl)cc(Cl)nc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1ncc2c(Cl)cc(-c3cccc(C#N)c3F)nc21
Temperature: 125 °C
Yield: 26.8 %

Procedure:
Potassium acetate (4 mL, 1M, 4 mmol) was added to a mixture of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5 (0.115 g, 0.569 mmol), 3-cyano-2-fluorophenylboronic acid 14 (0.075 g, 0.455 mmol) in DMF (2 mL) and acetonitrile (2 mL). Nitrogen was bubbled through the mixture followed by the addition of 10 mole % tetrakis(triphenylphosphine) palladium (0) and the reaction was heated at 125° C. in a microwave for 20 minutes. Solvent was removed, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and brine (15 mL). The organic portions were pooled and dried over anhydrous sodium sulfate and the solvent was removed. The crude material was purified by reverse phase chromatography (Biotage) using ethyl acetate and hexanes as solvents to give 15 as white solid (0.035 g, 20%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH2:47][CH:48]([CH3:50])[CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]([CH2:47][CH:48]([CH3:49])[CH3:50])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CC(C)Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (262 mg, 0.70 mmol) and 3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K37) (247 mg, 0.70 mmol) according to the general procedure M. Obtained as a light brown oil (320 mg, 70%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][S:28][CH2:29][C@H:30]([OH:45])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:52](Cl)(=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>C(Cl)Cl>[C:52]([O:45][C@H:30]([CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:29][S:28][CH2:27][C@@H:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[O:64])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCOC[C@@H](O)CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution (R)-tert-butyl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(((R)-3-(dodecyloxy)-2-hydroxypropyl)thio)propanoate (1 eq) in DCM (0.1 M) was cooled in an ice bath. Pyridine (3.0 eq) was added followed by dodecanoyl chloride (3.0 eq). The reaction mixture was stirred for 10 minutes then warmed up to room temperature, and stirred for 2 hours. The reaction mixture was diluted with DCM, and washed with saturated aqueous NH4Cl. The aqueous phase was back extracted with DCM. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-30% EtOAc/Hex to give the title product as a white solid.
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:10][OH:11]>CO>[CH3:1][CH2:2][C:3](=[N:10][OH:11])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(=O)CC
Reactant: NO
Agent: Cl
Solvent: CO
Product: CCCCC(CC)=NO

Procedure:
A mixture of (R)-1-azabicyclo 2.2.1!heptan-3-one (U.S. Pat. No. 5,306,718) (2.22 g, 20 mmol) and hydroxylamine hydrochloride (1.39 g, 20 mmol) in MeOH (75 mL) is stirred at 25° C. for 18 hours. The solvent is removed under reduced pressure, the residual solid dissolves in saturated Na2CO3, and is extracted with CHCl3. The organic extracts are dried (Na2CO3), and concentrated to give the oxime. The aqueous layer is concentrated, and re-extracted with CHCl3 to yield additional product.
Reaction SMILES: [OH:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7](C(OC)=O)[CH2:6][C:5]=2[O:4][N:3]=1.[BrH:15].[K+].[Br-].CO>C(O)(=O)C>[Br-:15].[OH:1][C:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[O:4][NH+:3]=1
Reactant: Br
Reactant: COC(=O)N1CCc2c(O)noc2C1
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1[nH+]oc2c1CCNC2

Procedure:
A solution of methyl 3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5, 4-c]-pyridine-6-carboxylate (309 mg; 1.6 mmol) in a solution of hydrogen bromide in glacial acetic acid (3 ml; 43%) was refluxed for 15 minutes. Upon evaporation to dryness in vacuo the residue was treated with the same reagent (3 ml) for further 15 minutes. Evaporation of the reaction mixture to dryness in vacuo and recrystallization (methanol-ether) of the residue gave Ia (salt) (193 mg; 56%) as faintly reddish crystals, m.p. 162-163° C. (decomp.). IR (KBr): 3700-3300 (m), 3070 (s), 3000-2300 (several bands, m-s), 1670 (m), 1580 (m), 1525 (s), 1505 (w) cm-1. UV (methanol): <210 nm. 1H NMR [D2O (sodium 3-(trimethylsilyl) propanesulfonate was used as an internal standard)]: δ4.77 (ca. 5 H, s), 4.43 (2 H, t, J 1 Hz), 3.7- 3.4 (2 H, q, J 6 and 7 Hz), 3.0-2.7 (2 H, t).
Reaction SMILES: [CH2:1]([C:3]1[C:4](O)=[N:5][CH:6]=[CH:7][N:8]=1)[CH3:2].P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:4]1[C:3]([CH2:1][CH3:2])=[N:8][CH:7]=[CH:6][N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nccnc1O
Product: CCc1nccnc1Cl
Temperature: 25 °C
Yield: 98 %

Procedure:
3-Ethyl-2-hydroxypyrazine (5 g) was heated with phosphorus oxychloride (15 ml) at reflux for 3 hours. The reaction was allowed to cool to ambient temperature and then poured onto 200 g of crushed ice. The mixture was extracted with dichloromethane (3×150 ml) and the combined extracts were dried (MgSO4). Volatile material was removed by evaporation to give a brown oil. The oil was purified by chromatography on silica gel, eluting with dichloromethane, to give 2-chloro-3-ethylpyrazine as a colourless oil (5.64 g, 98%); 1H NMR (d6 -DMSO, 200 MHz): 1.25 (t,3H), 2.93 (q,2H), 8.36 (d,1H), 8.59 (d,1H); mass spectrum (+ve CI): 143 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N:18]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)CCC>[NH2:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:20]2)[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCN(c2cc(N)ncn2)CC1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.4 g, 3.09 mmol) and diisopropylethylamine (0.399 g, 3.09 mmol) were suspended in n-butanol. tert-Butyl 1,4-diazepane-1-carboxylate 15-1 (0.618 g, 3.09 mmol) was then added. The reaction was stirred at 150° C. for 18 hours and then the product was filtered off, washed with n-butanol and ethyl ether and then air dried. 1H-NMR (CD3OD): 7.95 ppm (s, 1H); 5.65 ppm (s, 1H); 3.73 ppm (m, 2H); 3.61 ppm (m, 3H); 3.55 ppm (t, 1H); 3.38 ppm (m, 1H); 3.34 ppm (m, 1H); 1.89 ppm (m, 1H); 1.84 ppm (m, 1H); 1.41 ppm (s, 4H); 1.36 ppm (s, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:11])[CH2:5][NH:6][CH:7]1[CH2:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:11])[CH2:5][N:6]([C:16]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=1)[CH:7]1[CH2:10][CH2:9][CH2:8]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)C(C)CNC1CCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a mixture of 1.71 g (0.010 mole) of (rac)-3-cyclobutylamino-2-methyl-propanoic acid methyl ester, 1.94 g (0.010 mole) of 2,4-dichloro-5-nitro-pyrimidine, 50 mL of ethyl acetate and 25 mL of water was added 3.0 g (0.030 mole) of potassium bicarbonate. The mixture was stirred for 3 hours then diluted with 50 mL of ethyl acetate and 50 mL of water. The aqueous layer was extracted with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (100:0-97:3) to give 2.54 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-2-methyl-propanoic acid methyl ester (IV-52) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([C@@H:14]([NH2:16])[CH3:15])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH2:6]3.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([C@@H:14]([NH:16][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[CH3:15])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH2:6]3
Reactant: C[C@H](N)c1nc2ccc(F)c3c2n1CCC3
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c3c2n1CCC3
Temperature: 90 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
A mixture of (5)-1-(7-fluoro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)ethylamine (48.5 mg, 0.221 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (52.9 mg, 0.221 mmol), and DIPEA (0.113 mL, 0.663 mmol) in n-butanol (1 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT, volatiles were removed under reduced pressure. The residue was dissolved in MeOH (3 mL) and the resulting solution was cooled in an ice bath. HCl in isopropanol (1.25 M, 2 mL) was added and the mixture stirred at 0° C. for 1 h and then concentrated under reduced pressure. The residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5 M NH3 in MeOH, further purification by column chromatography (Si—PCC, gradient 2-14% 2M NH3/MeOH in DCM) afforded 398 as a white solid (43.4 mg, 58%). LCMS (Method J): RT 4.80 min [M+H]+ 338.2. 1H NMR ((CD3)2SO, 400 MHz): 12.81 (1H, bs), 8.23 (1H, s), 8.15 (1H, s), 7.96 (1H, d, J=7.8 Hz), 7.37 (1H, dd, J=8.8, 4.2 Hz), 6.92 (1H, dd, J=10.5, 8.8 Hz), 5.80 (1H, bs), 4.29-4.16 (2H, m), 2.87 (2H, t, J=6.1 Hz), 2.16-2.05 (2H, m), 1.68 (3H, d, J=6.8 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:10]([OH:17])[CH2:11]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]1[O:17][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)COS(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-methanesulfonyloxybutane(the 2-hydroxy-1-sulfonate compound:the 1-hydroxy-2-sulfonate compound:the diol compound:the 1,2-disulfonate compound=97.1:0.1:0.4:2.3 according to the HPLC area ratio) 50 g dissolved in ethyl acetate 510 ml was added 28% sodium methylate methanol solution 58.2 g under ice-cooling and stirred for 10 min. The reaction solution was diluted with water and adjusted with 6N-HCl to pH7 to separate an organic phase, which was distilled to remove the solvent. The concentrated residue was mixed with n-heptane, stirred at the ambient temperature for 1 hr to deposit crystals, which were filtered to remove. The filtrate was washed with water to separate an organic phase, which was mixed with active charcoal 2 g, stirred at the ambient temperature for 1 hr and filtered to remove charcoal. The filtrate was cooled down to −20° C. to deposit crystals, which were filtered and dried in vacuum to obtain the N-tert-butoxycarbonyl-3(S)-amino-1,2(R)-epoxy-4-phenylbutane(98.5% according to the HPLC area ratio) 28.8 g. The diol compound and the 1,2-disulfonate compound contained in a concentration of 0.5% or less in the crystals according to the HPLC area ratio respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:46][CH2:47]I>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([O:24][CH2:47][Cl:46])=[O:23])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)O)c1
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cccc(C(=O)OCCl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(N-benzyloxycarbonyl-valyloxy)benzoic acid (7.42 g, 20 mmole) in 1,4-dioxane (100 ml) was added a 40% solution of tetrabutylammonium hydroxide (12.97 g, 20 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in dichloromethane (50 ml) and chloroiodomethane (35.3 g, 200 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. Ethyl acetate (100 ml) was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure: The product was isolated by silica gel column chromatography. Yield: 3.8 g=45%.
Reaction SMILES: [Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9]([O:11]CC)=[O:10])[C:4]=2[CH:3]=1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1csc2cc(OC)c(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2scc(C(=O)O)c2cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
Ethyl 5-bromo-6-methoxybenzo[b]thiophene-3-carboxylate (D4) (0.42 g, 0.0013 mole) in ethanol (20 ml) and water (5 ml) was treated with sodium hydroxide powder (0.14 g, 0.0035 mole). The reaction mixture was heated under reflux for 2 hours and stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue diluted with water (25 ml), acidified with 5N hydrochloric acid, extracted into ethyl acetate, dried (Na2SO4) and evaporated in vacuo to afford the title compound (0.36 g, 93%) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:25])[C:23]#[CH:24]>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:25][CH2:22][C:23]#[CH:24])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCNC(=O)N1CC(Oc2ccc(Br)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.9 %

Procedure:
A stirred mixture of 5.8 g (0.02 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g (0.02 mole) of 2-propynylamine added dropwise from a needle and syringe. After stirring for 30 min, approximately 1 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 6.1 g. After drying, recrystallization from benzene-ligroin yielded 4.2 g (67.9%) of fine white crystals, m.p. 120°-122° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH2:10][CH3:11].[CH3:12][N:13]=[C:14]=[S:15]>>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH2:10][CH3:11])=[S:15]
Reactant: CCC1CCCCN1CCN
Reactant: CN=C=S
Product: CCC1CCCCN1CCNC(=S)NC

Procedure:
By the general method described in Example 1, 1-(2-aminoethyl)-2-ethylpiperidine is reacted with methyl isothiocyanate to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][CH2:15][C:16]1([N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CN(C)C(=O)C>[CH3:13][O:14][CH2:15][C:16]1([N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[CH2:18][CH2:17]1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C

Procedure:
A mixture of 20 parts of 1-(2-bromoethyl)-4-nitrobenzene, 21.8 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, 14.4 parts of N,N-diethylethanamine and 270 parts of N,N-dimethylacetamide is stirred and heated for 4.50 hours at 70° C. The reaction mixture is cooled to room temperature and poured onto water. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 4% of methanol as eluent. The first fraction is collected and the eluent is evaporated, yielding a first fraction of 14 parts of N-{4-(methoxymethyl)-1-[2-(4-nitrophenyl)ethyl]-4-piperidinyl}-N-phenylpropanamide; mp. 98.7° C. The second fraction is collected and the eluent is evaporated. The residue is purified once more by column-chromatography over silica gel using a mixture of trichloromethane and 4% of methanol as eluent. The pure fraction is collected and the eluent is evaporated, yielding a second fraction of 2.8 parts of N-{4-(methoxymethyl)-1-[2-(4-nitrophenyl)ethyl]-4-piperidinyl}-N-phenylpropanamide; mp. 98.7° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=2)=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[C:18]([C:15]1[CH:16]=[CH:17][C:12]2[O:11][C:10]([CH3:21])([CH3:20])[CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][N+:6]=3[O-:30])[C:13]=2[CH:14]=1)#[N:19]
Reactant: CC1(C)C=C(c2ccc(O)cn2)c2cc(C#N)ccc2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)C=C(c2ccc(O)c[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 7.1 %

Procedure:
400 mg of 4-(5-hydroxy-2-pyridyl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile and 350 mg of m-chloroperbenzoic acid were stirred overnight in 100 ml of dichloromethane. The mixture was washed in succession with sodium bisulphite solution, sodium bicarbonate solution and water, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 10% (v/v) methanol/ethyl acetate for the elution. There were obtained 30 mg of 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-hydroxypyridine N-oxide of melting point 260°-262° C. (from ethanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=C)[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[BH4-].[Na+].C[OH:21]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:21])[C:3]=1[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1
Reactant: C=Cc1nccc(C)c1COC1CCCCO1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccnc(CO)c1COC1CCCCO1
Temperature: -50 °C

Procedure:
4-Methyl-3-(tetrahydro-pyran-2-yloxymethyl)-2-vinyl-pyridine (300 mg. 1.29 mmol) was dissolved in DCM (36 mL) and cooled to −50° C. A gentle flow of ozone was bubbled through the reaction mixture until the colour of the solution changed to slight blue. NaBH4 (486 mg. 12.9 mmol) dissolved in MeOH (15 mL) was added and the reaction was allowed to warm to RT over a period of 1 h. The solvents were removed in vacuo and the residue pardoned between water (20 mL) and EtOAc (20 mL) extracted with EtOAc (3×20 mL). The combined organic fractions were washed with brine and dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM/MeOH 40:1→20:1) to give the title compound. MS (m/z): 238.0 [M+H+].