Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH:8]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][C:3]=1[C:21]#[N:22].ClC1C(C#N)=CC=C2C=1C1CC(NC(=O)C(C)C)CCC=1N2.[F:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH2:49]Br>>[Cl:1][C:2]1[C:3]([C:21]#[N:22])=[CH:4][CH:5]=[C:13]2[C:14]=1[C:10]1[CH2:9][CH:8]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH2:7][CH2:6][C:11]=1[N:12]2[CH2:49][C:48]1[CH:51]=[CH:52][CH:53]=[C:46]([F:45])[CH:47]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)C(=O)NC1CCc2[nH]c3cc(Cl)c(C#N)cc3c2C1
Agent: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)c(Cl)c3c2C1
Product: CC(C)C(=O)NC1CCc2c(c3c(Cl)c(C#N)ccc3n2Cc2cccc(F)c2)C1
Yield: 5 %

Procedure:
Prepare the title compound by essentially following the procedure as described in Example 96 with N-(7-chloro-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide and N-(5-chloro-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (50:50 mixture—Preparation 17) and 3-fluorobenzyl bromide, to obtain a mixture of regioisomers. Separate the title compound from this mixture of regioisomers using silica gel chromatography (0-20% EtOAc/CHCl3), to afford the title compound in 5% yield. MS (ES): m/z 424 (M+1), 422 (M−1); HPLC (Method B): Rt=6.87 min, (97%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][CH:7]=[N:8][CH:9]=1)=[O:4].C(N(CC)CC)C.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Li+].Cl>C(Cl)Cl.O>[C:18]([N:8]1[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[N:6]=[CH:7]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cnc[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3H-Imidazole-4-carboxylic acid methyl ester (9.86 g, 78.2 mmol) is taken up in 150 mL DCM, triethylamine (11.9 mL, 86.0 mmol) is added and the reaction mixture is stirred for 5 min at RT. Chlorotriphenylmethane (24.0 g, 86.0 mmol) is added and the reaction mixture is stirred overnight at RT. The reaction mixture is extracted with an aqueous 5% NaHCO3 solution, the organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue (20.7 g) is taken up in 100 mL MeOH, a solution of lithium hydroxide (4.80 g, 24.0 mmol) in 20 mL water is added drop wise and the reaction mixture is stirred over weekend at RT. The reaction mixture is acidified to pH 4 with 6N hydrochloric acid, 200 mL DCM is added and the two phase mixture is stirred vigorously. The phases are separated and the organic phase is dried over MgSO4 and concentrated under reduced pressure. Yield: 19.2 g. HPLC-MS: double peak tR=2.55/2.67 min, (M−H)−=353.
Reaction SMILES: [C:1]([NH:6][C:7]1[S:11][N:10]=[C:9]([CH3:12])[C:8]=1[C:13]([NH2:15])=[O:14])(=O)[CH2:2][CH2:3][CH3:4]>N>[CH3:12][C:9]1[C:8]2[C:13](=[O:14])[NH:15][C:1]([CH2:2][CH2:3][CH3:4])=[N:6][C:7]=2[S:11][N:10]=1
Reactant: CCCC(=O)Nc1snc(C)c1C(N)=O
Agent: N
Product: CCCc1nc2snc(C)c2c(=O)[nH]1
Temperature: 140 °C
Yield: 46.1 %

Procedure:
5-Butyrylamino-3-methyl-isothiazole-4-carboxylic acid amide (method 6) (1.9 g, 8.3 mmol) was suspended in 75 mL of 30% NH3 and then was heated to 140° C. for 4 h in a pressure reactor. The mixture was cooled and neutralized to pH 8. The precipitated 3-methyl-6-propyl-5H-isothiazolo[5,4-d]pyrimidin-4-one was filtered off, washed with water (100 mL) and dried in vacuum oven at 40° C. overnight to get 800 mg (34%) of pure product. 1H NMR (300 MHz) δ 1.03 (t, 3H), 1.74 (m, 2H), 2.67 (t, 3H), 2.78 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCCNC3CCN(Cc4ccccc4)CC3)c2c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1oc2cccc(OCCCNC3CCNCC3)c2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3-(1-benzyl-piperidin-4-ylamino)-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (the compound in Example 100, 100 mg) and acetic acid (2 ml) in ethyl acetate (6 ml) was added 10% Pd on charcoal catalyst (20 mg) under N2. The nitrogen atmosphere was replaced by hydrogen (1 atom) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through a pad of celite and the pad of celite was rinsed with methanol and dichloromethane. The filtrate combined was concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to give 3-methyl-4-[3-(piperidin-4-ylamino)-propoxy]-benzofuran-2-carboxylic acid ethyl ester (48 mg) as a colorless oil. FAB-MS: m/z 361 (MH+); 1H-NMR (CDCl3): δ 1.36 (2H, m), 1.43 (3H, t, J=7 Hz), 1.97 (2H, m), 2.07 (2H, quintet, J=6.5 Hz), 2.68 (3H, m), 2.74 (3H, s), 2.89 (2H, t, J=7 Hz), 3.17 (2H, br d, J=12.5 Hz), 4.16 (2H, t, J=6 Hz), 4.44 (2H, q, J=7 Hz), 6.62 (1H, d, J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.30 (1H, t, J=8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[C:12]([C:14]#[N:15])[N:13]=1.C(=O)(O)[O-:30].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:15])=[O:30])[N:13]=1
Reactant: O=C([O-])O
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(N2CCOCC2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccc(N2CCOCC2)cc1
Yield: 85 %

Procedure:
A solution of 2-(2,6-difluorophenyl)-5-(4-morpholinophenylamino)oxazole-4-carbonitrile (0.035 g, 0.09 mmol) in concentrated sulfuric acid (1.7 mL) was stirred at room temperature for 1.5 hours. The solution was neutralised by pouring into saturated sodium bicarbonate solution. The aqueous phase was extracted with EtOAc. The combined organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6-difluorophenyl)-5-(4-morpholinophenylamino)oxazole-4-carboxamide (0.031 g, 0.077 mmol, 85%) as a yellow solid. 1H NMR (DMSO) δ 3.06 (4H, t), 3.73 (4H, t), 6.94 (2H, d), 7.28 (2H, br. s), 7.32 (4H, m), 7.62 (1H, m), 9.13 (1H, s). LCMS (2) Rt: 2.60 min; m/z (ES+) 401.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[C:16]([C:21]([OH:23])=O)=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl.CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[C:16]([C:21]([Cl:27])=[O:23])=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(-c2ccccc2C(=O)O)cc(OC)c1OC
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(-c2ccccc2C(=O)Cl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve 3′,4′,5′-Trimethoxy-biphenyl-2-carboxylic acid (83) (54 mg, 0.18 mmol) in anhydrous DCM (1.3 mL) and add anhydrous DMF (1 drop, cat. amount). Then add slowly oxalyl chloride (21 μL, 0.24 mmol) by keeping temperature at ca. 20° C. with a water bath and stir the turbid mixture for additional 2 h at rt. Remove solvent and dry in vacuum to obtain crude 3′,4′,5′-Trimethoxy-biphenyl-2-carbonyl chloride (84) as a yellow solid. No further purification.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([OH:11])=[O:10])[CH:2]=[CH2:3].O[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:1]([O:4][C:5](=[O:18])[C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1)[C:9]([O:11][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C=CCOC(=O)c1cc(C(=O)ON2C(=O)CCC2=O)cc([N+](=O)[O-])c1
Yield: 54.7 %

Procedure:
A solution of 7(a) (10.00 g), N-hydroxysuccinimide (5.04 g) and DCCI (9.03 g) in dichloromethane(400 ml) was stirred at ambient temperature for 3.5 h. The white precipitate which formed was filtered off and the filtrate evaporated under reduced pressure to give a yellow oil. This was purified by flash chromatography eluting with ethyl acetate/hexane (75:25) to give 5-nitro-isophthalic acid 1-(2,5-dioxo-pyrrolidin-1-yl) ester 3-allyl ester (7(b)) as a yellow solid (7.58 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=O)[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.C1(C)C=CC(S([NH:20][NH2:21])(=O)=O)=CC=1>ClCCl>[N+:20](=[C:4]1[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=[C:3]1[O:2][CH3:1])=[N-:21]
Reactant: COC1=CC(=O)C=CC1=O
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: ClCCl
Product: COC1=CC(=O)C=CC1=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
An ice-cold soluton of 2 -methoxy-p-benzoquinone (69 mg, 0.5 mmol) in dichloromethane (2 ml) was added to an ice-cold solution of p-toluenesulfonhydrazide (102 mg, 0.55 mmol) in 2 ml of dichloromethane and the resulting solution was stirred at 0° C. for 1 hour. Additional p-toluenesulfonhydrazide (50 mg, 0.27 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for two hours. The solvent was then removed under reduced pressure and the residue was chromatographed on a silica gel column (2.5×18 cm) with chloroform:methanol (9:1, v/v). The bioactive fractions were combined and concentrated in vacuo to give 26.7 mg of 4-diazo-3-methoxy-2,5-cyclohexadien-1-one as a yellow solid: UV max in CH3OH (E1 cm1%) 335 (730), 250 (120): 1H NMR in CDCl3 δ: 3.90 (s,3H)., 6.05 (d, 1H, 1.5 Hz), 6.30 (dd, 1H, 9.5, 1.6 Hz), 7.28 (d, 1H, 9.5 Hz); 13C NMR in CDCl3 δ: 56.4, 71.2, 103.8, 122.9, 126.7, 161.5, 182.6; IR in chloroform: 2110, 1635, 1600 cm-1 ; and molecular weight by mass spectrum 150; Rf equals 0.25 in a TLC system on silica gel with chloroform:methanol, 9:1, v/v, as the solvent.
Reaction SMILES: CC(=O)C=C.CC1C(SC(C)CC(=O)C)CCO1.[CH3:19][C:20]1[S:21][CH:22]=[CH:23][C:24]=1[S:25][CH:26](C)[CH2:27][C:28](=[O:30])[CH3:29]>>[CH3:19][C:20]1[S:21][CH:22]=[CH:23][C:24]=1[S:25][CH2:26][CH2:27][C:28](=[O:30])[CH3:29]
Reactant: CC(=O)CC(C)Sc1ccsc1C
Agent: C=CC(C)=O
Agent: CC(=O)CC(C)SC1CCOC1C
Product: CC(=O)CCSc1ccsc1C

Procedure:
When using 2-methyltetrahydrofuryl-3-thiol or 2-methyl-thienyl-3-thiol instead of 2-methylfuryl-3-thiol and 3-buten-2-one instead of 3-penten-2-one, 4-(2-methyl-3-tetrahydrofuryl-thio)-pentan-2-one, 4-(2-methyl-3-thienyl-thio)-pentan-2-one and 4-(2-methyl-3-thienyl-thio)-butan-2-one were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)[CH:3]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:20][OH:21])[CH:3]=1
Reactant: COc1ccc(C(=O)Cc2cc(Cl)ccn2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(Cc2cc(Cl)ccn2)=NO)cc1

Procedure:
2-(4-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone in methanol (200 mL) was treated with hydroxylamine hydrochloride (27.2 g, 392 mmol) and a sodium hydroxide solution (15.7 g, 392 mmol in 50 mL of water) as described in Example 12 to give 2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (11.8 g) as a white solid. 1H NMR (CDCl3): δ 8.47 (d, 1H), 7.72 (d, 2H), 7.36 (d, 1H), 7.19 (dd, 1H), 6.91 (d, 2H), 4.43 (s, 2H), 3.84 (s, 3H); MS m/z 277 (M+1).
Reaction SMILES: [C:1]([N:9]1[CH2:17][CH2:16][CH:12]([C:13](O)=[O:14])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.CN(C=O)C.O>[OH:14][CH2:13][CH:12]1[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: O=C(O)C1CCN(C(=O)c2ccccc2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 2 g of 1-benzoylisonipecotic acid (Step A) in 50 mL THF at 0° C. were added 1.47 g of triethylamine and 1.99 g of isobutyl chloroformate. The reaction was stirred for 1 h at 0° C. To a solution of 1.10 g of sodium borohydride in 30 mL DMF at 0° C. was slowly added the above THF mixture. The reaction was again stirred for 1 h at 0° C. Water (80 mL) was slowly added to the reaction and the mixture was extracted 5×80 mL ethyl acetate and the combined organic layers were dried over magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 1:1 hexane:ethyl acetate followed by hexane:ethyl acetate: methanol, 50:50:5 to give 1.865 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15]Br.[H-].[Na+]>CN(C)C=O>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(CBr)OC
Reactant: COC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(OC)OC)cc1
Yield: 66.6 %

Procedure:
Methyl 4-hydroxybenzoate (15.52 g), bromoacetaldehyde dimethyl acetal (16.90 g) and 60% sodium hydride (5.00 g) were heated in dimethyl formamide (50 ml) at 80° C. for 18 hr. Dimethyl formamide was distilled away from the reaction mixture, and toluene and water were added. The separated toluene layer was dried over magnesium sulfate, and the solvent was distilled away to give the objective compound (16.00 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(O)c1cccnc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1c1cccnc1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
rac-6-Chloro-3-hydroxy-3-pyridin-3-yl-1,3-dihydro-indol-2-one (0.27 g, 1.0 mmol) (from Example 39a supra) was suspended in a mixture of triethylsilane (0.49 mL, 3.0 mmol) (Aldrich) and trifluoroacetic acid (1.77 g, 15.0 mmol) (Aldrich) and heated in an 78° C. oil bath for overweekend. After cooling to room temperature, the mixture was diluted with ethyl acetate and treated with solid sodium carbonate (1.0 g). After stirring for 30 minutes, mixture was extracted with water and brine. Aqueous layers were back washed with ethyl acetate. Organic layers were combined, dried (Na2SO4), filtered and concentrated to obtain rac-6-chloro-3-pyridin-3-yl-1,3-dihydro-indol-2-one (Yield 0.1 g, 40%) as yellow oil and carried out for the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+].Cl>C(O)C>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:7][CH:8]=1
Reactant: CC(=O)NC(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NC(C)c1ccc(CO)cc1
Temperature: 0 °C
Yield: 30.9 %

Procedure:
A solution of N-(1-(4-formylphenyl)ethyl)acetamide (0.32 g) and sodium borohydride (63 mg) in ethanol (10 ml) was stirred at room temperature for 1 hr. Thereto was added 2N hydrochloric acid (1 ml) to stop the reaction, and the reaction mixture was poured into ice water (100 ml) and extracted with ethyl acetate. The extract was washed successively with saturated sodium hydrogencarbonate solution (500 ml) and saturated brine (500 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (elution solvent; hexane:ethyl acetate=2:5, later 1:4) to give N-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg) as a colorless oil. A solution of the obtained N-(1-(4-hydroxymethylphenyl)ethyl)acetamide (100 mg) and thionyl chloride (0.050 ml) in chloroform (5 ml) was stirred at 60° C. for 1 hr. This was diluted with ethyl acetate (100 ml) and poured into a saturated sodium hydrogencarbonate solution (100 ml) to separate the organic layer. The aqueous layer was extracted with ethyl acetate (100 ml) and combined with the organic layer obtained earlier. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate alone) to give N-(1-(4-chloromethylphenyl)ethyl)acetamide (92 mg) as yellow crystals.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH:9]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:11][OH:12]>>[CH2:1]([N:9]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: OCCNCCO
Reactant: CCCCCCC=O
Product: CCCCCCCN(CCO)CCO

Procedure:
The n-heptyldiethanolamine is prepared from n-heptanal and diethanolamine (DEoA).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH3:12])[C:5]([C:13]([N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:16]2[CH2:21][C@@H:20]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:17]2)=[O:14])=[CH:4][CH:3]=1.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43](B(O)O)[CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1>[CH3:12][O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:2]([C:43]2[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=2)=[CH:3][CH:4]=[C:5]1[C:13]([N:15]([CH2:37][CH:38]([CH3:39])[CH3:40])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:17]1)=[O:14]
Reactant: OB(O)c1cccnc1
Reactant: COCCCCn1c(Br)ccc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)ccc1-c1cccnc1
Yield: 106.7 %

Procedure:
A mixture of tert-butyl(3S,5R)-3-[{[5-bromo-1-(4-methoxybutyl)-1H-pyrrol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (188 mg), pyridin-3-ylboronic acid (41 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg), sodium carbonate (371 mg), ethanol (2 ml), toluene (2 ml) and water (2 ml) was heated under reflux for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure, and crystals were collected by filtration to give the object product (200 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH:12]=[CH:11][C@@H:10]([OH:13])[CH2:9]1>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH2:9][C:10](=[O:13])[CH:11]=[CH:12]1
Reactant: O[C@@H]1C=C[C@@H](OC2CCCCO2)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: O=C1C=C[C@@H](OC2CCCCO2)C1
Yield: 67.4 %

Procedure:
Six milligrams of (S)-trans-5-tetrahydropyranyloxycyclopent-1-en-3-ol was dissolved in a solvent mixture of 3 milliliters of petroleum ether and 0.5 milliliter of benzene, and the resulting solution was refluxed after the addition of 10 milligrams of active manganese dioxide. Six hours later, the resulting precipitate was separated by filtration and, after distilling off the organic solvent, purified by thin-layer chromatography (cyclohexane-ethyl acetate = 7:3) to obtain 4 milligrams (67%) of (S)-4-tetrahydropyranyloxycyclopent-2-en-1-one. The IR and NMR data were in complete agreement with those of the corresponding (R)-isomer.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH3:3].[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[C:16]1[N:21]=[CH:20][C:19]([CH:22]=[O:23])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1)[CH3:7].[NH4+].[Cl-]>CCOCC>[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[C:16]1[N:21]=[CH:20][C:19]([CH:22]([OH:23])[CH2:1][CH2:2][CH3:3])=[C:18]([O:24][CH2:25][CH3:26])[CH:17]=1)[CH3:7]
Reactant: CCC[Mg]Cl
Reactant: CCOc1cc(-c2c(CC)cccc2CC)ncc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC(O)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Reaction time: 2 h

Procedure:
A solution of PrMgCl (2M in ether, 0.15 mL) is added dropwise to a solution of 6-(2,6-diethyl-phenyl)-4-ethoxy-pyridine-3-carbaldehyde (100 mg, 0.59 mmol) in ether (5 mL) at room temperature. After the mixture is stirred for 2 hours, aqueous NH4Cl solution (10 mL) is added and the organic layer is separated. The aqueous layer is extracted with ether (1×) and the organic layers are combined, dried and concentrated in vacuo. The residue is purified by PTLC purification (4:1 hexane/EtOAc) to give 1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butan-1-ol. 1H NMR (CDCl3) 8.48 (s, 1H), 7.26 (t, 1H), 7.12 (d, 2H), 6.74 (s, 1H), 4.90 (s, 1H), 4.08 (q, 2H), 2.70 (s, 1H), 2.33 (m, 4H), 1.85 (m, 2H), 1.30-1.60 (m, 5H), 0.90-1.05 (m, 9H).
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:10]([NH2:9])=[S:11])=[CH:15][C:14]=1[O:20][CH3:21]
Reactant: COc1cc(N)ccc1Cl
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(N)=S)ccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Benzoyl isothiocyanate (8.8 mL, 64 mmol) was added dropwise to a solution of 4-chloro-3-methoxy-benzenamine (10 g, 63 mmol) in 160 mL THF. The mixture was stirred at room temperature for 40 minutes, volatiles were removed and the residue was dissolved in 400 mL methanol. A solution of potassium carbonate (26.3 g, 190 mmol) in 200 mL water was added and the mixture was stirred at room temperature for 90 minutes. The tide product (13.5 g, 98%) precipitated after removal of 450 mL of the solvents.