Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[CH:61]=[C:62]([CH:66]=[CH:67][C:68]=1[F:69])[C:63](Cl)=[O:64]>>[F:59][C:60]1[CH:61]=[C:62]([CH:66]=[CH:67][C:68]=1[F:69])[C:63]([NH:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:39][CH:40]=1)=[O:64]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)c(F)c4)cc3)cc2C1=O
Yield: 85 %

Procedure:
The compound of example 139 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 3,4-difluoro benzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2I)=[O:16])[CH2:4][O:3]1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:1][C:2]1([CH3:25])[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)=[O:16])[CH2:4][O:3]1
Reactant: OB(O)c1ccsc1
Reactant: CC1(C)OC[C@H](NC(=O)Nc2ccccc2I)[C@H](c2ccccc2)O1
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: COCCOC
Solvent: CCO
Product: CC1(C)OC[C@H](NC(=O)Nc2ccccc2-c2ccsc2)[C@H](c2ccccc2)O1
Temperature: 80 °C
Yield: 49.9 %

Procedure:
To a reaction flask charged with 14.7 mg (0.013 mmol) of tetrakis(triphenylphosphine)palladium(0) in ethylene glycol dimethyl ether (2.5 mL) under nitrogen was added 125 mg (0.27 mmol) of the product from Example 6. The resulting yellow solution was stirred for 10 min before the addition of 41.0 mg (0.32 mmol) of 3-thiopheneboronic acid dissolved in ethanol (0.2 mL) and the subsequent addition of 0.27 mL (0.54 mmol) of a 2 M sodium carbonate aqueous solution. The reaction mixture was heated at 80° C. for ˜20 h and then cooled to room temperature. The liquid was separated from the solid residue, and the residue was rinsed with dichloromethane, which was subsequently combined with the isolated liquid. The solvent was evaporated, and the crude product was partitioned between brine (˜4 mL) and dichloromethane (˜4 mL). The organic layer was washed with additional brine, dried over magnesium sulfate, and filtered. The solvent was evaporated, and the residue was purified by column chromatography (hexane/ethyl acetate) to yield 55 mg (50%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30](Cl)=[O:31])=[CH:22][CH:21]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7]/[C:6]/1=[N:12]\[C:30]([C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]=[CH:21][CH:22]=1)=[O:31]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1ccnc2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccnc2ccccc12
Reaction time: 18 h
Yield: 33 %

Procedure:
To a suspension of the product of Example 126A (0.20 g, 1.1 mmol) in 25 mL THF was added Et3N (0.3 mL, 2.2 mmol) followed by the freshly prepared quinoline-4-carbonyl chloride. This mixture was warmed to reflux and allowed to stir for 18 hours. The material was then concentrated under reduced pressure and 10 mL EtOAc, 5 mL H2O and 5 mL NH4OH were added. The layers were separated and the aqueous layer was extracted 2×5 mL EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 5% CH3OH in EtOAc) to afford the title compound (0.12 g, 0.35 mmol, 33% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.32 (d, J=0.7 Hz, 3H), 2.35 (d, J=0.7 Hz, 3H), 3.31 (s, 3H), 3.78 (t, J=5.3 Hz, 2H), 4.48 (t, J=5.1 Hz, 2H), 7.65 (ddd, J=8.5, 7.0, 1.2 Hz, 1H), 7.80 (ddd, J=8.4, 6.9, 1.4 Hz, 1H), 8.00 (d, J=4.4 Hz, 1H), 8.06-8.11 (m, 1H), 8.84 (ddd, J=8.5, 1.4, 0.7 Hz, 1H), 8.93 (d, J=4.4 Hz, 1H); MS (DCI/NH3) m/z 342 (M+H)+; Anal. calculated for C18H19N3O2S: C, 63.32; H, 5.61; N, 12.31. Found: C, 63.23; H, 5.46; N, 12.10.
Reaction SMILES: [CH:1]1([N:7]2[C:16](=[O:17])[C:15]3[NH:14][C:13]([N+]([O-])=O)=[N:12][C:11]=3[N:10]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:29])=O>CN(C)C=O>[CH:1]1([N:7]2[C:16](=[O:17])[C:15]3[NH:14][C:13]([Cl:29])=[N:12][C:11]=3[N:10]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1c2[nH]c([N+](=O)[O-])nc2n(C2CCCCC2)c(=O)n1C1CCCCC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=c1c2[nH]c(Cl)nc2n(C2CCCCC2)c(=O)n1C1CCCCC1

Procedure:
1,3-Di-cyclohexyl-8-chloro xanthine was prepared from 1,3-di-cyclohexyl-8-nitro xanthine (2 g, 0.006 mol) and phosphorous oxychloride (3.9 g) in dimethylformamide (6 ml), using an analogous procedure to that described in Example 17. The product was obtained as a crystalline product after recrystallisation from ethyl acetate, m.pt., 135° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[C:11]([NH2:22])[N:10]([CH3:23])[N:9]=1)(=O)C.[CH:24]([C:27]1[CH:28]=[CH:29][C:30]([S:33](Cl)(=[O:35])=[O:34])=[N:31][CH:32]=1)([CH3:26])[CH3:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:17]1[C:16]2[CH:20]=[CH:21][C:13]([C:12]3[C:8]([O:7][CH2:6][CH2:5][OH:4])=[N:9][N:10]([CH3:23])[C:11]=3[NH:22][S:33]([C:30]3[CH:29]=[CH:28][C:27]([CH:24]([CH3:26])[CH3:25])=[CH:32][N:31]=3)(=[O:34])=[O:35])=[CH:14][C:15]=2[O:19][CH2:18]1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Reactant: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2C)nc1
Reaction time: 8 h
Yield: 2.5 %

Procedure:
To a solution of 2-{[5-amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 33) (500 mg) in anhydrous pyridine (5 ml) at room temperature and under an atmosphere of nitrogen was added 4-dimethylaminopyridine (191 mg) and 5-isopropyl-2-pyridinesulfonyl chloride (1.72 g). After being left to reflux overnight, the reaction mixture was poured onto saturated citric acid solution (50 ml) and extracted with ethyl acetate (2×50 ml). The organic fractions were washed with brine (50 ml), followed by drying over magnesium sulfate, filtering and concentration under reduced pressure. To a solution of the residue in ethanol (50 ml) was added sodium hydroxide solution (5 ml of 2M). The mixture was stirred overnight before being concentrated to approximately 5 ml under reduced pressure and partitioned between ethyl acetate (2×100 ml) and saturated citric acid solution (100 ml). Washing of the organic fractions with brine (100 ml), drying over magnesium sulfate, filtering and concentration under reduced pressure afforded a brown residue. Purification by column chromatography on silica gel (5 g), eluting in an isocratic fashion with ethyl acetate:hexane (2:1) afforded the title compound as a gum (18 mg).
Reaction SMILES: CN(C)[C:3](=[O:5])[CH3:4].P(Cl)(Cl)(Cl)=O.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[CH3:22]>>[C:3]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([CH3:12])[C:14]=1[CH3:22])(=[O:5])[CH3:4]
Reactant: CC(=O)N(C)C
Reactant: Cc1cc2ccccc2n1C
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1c(C)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 6 moles of N,N-dimethylacetamide and cooled at 0° C., 1.5 moles of phosphorus oxychloride was added dropwise in 30 minutes with stirring. After further adding 1 mole of 1,2-dimethylindole thereto, the reaction was carried out at 85°-90° C. for 2 hours. Then, the reaction solution was poured into 2 liters of ice water. The reaction solution was made alkaline, extracted with 0.5 liter of ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was recrystallized from ethyl acetate to give yellow crystals in yield of 80%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5](Cl)=[O:6].[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([N+:38]([O-:40])=[O:39])=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([N+:38]([O-:40])=[O:39])=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)=[O:6]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Methoxy-6-pentadecyl-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Methoxy-N-(4-nitro-3-trifluromethyl-phenyl)-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10])[CH3:2].[CH2:11]([NH2:14])[CH:12]=[CH2:13].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.[Na+].[Na+]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:11]([NH2:14])=[CH:12][CH:13]=[N:10]1)[CH3:2]
Reactant: CCc1ccccc1NN
Reactant: C=CCN
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCc1ccccc1-n1nccc1N
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution (2-Ethyl-phenyl)-hydrazine 1 (35 mmol) and disodium ethylenediaminetetraacetate (20 mg) in methanol (60 ml), 2-chloroacrylonitrile 2 (105 mmol) was added dropwise at 60° C., and the mixture was stirred under reflux for 8 hours. Then concentrated sulfuric acid (94 mmol) was added and the mixture was further heated for 6 hours. After cooling to room temperature the mixture was quenched with anhydrous sodium carbonate (105 mmol) and the solvent was removed under reduced pressure. The residue was treated with water (100 mL) and the product extracted with ethyl acetate (3*100 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography to give (28 mmol) of 2-(2-Ethyl-phenyl)-2H-pyrazol-3-ylamine 3. 1H NMR (300 MHz, CDCl3/TMS) δ 7.44-7.35 (m, 3H), 7.30-7.25 (m, 2H), 5.57 (d, J=2.1 Hz, 1H), 3.57 (br s, 2H), 2.49 (q, J=7.6 Hz, 2H), 1.10 (t, J=7.6 Hz, 3H), 13C NMR (75 MHz, CDCl3/TMS) δ 145.20, 142.60, 139.62, 135.93, 129.47, 129.41, 127.88, 126.55, 88.70, 24.04, 14.34.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=[O:20]>CO>[CH2:7]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:19]=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(C=O)cc1OCc1ccccc1

Procedure:
1.2 equivalents of K2CO3 and 1.2 equivalents of benzyl bromide are added to a suspension of 0.33 mol of 3-hydroxy-4-methoxybenzaldehyde in 400 ml of methanol. After 24 hours' reflux, the reaction mixture is filtered while hot and the organic phase is then evaporated off under reduced pressure. The isolated residue is taken up in 300 ml of chloroform and then washed with water. After extraction, drying and filtration, evaporating off the organic phase under reduced pressure allows the expected product to be isolated.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:21]2[CH:25]=[C:24]([C:26](=[O:29])[CH2:27][CH3:28])[N:23]([CH2:30][CH3:31])[CH:22]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=2)[N:7]=1.C(OCC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[NH2:5][C:6]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:21]2[CH:25]=[C:24]([C:26](=[O:29])[CH2:27][CH3:28])[N:23]([CH2:30][CH3:31])[CH:22]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[N:7]=1
Reactant: CCC(=O)c1cc(C2(c3cccc(OC)c3)N=C(N)N(C)C2=O)cn1CC
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(=O)c1cc(C2(c3cccc(O)c3)N=C(N)N(C)C2=O)cn1CC
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.2 %

Procedure:
Boron tribromide (1M in dichloromethane, 21 mL, 21.17 mmol) was added dropwise to a cold (−78° C.) suspension of 2-amino-5-(1-ethyl-5-propionyl-1-H-pyrrol-3-yl)-5-(3-methoxy-phenyl)-3-methyl-3,5-dihydro-imidazol-4-one (1.3 g, 3.52 mmol) in CH2Cl2. The mixture was allowed to warm to room temperature, stirred for 20 h, and poured slowly into cold (0° C.) ethyl ether, treated slowly with methanol over a 10 minute period, basified to pH 8 at 0° C. with saturated aqueous NaHCO3 and extracted with CHCl3. The combined CHCl3 extracts were washed with brine, dried over MgSO4 and evaporated to dryness. The resultant residue was purified by flash chromatography (ethyl acetate/methylene chloride/methyl alcohol/triethyl amine, 5/4.4/0.5/0.1) to give the title compound as a white solid (0.95 g, 72% yield), mp 101° C., 1H NMR (400 MHZ, DMSO-d6) δ 0.99 (t, 3H), 1.17 (t, 3H), 2.66-2.68 (q, 2H), 2.90 (s, 3H). 4.19-4.21 (q, 2H), 6.5 (bs, 2H), 6.55 (m, 1H), 6.84-6.88 (m, 3H), 7.01 (m, 2H), 9.21 (bs, 1H), MS m/e (M−H)− 353.1.
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:22]([CH:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][N:25]2C(OC(C)(C)C)=O)=[O:23])[CH3:20])=[CH:15][CH:14]=1)=[O:12]>>[CH3:31][C:28]1([CH3:30])[CH2:27][CH2:26][NH:25][CH:24]([C:22]([NH:21][C@H:19]([C:16]2[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=2)[CH3:20])=[O:23])[CH2:29]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2CC(C)(C)CCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2CC(C)(C)CCN2)cc1
Yield: 85.7 %

Procedure:
The title compound (D94) (150 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from tert-butyl 2-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-4,4-dimethylpiperidine-1-carboxylate (diastereoisomers mixture) (D59) (230 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]([C:13]([O:15]C)=[O:14])=[C:8]([C:9]([F:12])([F:11])[F:10])[C:4]=2[CH:3]=1.[Li+].[OH-]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][C:7]([C:13]([OH:15])=[O:14])=[C:8]([C:9]([F:12])([F:11])[F:10])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1sc2ccc(Cl)cc2c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1sc2ccc(Cl)cc2c1C(F)(F)F
Reaction time: 4 h

Procedure:
A mixture of compound 11e (390 mg, 1.33 mmol) and LiOH (159 mg, 6.65 mmol) in THF/MeOH/H2O (4/4/4 mL) was stirred for 4 h. The reaction was concentrated under reduced pressure and then water was added to the residue. The aqueous mixture was acidified with 1N HCl to pH˜4. A white precipitate was filtered and washed with water and Et2O. The crude product was dried under vacuum to give compound 11f which was used without purification.
Reaction SMILES: [NH2:1][CH:2]([CH:18]([CH3:20])[CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[NH:31][N:30]=[C:29]([C:32](O)=[O:33])[CH:28]=2)[CH:22]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH:2]([NH:1][C:32]([C:29]3[NH:30][N:31]=[C:27]([C:23]4[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=4)[CH:28]=3)=[O:33])[CH:18]([CH3:20])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc(-c2cccnc2)[nH]n1
Reactant: CC(C)C(N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(C)C(Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cccnc2)n[nH]1
Yield: 12 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 4-(1-(2-amino-3-methylbutyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.060 g; 0.21 mmol) and 5-(pyridin-3-yl)-1H-pyrazole-3-carboxylic acid (0.039 g; 0.21 mmol). The crude product was purified by flash chromatography using cyanocolumn and EtOAc/heptane as eluent. Yield 12%. 1H-NMR (400 MHz; MeOD): δ 1.14 (m, 6H), 1.95 (m, 1H), 4.35 (m, 2H), 4.55 (m, 1H), 6.71 (s, 1H), 7.02 (m, 1H), 7.53 (m, 1H), 7.72 (m, 3H), 7.95 (s, 1H), 8.25 (m, 1H), 8.54 (m, 1H), 8.88 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[CH3:13])=O.Cl.[CH3:15][C@H:16]1[CH2:21][NH:20][CH2:19][CH2:18][N:17]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][N:20]2[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:16]([CH3:15])[CH2:21]2)=[C:4]([CH3:13])[CH:5]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(C=O)c(C)c1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
D5 (326 mg, 1.8 mmol), 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate hydrochloride (436 mg, 1.8 mmol), triethylamine (0.282 mL, 2 mmol) and sodium triacetoxyborohydride (781 mg, 3.7 mmol) were stirred together in 1,2-DCE (15 mL) for 17 h. Saturated aqueous NaHCO3 was added and the reaction mixture stirred for 1 h. The organic layer was separated and washed with water and brine, then dried and concentrated. The crude product was purified by chromatography. Elution with 0-100% EtOAc/petroleum ether yielded the title compound as a colourless oil (573 mg). δH (CDCl3, 400 MHz) 7.28 (2H, m), 7.15 (2H, m), 4.17 (1H, br.s), 3.76 (1H, d), 3.36 (2H, s), 3.00 (1H, m), 2.70 (1H, d), 2.56 (1H, d), 2.36 (3H, s), 2.17 (4H, m), 1.95 (1H, m), 1.45 (9H, s), 1.18 (3H, d). MS (ES+): MH+ 362.3.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:11])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[CH3:17]I.Cl>CN(C)C=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH3:17])[N:3]=1
Reactant: Cc1cc2c(I)n[nH]c2cc1[N+](=O)[O-]
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(I)nn(C)c2cc1[N+](=O)[O-]
Yield: 36.2 %

Procedure:
The compound (16.1 g, 53.1 mmol) of step A was dissolved in N,N-dimethylformamide (200 ml), 60% sodium hydride (2.41 g, 60.3 mmol) was added under ice-cooling with stirring, and the mixture was stirred at 0° C. for 45 min. Then, methyl iodide (5.0 ml, 80.3 mmol) was added, and the mixture was stirred at the same temperature for 100 min. To the reaction mixture was added diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated. The obtained solid was purified by silica gel column chromatography (hexane:dichloromethane:ethyl acetate-10:1:1) to give the title compound (6.09 g, yield 36%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13].Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>CC#N>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[C:3]2[N:10]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[C:18](=[O:20])[NH:1][C:2]=2[CH:7]=1
Reactant: Cc1cc(C)c(NCC(=O)N(C)C)c(N)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1cc(C)c2c(c1)[nH]c(=O)n2CC(=O)N(C)C
Reaction time: 1 h

Procedure:
To a solution of N2-(2-amino-4,6-dimethylphenyl)-N1,N1-dimethylglycinamide from Step B (930 mg, 4.20 mmol) in CH3CN (20 mL) at 0° C. was added triphosgene (1.25 g, 4.20 mmol). The reaction mixture was stirred for 1 h, then quenched with H2O (50 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=248 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([C:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]2[CH:21]=O)=[O:14])=[C:11]([N+:27]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO.O1CCOCC1>[CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]2[C:13](=[O:14])[N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]3[CH:21]=[N:27][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)N2CCCC[C@@H]2C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OCc1ccccc1)N=C[C@H]1CCCCN1C2=O
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To (R)-1-(4-(benzyloxy)-5-methoxy-2-nitrobenzoyl)piperidine-2-carbaldehyde (1.0 g, 2.51 mmol) in a mixture solution of 25 ml of THF and 15 ml of water was added Na2S2O4 (3.0 g, 17.25 mmol). The mixture was stirred for 4 h, diluted with methanol and dioxane, evaporated and co-evaporated with dioxane (3×60 ml) to dryness. The solid was sonicated with a mixture of CH3OH/CH2Cl2 (1:1, 80 ml), filtered and evaporated to solid. The yield solid was dissolved in CH3OH (100 ml) and 0.4 ml of HCl (conc) was added. The mixture was stirred for 1 h, neutralized to pH 3.0 with 0.1 M NaHCO3, concentrated, and extracted with CH2Cl2 (4×60 ml), The organic layers were combined, washed with 1M NaHCO3/NaCl (conc.), dried over Na2SO4, filtered, evaporated and purified on SiO2 chromatography eluted with EtAc/CH2Cl2 (1:3) to afford 615 mg (70%) of the title product. 1H NMR (CDCl3), 7.81 (d, 1H, J=5.7 Hz), 7.38˜7.23 (m, 6H), 6.74 (s, 1H), 5.12 (dd, 2H, J=2.3, 21.8 Hz), 4.18 (m, 1H), 3.88 (d, 3H), 3.69 (m, 1H), 3.15 (m, 1H), 1.99 (m, 1H), 1.87 (m, 1H), 1.79˜1.65 (m, 4H); 13C NMR 167.76, 163.31, 150.72, 148.48, 140.09, 136.46, 128.87, 128.28, 127.53, 121.77, 111.01, 71.02, 56.41, 49.84, 39.93, 24.76, 23.21, 18.62; MS m/z+ 373.2 (M+Na), 391.2 (M+Na+H2O), 405.3 (M+Na+CH3OH).
Reaction SMILES: [CH2:1]1[O:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12]([NH2:15])[CH2:13][NH2:14]>C(O)C>[CH2:12]([NH:15][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][NH:14][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC1CO1
Reactant: NCCN
Solvent: CCO
Product: CCCCCCCCC(O)CNCCNCC(O)CCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-decene oxide (100 g.) and ethylenediamine (19.2 g.) and recrystallization of a portion (20 g.) of the resulting solid (45 g.) from ethanol gave N,N'-ethylenebis[2-hydroxydecylamine] (I: R= CH3 (CH2)7, R' = H, X= (CH2)2, Z= H) (13.6 g., m.p. 140.0°-145.8° C.).