Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:26]3[CH:25]=[C:24]4[C:29](=[CH:28][CH:27]=3)[N:20]=[CH:21][CH:22]=[CH:23]4)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc2ncccc2c1
Yield: 9.9 %

Procedure:
Using the general method of Example 18, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.5 g, 1.96 mmol) was coupled with 6-quinolinecarboxylic acid (0.34 g, 1.96 mmol) to provide 0.08 g of N6-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl) butyl]-6-quinolinecarboxamide as a tan powder, m.p. 122-127° C. (foaming). 1H NMR (300 MHz, DMSO-d6) δ 8.98 (m, 1H), 8.73 (t, J=5.4 Hz, 1H), 8.43 (m, 2H), 8.23 (s,1H), 8.13-8.03 (m, 3H), 7.60 (m, 2H), 7.40 (m, 1H), 7.20 (m, 1H), 6.58 (broad s, 2H), 4.66 (t, J=6.7 Hz, 2H), 3.37 (m, 2H), 1.96 (m, 2H), 1.64 (m, 2H); MS (EI) m/e 410.1847 (410.1855 calcd for C24H22N6O).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:25][NH:24][N:23]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[C:22]3[N:21]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1C(F)(F)F
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: Cc1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)cc1C(F)(F)F
Yield: 57.8 %

Procedure:
Reaction of 1-(4-methyl-3-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (149 mg, 0.5 mmol), prepared from 4-methyl-3-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (122 mg, 58%). MS (ISP) 423.1 [(M+H)+]; mp 218° C.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]=O)[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH2:15][N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)[CH:11]=[C:10]([C:17]([NH:19][CH2:20][C:21]4[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=4[CH3:27])=[O:18])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C=O)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: CN1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(CN3CCN(C)CC3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-formyl-1H-indazole-4-carboxamide (0.1 g, 0.255 mmol) in methanol (2 mL) was added acetic acid (0.015 g, 0.255 mmol) and 1-methylpiperazine (0.077 g, 0.765 mmol) and stirred it at room temperature for 3 h. NaBH3CN (0.016 g, 0.255 mmol) was then added. The resulting reaction mixture was stirred at room temperature overnight. After completion of reaction, the solvent was removed under reduced pressure and water was added. Extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-indazole-4-carboxamide (0.027 g, 28.8%). LCMS: 477.25 (M+1)+; HPLC: 99.71% (@ 254 nm) (Rt; 4.649); 1H NMR (DMSO-d6, 400 MHz) δ 11.53 (s, 1H), 8.39 (t, 1H, J=4.8 Hz), 8.27 (s, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 5.89 (s, 1H), 5.19-5.14 (m, 1H), 4.35 (d, 2H, J=5.2 Hz), 3.58 (s, 2H), 2.39-2.33 (m, 8H), 2.21 (s, 3H), 2.12 (s, 3H), 2.07 (s, 3H), 2.00 (m, 2H), 1.99-1.96 (m, 2H), 1.91-1.86 (m, 2H), 1.69-1.68 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=O)[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:13]>>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:30]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1C
Yield: 26 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (0.17 g, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (0.2 g) to give 0.09 g (26%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:30].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:30])=[CH:7][N:6]=1
Reactant: N#Cc1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2Cl)nc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2Cl)nc1
Yield: 126.6 %

Procedure:
Using a similar method to Example 371, and using (±)-6-[2-chloro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile (step 2 above) (0.198 g, 0.508 mmol), potassium carbonate (0.0337 g, 0.244 mmol), and 30% hydrogen peroxide solution (aq) (0.180 mL, 1.59 mmol) in dimethylsulfoxide (5.0 mL) provides 0.126 g (61%) of the title compound as a yellowish syrup: high resolution mass spectrum (electrospray): m/z calc for C23H23ClN3O, 408.1479, found 408.1449; 1H NMR (methanol-d4): 8.61 (d, 1H, J=2.4 Hz), 8.32 (d, 1H, J=2.4, 8.8 Hz), 7.61 (d, 1H, J=2.0 Hz), 7.44 (dd, 1H, J=2.0, 8.3 Hz), 7.35-7.29 (m, 4H), 7.27 (d, 1H, J=8.3 Hz), 7.24-7.18 (m, 1H), 7.11 (d, 1H, J=8.8 Hz), 3.80 (d, 1H, J=13.2 Hz), 3.76 (d, 1H, J=13.2 Hz), 3.50-3.39 (m, 1H), 3.15 (dd, 1H, J=7.8, 9.3 Hz), 2.99-2.91 (m, 1H), 2.82 (td, 1H, J=6.3, 8.8 Hz), 2.60 (t, 1H, J=8.8 Hz), 2.45-2.34 (m, 1H), 2.03-1.92 (m, 1H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1>ClC1C=CC=CC=1Cl>[Cl:19][C:14]1[C:13]([N:12]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cccnc1Cl
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1c1cccnc1Cl
Temperature: 30 °C
Yield: 99 %

Procedure:
A stirred slurry containing 15 grams of phthalic anhydride, 13 grams of 3-amino-2-chloropyridine, one gram of toluenesulfonic acid and 200 ml. of o-dichlorobenzene was heated at reflux for 6 hours. During this heating period 100 ml. of solvent and 1.8 ml. of water were removed. After cooling to 30° C., 50 ml. of heptane and 10 ml. of water were added and stirring was continued. The solid was collected by filtration and air dried. A 99 percent yield of N-(2-chloro-3-pyridyl) phthalimide, m.p. 156°-7° C., was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13]O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].CN(C=O)C.S(Br)([Br:22])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][Br:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: OCc1ccc(OC(F)(F)F)c(Br)c1
Reactant: O=S(Br)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(CBr)cc1Br
Temperature: 23 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
To a solution of (3-bromo-4-(trifluoromethoxy)phenyl)methanol 19.1 (6.78 g, 25 mmol) in 30 mL of DCM, was added DMF (0.5 mL) and thionyl bromide (2 mL, 26 mmol). The mixture was stirred at 23° C. for 4 hours. DCM (120 mL) was added to the reaction mixture, and the resulting mixture was washed with aqueous saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give 19.2 (8.3 g, 99% yield) as a yellow oil, which was used directly in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.74 (1H, d, J=2.0 Hz), 7.38-7.53 (2H, m), 4.53 (2H, d, J=5.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[C:21]([C:25]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:29]=[C:28]([NH:30][C:31]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[N:15]=[CH:14][C:13](=[O:17])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:20])=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2F)cc1

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to afford the title compound as an off-white solid. Yield: 35 mg (42%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH2:42][F:43]>CN(C)C=O.C(OCC)(=O)C>[F:43][CH2:42][CH2:41][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:6][CH:7]=1
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(C)n(-c2ccc(OCCF)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 100 %

Procedure:
A solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g), potassium carbonate (0.48 g) and 1-bromo-2-fluoroethane (0.25 mL) in N,N-dimethylformamide (10 mL) was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.1 g, 100%) as a pale-yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[N:7]([CH3:14])[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[Na+].[I-].Cl[CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=1)=[O:28]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[N:7]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:24][CH2:25][NH:26][C:27]([NH:29][C:30]2[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[CH:31]=2)=[O:28])[CH2:10][CH2:9]1)[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(NC(=O)NCCCl)cc(C)n1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(N(C)C(=O)OC(C)(C)C)CC2)cc(C)n1
Temperature: 50 °C
Reaction time: 336 h

Procedure:
A suspension of methyl-piperidin-4-yl-carbamic acid tert-butyl ester (3.57 g, 16.7 mmol), NaHCO3 (6.7 g, 79 mmol), NaI (1.5 g, 10 mmol) and 1-(2-chloro-ethyl)-3-(2,6-dimethyl-pyridin-4-yl)-urea (Example D1, 2.14 g 9.4 mmol) in THF (30 mL) is stirred at 50° C. for 14 days. The mixture is quenched with Na2CO3 (50 mL) and extracted with CH2Cl2 (5×50 mL). The organic extracts are washed with sat. aq. Na2CO3 (30 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by FC to provide the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])[CH:4]=[N:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(CO)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(COS(C)(=O)=O)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a partial suspension of (1-methyl-1H-pyrazol-4-yl)methanol (75 mg, 0.67 mmol) in CH2Cl2 (4 mL) at 0° C. was added triethylamine (0.19 mL, 1.34 mmol) followed by methanesulfonyl chloride (57 μL, 0.74 mmol). The cloudy reaction mixture was stirred at 0° C. for 1 h then quenched with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated to give 110 mg of methanesulfonic acid 1-methyl-1H-pyrazol-4-ylmethyl ester a colorless oil which was used without further purification.
Reaction SMILES: Cl[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C)C=O>[N:16]([CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1)=[N+:17]=[N-:18]
Reactant: CC1(C)CC(Cl)c2cc(C#N)ccc2O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(N=[N+]=[N-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-chloro-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran(3g) and sodium azide (0.9g) in N,N-dimethylformamide (20 ml) was stirred for 3 days at room temperature. Water was added and the mixture extracted with ethyl acetate, the organic phase was separated and further washed with water, then dried over anhydrous sodium sulphate. Filtration and evaporation of the solvent in vacuo gave the title compound (3.03g) as a solid, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]([CH3:15])C(OCC)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:23]1CCC[CH2:24]1>>[CH3:16][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][CH2:15][CH2:24][OH:23]
Reactant: CCOC(=O)C(C)c1cnccc1N(C)C
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)c1ccncc1CCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the product of step iv) (2.6 g) in tetrahydrofuran (100 ml) was added lithium aluminium hydride (1.2 g) and the resulting suspension stirred for 4 hours at ambient temperature. Excess reducing agent was destroyed by the sequential addition of ethyl acetate, water, and conc. HCl. The mixture was then basified and extracted sequentially with ethyl acetate and dichloromethane. The organic extracts were combined, dried (PS paper and MgSO4) and evaporated to yield 4-dimethylamino-3-(3-hydroxypropyl)pyridine as a pale yellow oil (2.2 g), essentially pure by Tlc; NMR (d6DMSO) δ 1.6-1.8(2H,m): 2.65(2H,t); 2.8(6H,s); 3.5(2H,t); 4.5(1H,brs); 6.7(2H,d); 8.2(2H,d); m/e 181 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH3:9][O:10][CH:11]([O:15][CH3:16])[CH2:12][C:13]#[N:14]>CO>[OH:3][NH:2][C:13](=[NH:14])[CH2:12][CH:11]([O:15][CH3:16])[O:10][CH3:9]
Reactant: COC(CC#N)OC
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(CC(=N)NO)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of hydroxylamine monohydrochloride (3.2 g, 45.6 mmol) in MeOH (70 mL), NaHCO3 (3.8 g, 45.6 mmol) was added and stirred for 30 minutes at room temperature, and then a solution of 3,3-dimethoxypropanenitrile (5.0 g, 43.4 mmol) in MeOH (30 mL) was added dropwise thereto. The reaction mixture was stirred for 15 hours at 80° C. The mixture was allowed to cool to room temperature to filter off the salt produced, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100 g, CHCl3/MeOH=99/1 to 90/10) to obtain the title compound (4.5 g) (pale yellow oil).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)=[CH:24][N:23]=1.O>N1C=CC=CC=1>[S:1]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][C:33]([N:36]([CH3:38])[CH3:37])=[CH:32][CH:31]=2)=[CH:24][N:23]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)c1ccc(/C=C/c2ccc(OCCOCCOCCO)nc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc(/C=C/c3ccc(N(C)C)cc3)cn2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
Tosyl chloride (52 mg, 0.27 mmol) was added to a solution of compound 9 (43 mg, 0.116 mmol) in pyridine (5.0 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then warmed up to room temperature and stirred for 3 h. Water was added and reaction mixture was extracted with ethyl acetate. Organic layer was separated, washed with brine, dried over sodium sulfate and evaporated. The residue was purified by PTLC (4% MeOH in DCM as developing solvent) to give product 10 (25 mg, Yield: 41%): 1H NMR (200 MHz, CDCl3): δ.8.14 (1H, d, J=2.0 Hz), 7.76 (3H, m), 7.39 (2H, d, J=8.8 Hz), 7.32 (2H, d, J=8.0 Hz), 6.87 (2H, m), 6.75 (3H, m), 4.46 (2H, t, J=4.6 Hz), 4.16 (2H, t, J=4.8 Hz), 3.81 (2H, t, J=4.8 Hz), 3.66 (6H, m), 2.99 (6H, s), 2.43 (3H, s), HRMS (EI) m/z calcd. for [C28H34N2O6S]+ 526.2138.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[S:24][CH:25]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[N:22]=[C:23]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[S:24][CH:25]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.6 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionate (706 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 6 hours, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-pyrrolyl]propionic acid (619 mg, yield: 93%). This was recrystallized from ethanol-hexane. Melting point: 111–112° C.
Reaction SMILES: C([CH:8]([CH:10]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:18]([C:19]3[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=3[Cl:27])[C:12]=2[O:11]1)[NH2:9])C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>>[Cl:27][C:20]1[CH:21]=[C:22]([Cl:26])[CH:23]=[C:24]([Cl:25])[C:19]=1[C:18]1[C:12]2[O:11][CH:10]([CH2:8][NH:9][C:38](=[O:39])[O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:14][C:13]=2[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1ccccc1)C1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1)OCc1ccccc1
Yield: 86.8 %

Procedure:
Treatment of (±)-benzyl[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.83 g, 8.61 mmol) with diisopropylethylamine (1.67 g, 12.92 mmol) and benzyl chloroformate (1.76 g, 10.33 mmol) generally according to the procedure described for Intermediate 12 provided 3.46 g (87%) of (±)-benzyl {[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH:10]2[CH2:15][N:14](CC3C=CC=CC=3)[CH2:13][CH2:12][N:11]2CC2C=CC=CC=2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.O.[C].[Pd]>[C:1]1([CH2:7][C:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([CH:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)[OH:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(Cc1ccccc1)(Cc1ccccc1)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: OC(Cc1ccccc1)(Cc1ccccc1)C1CNCCN1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
α,α,1,4-Tetrakis(phenylmethyl)-2-piperazinemethanol (4.9 g, 10 mmol) was dissolved in ethanol/water (100 mL/5 mL). 10% Palladium carbon (0.49 g) was added thereto, and the mixture was stirred under hydrogen pressure (3.0 bar) at room temperature one whole day and night. The reaction system was filtered through a Celite, the Celite was washed with ethanol, and then the filtrate was concentrated under reduced pressure. The resulting crystals were washed with diethyl ether to obtain the title compound (2.8 g, yield 91%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][N:15]=[C:16]([C:20](=[O:22])[CH3:21])[C:17](=[O:19])[CH3:18])([CH3:6])([CH3:5])[CH3:4].[CH2:23]([O:30][CH2:31][C:32](Cl)=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C1COCC1>[CH2:23]([O:30][CH2:31][C:32](=[O:33])[CH2:21][C:20](=[O:22])[C:16](=[N:15][NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][C:3]([CH3:6])([CH3:4])[CH3:5])[C:17](=[O:19])[CH3:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)C(=NNc1ccccc1OC(C)(C)C)C(C)=O
Reactant: O=C(Cl)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(=NNc1ccccc1OC(C)(C)C)C(=O)CC(=O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
NaH (4.28 g) was suspended in THF (30 mL), and a solution of 3-[(2-tert-butoxyphenyl)hydrazono]pentane-2,4-dione (7.47 g) in THF (100 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 40 min, a solution of (benzyloxy)acetylchloride (5.55 mL) in THF (20 mL) was added at 0° C., and the mixture was stirred at 0° C. for 5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.58 g).