Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.C(N1C=CN=C1)([N:29]1C=CN=C1)=O.CN(C1C=CC=CN=1)C.[OH-].[NH4+]>O>[C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=2)[CH2:7][C:8]([NH2:29])=[O:9])[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCOc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Agent: CN(C)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CCCOc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 36.4 %

Procedure:
To a stirred solution of 3-phthalimido-3(4-propoxyphenyl)propionic acid (1.41 g, 4.0 mmol) in 25 mL of under nitrogen was added carbonyldiimidazole (0.68 g, 4.2 mmol) followed by a catalytic amount of dimethylaminopyridine. The mixture was stirred for 45 minutes at room temperature. To the reaction mixture was then added concentrated ammonium hydroxide (0.29 mL, 4.4 mmol) and the reaction mixture was stirred for 30 minutes at room temperature. The mixture was then diluted with 10 mL of water and the tetrahydrofuran was removed in vacuo. The resulting slurry was filtered and the solid was washed with copious amounts of water. The solid was dried in vacuo (60° C., <1 mm) to afford 1.2 g of crude product. The crude product was purified by dissolving in 200 mL of ethyl acetate, stirring for 3 h and then concentrating to an 80 mL volume. The resulting slurry was filtered and the solid was washed with ethyl acetate (2×20 mL). The solid was air-dried to afford 0.513 g (36%) of 3-phthalimido-3-(4-propoxyphenyl)propionamide as a white powder: mp 109.5°-110.4° C.; 1H NMR (DMSO-d6, 250 MHz) δ7.85 (br s, 4H), 7.55 (br s, 1H), 7.33 (d, 2H, J=8 Hz), 6.75-7.00 (m, 3H), 5.69 (t, 1H, J=8 Hz), 3.88 (t, 2H, J=6 Hz), 3.10-3.30 (m, 2H), 1.60-1.80 (m, 2H), 0.95 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ171.2, 167.7, 158.0, 134.5, 131.23, 131.19, 128.4, 123.1, 114.3, 68.9, 49.9, 36.9, 22.0, 20.4, 10.4; Anal. Calcd. for C20N2O4 0.37 H2O. Theoretical: C, 66.90; H, 5.61; N, 7.80. Found: C, 66.90; H, 5.52; N, 7.75.
Reaction SMILES: N1C=CC=CC=1S[S:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH-:15][CH:16]=[CH:17][CH:18]=1)=[O:13].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24].C(S)[C@@H](O)[C@H](O)CS.CCN(CC)CC>CO>[SH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH-:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[CH-:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.[Fe+2:24]
Reactant: O=C(NCCSSc1ccccn1)c1ccc[cH-]1
Agent: [Fe+2]
Agent: O[C@H](CS)[C@H](O)CS
Agent: c1cc[cH-]c1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NCCS)c1ccc[cH-]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
To a solution of 12 (113 mg, 0.28 mmol) dissolved in 6 mL of MeOH was added DTT (438 mg, 2.8 mmol) and Et3N (79 mL, 0.57 mmol). The solution was stirred at room temperature for 18 h, followed by evaporation of the solvent. The residue was dissolved in 15 mL of EtOAc and rinsed with H2O (8×15 mL) to remove excess DTT. After drying over MgSO4 and concentrating, the residue was purified by flash chromatography (hexanes/EtOAc, 1:1, v/v) to afford 46 mg (57%) of 13. 1H NMR 400 MHz (CDCl3) d 6.16 (br s, 1H), 4.66 (t, J=1.8 Hz, 2H), 4.33 (t, J=1.8 Hz, 2H), 4.19 (s, 5H), 3.53 (q, J=6.4 Hz, 2H), 2.75 (m, 2H).
Reaction SMILES: C12BC(CCC1)CCC2.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[N:30]([S:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)(=[O:35])=[O:34])[CH:31]=[CH:32][C:25]=34)=[CH:22][N:21]([CH2:42][CH:43]=[CH2:44])[N:20]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11].[O:45]1CCCC1>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]4[N:30]([S:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)(=[O:35])=[O:34])[CH:31]=[CH:32][C:25]=34)=[CH:22][N:21]([CH2:42][CH2:43][CH2:44][OH:45])[N:20]=2)=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: C1CCOC1
Reactant: C=CCn1cc(-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: B1C2CCCC1CCC2
Product: O=[N+]([O-])c1ccc(-c2nn(CCCO)cc2-c2ccnc3c2ccn3S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 84 %

Procedure:
To a solution of 0.5M 9-borabicyclo[3.3.1]nonane in tetrahydrofuran (6.16 mL) cooled to 0° C. was added a solution of 4-[3-(4-nitrophenyl)-1-(2-propen-1-yl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.06 mmol) in tetrahydrofuran (14 mL). The reaction mixture was stirred at room temperature under an inert atmosphere for 4.5 h and then re-cooled to 0° C. followed by quenching with water (1.7 mL). After 15 minutes of stirring at 0° C., 6N aqueous sodium hydroxide (1.24 mL) was added dropwise followed by 30% aqueous hydrogen peroxide (0.865 mL). The reaction mixture was stirred for 1.5 h at 0° C., neutralized with 6N aqueous hydrochloric acid and concentrated in vacuo. Water (10 mL) was added to the residue and the solution extracted with ethyl acetate (3×15 mL), the combined organic layers dried over magnesium sulfate and concentrated in vacuo to afford the title compound (84%). ESMS [M+H]+: 504.2
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]=1Br.C(=O)([O-])O.[Na+].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:15]1([S:21][C:3]2[C:4](=[O:5])[NH:6][C:7](=[O:8])[C:2]=2[S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1NC(=O)C(Br)=C1Br
Reactant: Sc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C1NC(=O)C(Sc2ccccc2)=C1Sc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
To dibromomaleimide (80.0 mg, 0.3 mmol) and sodium hydrogencarbonate (130.2 mg, 1.6 mmol) in methanol (6 ml) was slowly added benzenethiol (66.6 μl, 0.7 mmol) in methanol (1 ml). The reaction was stirred for 15 min at RT. The solvent was removed in vacuo and the residual material was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, gradient elution from 9:1 to 7:3) to afford the desired product as bright yellow crystals (73 mg, 75%). λmax (50 mM sodium phosphate, pH 6.2, 40% MeCN, 2.5% DMF)/412 nm (ε/dm3 mol−1 cm−1 2245); 1H NMR (500 MHz, MeOD): δ=7.27-7.22 (m, 6H, Ar—H), 7.16-7.14 (m, 4H, Ar—H); 13C NMR (125 MHz, MeOD): δ=169.3 (C), 137.6 (C), 135.4 (C), 132.4 (CH), 130.1 (CH), 129.1 (CH); IR (solid, cm−1): 3285 (m), 3059 (w), 2924 (w), 1774 (m), 1715 (s); MS (CI) m/z, (%): 314 (M+H, 100), 206 (13), 111 (12); Mass calc. for C16H11O2NS2[H]: 314.0231. Found: 314.0309; m.p. 102-104° C. (Literature: 123-126° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[S:8][CH3:9].C[O-].[Na+].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20].Cl>C(OCC)C.C(OCC)(=O)C>[F:10][C:6]1[CH:5]=[C:4]([C:11](=[O:13])[CH2:12][C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])[CH:3]=[C:2]([F:1])[C:7]=1[S:8][CH3:9]
Reactant: CSc1c(F)cc(C(C)=O)cc1F
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CSc1c(F)cc(C(=O)CC(=O)C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-[3,5-difluoro-4-(methylthio)phenyl]ethanone (4.84 g, 23.9 mmol) was dissolved in diethyl ether (200 mL). Sodium methoxide (24 mL of 25% in methanol, 30 mmol) was added and stirred 10 min at ambient temperature. Ethyl trifluoroacetate (3.79 g, 23.9 mmol) was added. The solution was stirred for 1 hour then aqueous hydrochloric acid was added (100 mL, 1 M). The layers were separated and the organic layer collected. The organic layer was washed with water (2×100 mL), saturated ammonium chloride (2×200 mL) and dried over sodium sulfate. The solvent was removed in vacuo to afford a yellow oil. The 1-[3,5-difluoro-4-(methylthio)phenyl]-4,4,4-trifluorobutane-1,3-dione was isolated by crystallization from ethyl acetate and hexanes (5.50 g, 77%). 1H NMR (CDCl3/300 MHz) 7.49 (m, 2H), 6.50 (s, 1H), 2.62 (s, 3H). ESHRMS m/z 297.0012 (M+H+, Calcd 297.0009). Anal. Calcd for C11H7F5O2S: C, 44.30; H, 2.37; Found: C, 44.36; H, 2.26.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:16]=1.[O:17]1[CH2:19][CH:18]1[CH2:20][N:21]1[C:29]2[CH2:28][CH2:27][N:26]([C:30](=[O:32])[CH3:31])[CH2:25][C:24]=2[C:23]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[N:22]1>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:19][CH:18]([OH:17])[CH2:20][N:21]4[C:29]5[CH2:28][CH2:27][N:26]([C:30](=[O:32])[CH3:31])[CH2:25][C:24]=5[C:23]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=5)=[N:22]4)[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:16]=1
Reactant: Clc1ccc2oc(C3CCNCC3)nc2c1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: CCO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(c3nc4cc(Cl)ccc4o3)CC2)C1
Temperature: 60 °C
Yield: 96 %

Procedure:
A solution of 130 mg (0.55 mmol) of 5-chloro-2-piperidin-4-yl-benzooxazole was dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 156 mg (95%) of a white solid. MS (electrospray): exact mass calculated for C30H31ClF3N5O3, 601.21; m/z found, 602.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers):7.76 (d, J=8.41 Hz, 1H), 7.71 and 7.67 (A and B of AB quartet, J=8.41 Hz, 2H), 7.65-7.61 (m, 2H), 7.38 (d, J=8.61 Hz, 1H), 7.26 (dd, J=8.61, 1.96, 1H), 4.86 and 4.74 (A and B of AB quartet, J=15.65 Hz, 1H), 4.64 (br s, 1H), 4.24-4.10 (m, 2.3H), 4.07-3.97 (m, 1.7H), 3.89-3.67 (m, 2H), 3.06-3.00 (m, 1H), 3.00-2.90 (m, 2H), 2.90-2.74 (m, 2H), 2.51-2.38 (m, 3H), 2.25-2.10 (m, 2.3H), 2.20 (s, 1.5H), 2.15 (s, 1.5H), 2.06-1.83 (m, 2.7H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](Cl)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[F-:12].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([F:12])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(F)c(Cl)cc1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(F)c(F)cc1Cl
Temperature: 0 °C
Yield: 68.6 %

Procedure:
A mixture comprising 5.70 g (0.03 ) of 2,4-dichloro-5-fluorobenzonitrile, 3.48 g (0.06 mol) of spray dried KF and 30 ml of dimethylsulfoxide, was reacted at a temperature of from 140° to 150° C. for 3.5 hours in a glass reactor. After completion of the reaction, the mixture was poured into ice water (50 ml) and extracted with chloroform. The chloroform extract was washed five times with water and then dried. Then chloroform was distilled off. The residue was distilled under reduced pressure to obtain 3.57 g (yield: 68.6%) of 2-chloro-4,5-difluorobenzonitrile. Boiling point: 105°-107° C./37 mmHg; melting point: 35°-37° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.O1CCOCC1.C1COCC1.[Al]>O=[Mn]=O.CCOCC>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:20][CH3:21])[C:3]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=1
Reactant: COc1nc2ccc(C(O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: O=[Mn]=O
Agent: [Al]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1nc2ccc(C(=O)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a 100 mL flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (745 mg, 1.61 mmol, Intermediate 50: step b) was added 1,4-dioxane (36 mL) and THF (11 mL) to give a suspension at room temperature. Heating to approximately 45° C. formed a homogeneous solution. Then, activated MnO2 (719 mg, 8.3 mmol) was introduced and the mixture was heated to 80° C. in an aluminum heating mantle under an atmosphere of N2. After 2 hours, the mixture was filtered through a Celite® pad, rinsed with THF and concentrated to give a white solid. Trituration from Et2O gave the title compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.Br[CH2:12]CC#N.C(#N)CC.[CH3:20][C:21]([NH:23][CH2:24][CH2:25]C1C2C=C(OC)C=CC=2NC=1)=[O:22]>>[CH3:10][O:9][C:5]1[CH:4]=[C:3]([N:2]([CH3:12])[CH2:1][CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH3:20])[CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCBr
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reactant: CNc1cccc(OC)c1
Solvent: CCC#N
Product: COc1cccc(N(C)CCCNC(C)=O)c1

Procedure:
N-cyanoalkylation of N-methyl-3-methoxyaniline (3j) with 3-bromopropionitrile, followed by hydrogenation and N-acetylation of the intermediate propionitrile 4m [Yield (4m): 88%; oil; 1H-NMR (CDCl3): δ 2.57 (t, 2H), 3.02 (s, 3H), 3.70 (t, 2H), 3.80 (s, 3H), 6.25 (t, 1H), 6.31-6.38 (m, 2H), 7.18 (t, 1H)], according to the procedure previously described for the preparation of 5a, provided the title compound 5m. Yield (5m): 52%; oil. 1H-NMR (CDCl3): δ 1.80 (m, 2H), 1.95 (s, 3H), 2.91 (s, 3H), 3.24-3.40 (m, 4H), 3.80 (s, 3H), 5.60 (brs, 1H), 6.24-6.37 (m, 3H), 7.15 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.[Cl:22]C1C=C(C=C(C)C=1O)C#N.CC1(C)O[C@H](CO)CO1>>[Cl:22][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:19])[C:9]=1[O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:21])([CH3:1])[O:6]1)[C:13]([NH:15][OH:16])=[NH:14]
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: Cc1cc(C#N)cc(Cl)c1O
Agent: CC1(C)OC[C@@H](CO)O1
Product: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a colorless oil (1.39 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 3-chloro-4-hydroxy-5-methyl-benzonitrile and L-α,β-isopropylidene glycerol. LC-MS: tR=0.66 min, [M+H]+=314.96.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2].[Cl:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:26][CH2:25][O:24][CH2:23][CH2:22][Cl:21])[C:8]=1[CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCCl
Reaction time: 24 h
Yield: 72 %

Procedure:
A mixture of 6.0 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, 25 ml of bis(2-chloroethyl)ether and 2.2 g of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux. After 24 hours, 2 g of potassium iodide and 50 ml of anhydrous dimethylformamide were added and reflux was continued. After 50 hours, 2.2 g of potassium carbonate and 2 g of potassium iodide were added and after 77 hours, 2.0 g of potassium carbonate was added. After a total reflux time of 108 hours, the reaction mixture was concentrated in vacuo and the residue was purified by high pressure liquid chromatography using 25% ethyl acetate-hexane to give 5.96 g (72% yield) of [4-acetyl-3-[2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>ClCCl>[CH3:34][S:35]([O:26][CH2:25][CH2:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH2:8]3)=[CH:15][N:14]=2)=[CH:23][CH:22]=1)(=[O:37])=[O:36]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CCO)cc3)nc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CCOS(C)(=O)=O)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a solution of 2-(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)ethanol (354.1 mg, 1.002 mmol) in dichloromethane (14 ml) were added triethylamine (0.25 ml, 1.5 mmol) and methanesulfonyl chloride (0.116 ml, 1.67 mmol), and the mixture was stirred at room temperature for 45 mins. Water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness to give 2-(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)ethyl methanesulfonate (415.0 mg, yield 96.0%) as a slightly brown solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: CCOC(=O)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCCCCn1cnc(-c2ccccc2)c1

Procedure:
4-Phenylimidazole was treated with ethyl 8-bromooctanoate and potassium carbonate in butanone to give after work-up the title compound, m.p. 56°-57° C., Found: C, 72.8; H, 8.4; N, 9.0%; C19H26N2O2Requires: C, 72.6; H, 8.3;N, 8.9%
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[CH2:32][CH3:33]>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:31][CH2:32][CH3:33])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC)c1OCC1CC1
Temperature: 70 °C
Yield: 22.1 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.745 mmol) and propyl bromide (91 mg, 0.745 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-15% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 22%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]([OH:10])=[O:9])[N:6]=1.[C:19](OC(=O)C)(=[O:21])C.C(=O)(O)[O-].[Na+].Cl>C(O)=O>[CH:19]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:8]([OH:10])=[O:9])[N:6]=1)=[O:21]
Reactant: Nc1nc(C(=NOC2CCCCC2)C(=O)O)cs1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: O=CNc1nc(C(=NOC2CCCCC2)C(=O)O)cs1
Yield: 60.4 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 1.5 g.), acetic anhydride (2.27 g.) and formic acid (1.03 g.) were treated in a similar manner to that of Example F-(5), and the oil obtained was suspended in an aqueous solution of sodium bicarbonate. The suspension was adjusted to pH 3.5 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried and give 2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetic acid (syn isomer, 1.0 g.), mp. above 230° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=O)[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].B(F)(F)F.CCOCC.[BH4-].[Na+]>C1COCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:11][N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][CH2:23][OH:24])=[C:2]2[CH3:1])=[CH:14][CH:15]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CCO)c(C)n2Cc1ccc(Cl)cc1
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
A solution of indomethacin (10 g, 28 mmol) in THF (90 mL) was immersed in an ice bath to maintain an internal temperature of 10-15° C. To this solution was added BF3-Et2O (30 mL, 230 mmol) over 5 min, resulting in the formation of a precipitate. Sodium borohydride (4.2 g, 110 mmol) was added portionwise over 10 min resulting in vigorous effervescence. After gas evolution subsided the flask was stoppered and allowed to warm to room temperature. After 1 hour the pressure was vented through a needle. The heterogeneous mixture was stirred for 6 hours. The mixture was cooled in an ice bath and was quenched by adding saturated NaHCO3. To break the resultant emulsion the mixture was made acidic with 1N HCl and extracted with a 3:1 mixture of Et2O:Hexane (270 mL). The organic layer was washed with brine, dried over Na2SO4, and evaporated. The residue was taken up in a 3:1 mixture of hot Hex:EtOAc (80 mL). Upon cooling to room temperature, crystals began to form. Crystallization was completed by cooling to −20° C. The solid was removed by filtration, washed with cold 3:1 Hex:EtOAc (2×25), Hexane (1×25) and dried in vacuo. This gave the title compound (4.5 g, 49%) as a white solid. mp 113-115° C. 1H-NMR (300 MHz, CDCl3) δ 7.24 (d, J=8.4 Hz, 2H), 7.06 (d, J=9.1 Hz, 1H), 7.03 (d, J=3.5 Hz, 1H), 6.87 (d, J=8.3 Hz, 2H), 6.78 (dd, J=2.4 and 8.7 Hz, 1H), 5.23 (s, 2H), 3.86 (s, 3H), 3.84 (t, J=6.5 Hz, 2H), 2.99 (t, J=6.5 Hz, 2H), 2.29 (s, 3H); mass spectrum (API-TIS) m/z 330 (MH+). Anal calcd for C19H20ClNO2: C, 69.19; H, 6.11; N, 4.25; Cl, 10.75. Found: C, 68.98; H, 6.30; N, 4.08; Cl, 10.60.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][C:14]1[CH:30]=[CH:29][C:17]2[NH:18][C:19]([S:21][C:22]3[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=3)=[N:20][C:16]=2[CH:15]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1.C(N(CC)C(C)C)(C)C>C(O)C>[CH2:11]([O:10][C:8]([C:4]1[NH:5][CH:6]=[C:7]2[CH:27]([C:25]3[O:26][C:22]([S:21][C:19]4[NH:18][C:17]5[CH:29]=[CH:30][C:14]([CH3:13])=[CH:15][C:16]=5[N:20]=4)=[CH:23][CH:24]=3)[C:32]3[C:33](=[O:37])[CH2:34][CH2:35][CH2:36][C:31]=3[NH:2][C:3]=12)=[O:9])[CH3:12]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: Cc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(C)ccc3[nH]2)o1
Temperature: 20 °C
Reaction time: 0.19 h

Procedure:
774 μmol of 3-amino-2-ethoxycarbonylpyrrole hydrochloride, 774 μmol of 5-(5-Methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (obtained from step 1), 774 μmol of 1,3 cyclohexanedione and 400 μL of N,N-diisopropylethylamine in 3 mL of ethanol are poured into a flask suitable for microwave irradiation (Personal Chemistry model Emrys Optimizer instrument). The flask is locked then irradiation is performed at 100° C. during 700 seconds. After cooling down to 20° C., the reaction mixture is concentrated under reduced pressure. The residue is purified on silica gel (Analogix model Intelliflash 280 instrument, SiO2 75 g; Eluent EtOAc/cyclohexane; from 10/90 to 80/20. (v/v), rate: 25 mL/min). The fractions containing the expected compound are combined and concentrated under reduced pressure. The remaining oil is solubilized in 0.5 mL of dichloromethane (DCM) then crystallized by addition of small amounts of diisopropyloxide. 60 mg of solid were collected.