Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][O:6][N:27]1[C:31](=[O:32])[C:30]2[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]1=[O:37]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CSCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 65.4 %

Procedure:
3-Methylsulfanyl-propan-1-ol (4.133 g, 38.92 mmol) was dissolved in THF (anhydrous, 100 mL). To this solution, triphenylphosphine (10.2 g, 38.92 mmol) and N-hydroxyphthalimide (6.4 mg, 38.92 mmol) were added and dissolved with stirring. Diisopropyl azodicarboxylate (8.5 mL, 42.812 mmol) was added dropwise thereto with cooling the reaction vessel in an ice-bath under nitrogen atmosphere. The reaction mixture was warmed to room temperature, and stirred for 5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and triturated with diethyl ether:hexane (1:1, about 100 ml) to precipitate triphenylphosphine oxide as a white solid, which was filtered off. The filtrate was concentrated under reduced pressure to give a yellow oily residue. The resultant yellow oil was purified by silica gel flash chromatography (BW300, Fuji Silysia Chemical, 20% ethyl acetate/hexane as an eluent) to give 2-(3-methylsulfanyl-propoxy)-isoindole-1,3-dione (6.4 g, 65%).
Reaction SMILES: Cl.[NH2:2]O.C(=O)(O)[O-].[Na+].O.[N:10]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[N:15]=[CH:14][C:13]=2[NH:12][CH:11]=1>C(O)C>[N:10]1[C:18]2[CH:17]=[C:16]([C:19](=[NH:2])[NH2:20])[N:15]=[CH:14][C:13]=2[NH:12][CH:11]=1
Reactant: NO
Reactant: N#Cc1cc2nc[nH]c2cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(N)c1cc2nc[nH]c2cn1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (27.2 mg, 0.39 mmol), sodium bicarbonate (49.4 mg, 0.59 mmol), and water (0.392 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(1R or S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (99 mg, 0.196 mmol), dissolved in ethanol (0.915 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-2-[(4aR,7aR)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N-hydroxy-3-[(1R or S)-1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C28H36ClN7O2 [M+H]+ 538. found 538.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[C:1]([N:23]1[CH2:24][CH2:25][CH:20]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=2)[CH2:21][CH2:22]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: Clc1ccc(C2CCNCC2)cc1
Product: CCCCCCC/C=C/C(=O)N1CCC(c2ccc(Cl)cc2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 4-(4-chlorophenyl)piperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([NH2:14])[CH2:10][CH2:11][CH2:12][CH3:13]>C(Cl)Cl>[CH2:9]([NH:14][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(=O)Cl
Reactant: CCCCCN
Solvent: ClCCl
Product: CCCCCNC(=O)CCCCC
Reaction time: 4 h

Procedure:
275 g of caproyl chloride are added dropwise within 30 minutes to a solution of 500 ml of n-pentylamine in 1.41 of methylene chloride while cooling with ice and stirring. After standing at room temperature for 4 hours the reaction solution is washed in succession with 11 of 0.1N HCl, 11 of 0.1N NaOH and 1.51 of NaCl solution. The organic phase is concentrated on a rotary evaporator and dried in a high vacuum and gives 370 g of a crystalline mass (98% of theory). M.p. 37° C.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].[Br:13]Br.Cl>C(Cl)(Cl)Cl>[Br:13][C:7]1[CH:8]=[C:4]([C:1](=[O:3])[CH3:2])[S:5][CH:6]=1
Reactant: BrBr
Reactant: CC(=O)c1cccs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(Br)cs1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
2-Acetylthiophene (21.6 ml, 0.20 mol) was dissolved in 200 ml CHCl3 at 0° C. AlCl3 (40 g, 0.30 mol) was added in small portions at such a rate as to maintain the temperature at 5-10° C. The reaction mixture was then cooled to 0° C. and bromine, Br2 (11.34 ml, 0.22 mol) was added quickly. The reaction mixture was refluxed for two hours, then was allowed to cool and was poured into a mixture of 400 ml ice water and 50 ml concentrated HCl and stirred for 30 minutes. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum. The crude product was distilled under vacuum to yield pure 4-bromo-2-acetylthiophene (27.6 g, 67%). MS (M−H)−: 204.85; 1H NMR (300 MHz, CDCl3) δ7.58 (1H, d, J=1.3 Hz), 7.53 (1H, d, J=1.3 Hz), 2.55 (3H, s).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([CH2:20][O:21][CH3:22])[NH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=[O:13])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([C:4]2[N:5]=[C:6]([CH2:20][O:21][CH3:22])[NH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([OH:14])=[O:13])[CH2:2][CH2:3]1
Reactant: COCc1nc(C2CC2)c(-c2cc(C(=O)OC)ccc2C)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCc1nc(C2CC2)c(-c2cc(C(=O)O)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Into a round-bottom flask, was placed a solution of methyl 3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoate (compound 4.8, 35 mg, 0.12 mmol) in methanol (5 mL), a solution of sodium hydroxide (9.6 mg, 0.24 mmol) in water (0.3 mL) was added to the reaction mixture. The resulting solution was stirred for 2 h at room temperature, then diluted with water (5 mL). Aqueous HCl (6 M) was carefully added to adjust the pH to 1-2 and the mixture was extracted with dichloromethane (4×10 mL). The combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure to yield the title compound as a yellow oil (30 mg, crude), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>CN(C)C=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.3 %

Procedure:
To a solution containing 4-bromoaniline (7.42 g, 0.0431 mol) and 2-bromoacetophenone (8.58 g, 0.0431 mol) in N,N-dimethylformamide (200 mL) N,N-diisopropylethylamine was added dropwise and the reaction mixture was stirred at ambient temperature for five hours. The solvent was removed under reduced pressure and the residue partitioned between dichloromethane (150 mL) and water (100 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was suspended in diethyl ether and the precipitate was collected by filtration and dried to yield 2-(4-bromoanilino)-1-phenyl-1-ethanone (10.03 g, 0.0346 mol) as an off-white solid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH:21][C@@H:22]([CH2:25][CH3:26])[CH2:23][OH:24])[S:19][CH:20]=2)=[CH:12][CH:11]=1>C(Cl)Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:17]=[C:18]([NH:21][C@@H:22]([CH2:25][CH3:26])[CH2:23][OH:24])[S:19][C:20]=2[Cl:1])=[CH:14][CH:15]=1
Reactant: CC[C@@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC[C@@H](CO)Nc1nc(-c2ccc(Br)cc2)c(Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
A solution of N-chlorosuccinimide (975.0 mg, 7.30 mmol) in 50 mL of methylene chloride was added under nitrogen at room temperature dropwise over 45 min to a solution of (2S)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}butan-1-ol (2.1611 g, 6.60 mmol), prepared in step 1 of Example 7, in 50 mL of methylene chloride. After the addition, the reaction was stirred at room temperature for 3 h. The reaction was poured directly onto a column of silica gel (230-400 mesh). Elution of the column with 5% ethyl acetate-methylene chloride to 15% ethyl acetate-methylene chloride gave (2S)-2-{[4-(4-bromophenyl)-5-chloro-1,3-thiazol-2-yl]amino}butan-1-ol (1.5371 g, 64%) as a yellow foam, MS (ES) m/z 358.8 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1.Cl.[NH2:23][OH:24]>N1C=CC=CC=1>[O:1]=[C:2]1[CH2:7][CH2:6][C:5](=[N:23][OH:24])[CH:4]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:3]1
Reactant: NO
Reactant: O=C1CCC(=O)C(C(c2ccccc2)c2ccccc2)N1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(=NO)C(C(c2ccccc2)c2ccccc2)N1
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To a stirred solution of 2,5-dioxo-6-benzhydrylpiperidine (15.35 gm, 55 mmole) in pyridine (150 ml) was added hydroxylamine hydrochloride (10.63 gm, 165 mmole) and the reaction mixture was stirred for 15 min. The reaction mixture was concentrated under vacuum, and the contents were poured into 1N HCl (250 ml). The aqueous phase was extracted with methylene chloride (2×300 ml) and dried (anhyd. magnesium sulfate). The methylene chloride was removed under vacuum to afford 2-oxo-5-oximino-6-benzhydrylpiperidine (10.62 gms, 65%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:23]=[C:24]=[O:25])(=O)=O>O1CCCC1>[C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:24]([NH2:23])=[O:25])[C:13](=[O:18])[CH2:12]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)N1C(=O)Cc2cc(C(=O)c3ccccc3)ccc21

Procedure:
A mixture of 10.1 g. (42 mmole) of 5-benzoyl-2-oxindole, 4.4 ml. (51 mmole) of chlorosulfonyl isocyanate and 300 ml. of tetrahydrofuran was stirred at room temperature for 6 hours, and then the solvent was removed by evaporation in vacuo. The residue was added to 150 ml. of glacial acetic acid and 300 ml. of water and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was cooled and the supernatant liquid was removed by decantation. The remaining gummy residue was triturated under acetonitrile to give a solid which was recovered by filtration and then recrystallized from a 1:1 mixture of n-propanol and acetonitrile. This gave 4.1 g. of the title compound as a solid, mp. 210°-211° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:30]I>C(Cl)Cl.N1C=CN=C1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][I:30])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Brc1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A solution of 2-(4-bromophenyl)ethanol (20.0 g, 100 mol) in CH2Cl2 (10 mL) was added dropwise to a solution of imidazole (22.4 mg, 0.33 mmol), PPh3 (33.3 g, 127 mmol), and I2 (32.5 g, 130 mmol) in CH2Cl2 (50 mL) at 0° C., and the reaction was warmed to room temperature and stirred overnight. The reaction mixture was washed with saturated aqueous sodium thiosulfate (2×50 mL), brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE) to yield 1-bromo-4-(2-iodoethyl)benzene (9.2, 22.7 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.13 (t, J=7.6 Hz, 2H), 3.32 (t, J=7.6 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([OH:19])=O)=[C:4]2[CH2:3]1.[CH:20]1([C:23](=[N:25]O)[NH2:24])[CH2:22][CH2:21]1>CN(C)C=O>[CH:20]1([C:23]2[N:25]=[C:17]([C:16]3[N:15]=[CH:14][N:5]4[C:6]5[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=5[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=34)[O:19][N:24]=2)[CH2:22][CH2:21]1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccccc2C1=O
Reactant: NC(=NO)C1CC1
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nc(C4CC4)no3)ncn2-c2ccccc2C1=O
Reaction time: 1 h

Procedure:
A mixture of 9.77 g (39 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, 40 ml of N,N-dimethylformamide and 6.48 g (40 mmol) of N,N'-carbonyldiimidazole is stirred at 100° for 1 hour. 4.01 g (40 mmol) of cyclopropanecarboxamidoxime are subsequently added thereto and the mixture is stirred at 100° for a further 4 hours. The mixture is then evaporated and the residue is heated to 115° for 4 hours with 100 ml of acetic acid. The solution is evaporated to dryness and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulphate and evaporated. By recrystallization from methylene chloride and ethyl acetate there is obtained 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 202°-203°.
Reaction SMILES: [I:1][C:2]1[C:14]2[C:15](=[O:19])[NH:16][C:17](=[O:18])[C:13]=2[C:12]2[C:11]3[CH:10]=[C:9]([O:20]C)[CH:8]=[CH:7][C:6]=3[NH:5][C:4]=2[CH:3]=1>O>[OH:20][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][C:4]3[CH:3]=[C:2]([I:1])[C:14]4[C:15](=[O:19])[NH:16][C:17](=[O:18])[C:13]=4[C:12]=3[C:11]=2[CH:10]=1
Reactant: COc1ccc2[nH]c3cc(I)c4c(c3c2c1)C(=O)NC4=O
Solvent: O
Product: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
Powdered 4-Iodo-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (0.50 g, 1.27 mmol) prepared as in example 6 was added in one portion to dry, freshly-prepared pyridine hydrochloride melt at 200° C. under a CaCl2 drying tube and the mixture was stirred at this temperature for 15 min. Water was added and the mixture was extracted with EtOAc. The EtOAc extracts were dried, the drying agent was removed and the solution was concentrated to dryness to give a solid which was chromatographed on silica. Elution with EtOAc gave 9-Hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (8) (0.43 g, 89%) as an orange powder; mp>350° C. 1H NMR δ [(CD3)2SO] 11.76 (br s, 1H), 11.24 (br s, 1H), 9.29 (br s, 1H), 8.27 (d, J=2.4 Hz, 1H), 8.13 (s, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.08 (dd, J=8.7, 2.4 Hz, 1H). Found: C, 44.90; H, 1.79; N, 7.14. C14H71N2O3 requires C, 44.47; H, 1.87; N, 7.40.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:20])=[C:8]([CH3:11])[C:7]=2[CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2occ(C)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COc1ccc2oc(C(=O)c3ccccc3)c(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a mixture of 5-methoxy-3-methyl-1-benzofuran (2.00 g) synthesized in Example A104(2), benzoyl chloride (1.68 mL) and nitromethane (20 mL) was added aluminum chloride (3.28 g), and the mixture was stirred at room temperature for 2 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) and further by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (2.03 g, 62%) as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:5]1([CH2:22][CH3:23])[CH2:20][CH2:19][N:8]2[C:9]3[C:14]([C:15]([CH3:16])=[C:7]2[C:6]1=[O:21])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3)[CH3:4]>C(O)C>[CH2:22]([C:5]1([CH2:3][CH3:4])[CH2:20][CH2:19][N:8]2[C:9]3[C:14]([C:15]([CH3:16])=[C:7]2[CH:6]1[OH:21])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3)[CH3:23]
Reactant: CCC1(CC)CCn2c(c(C)c3cc(OC)ccc32)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC1(CC)CCn2c(c(C)c3cc(OC)ccc32)C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
Sodium borohydride (380 mg, 10 mmol) was added portionwise to a solution of 8,8-diethyl-6,7,8,9-tetrahydro-2-methoxy-10-methylpyrido[1,2-a]indol-9-one (710 mg, 2.5 mmol) in ethanol (50 mL). The reaction mixture was stirred at 25° C. overnight. The solvent was evaporated in vacuo and the residue partitioned between 1% ammonium hydroxide (30 mL) and chloroform (40 mL). The separated organic layer was dried over MgSO4, filtered, and evaporated to afford 530 mg (74%) of the desired alcohol as a light amber oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([O:31][CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][C:45](Cl)=[O:46]>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][C:40]5[S:39][CH:43]=[CH:42][CH:41]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)=[CH:25][C:26]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(Cl)c(OCCN4CCCC4)c3)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc(Cl)c(OCCN4CCCC4)c3)n2)c1
Yield: 71 %

Procedure:
The title compound was prepared from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-chloro-3-{[2-(1-pyrrolidinyl)ethyl]oxy}phenyl)-2-pyrimidinamine and 2-thiopheneacetyl chloride using acylation conditions described in Example 1, Step F, and purification via column chromatography using a 0-20% gradient of EtOAc/MeOH w/NH4OH to generate the product in 71% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.7 (s, 4H) 3.8 (s, 3H) 4.0 (s, 3H) 6.5 (s, 1H) 6.9 (d, J=4.4 Hz, 2H) 7.1 (t, J=6.9 Hz, 2H) 7.2 (t, J=9.0 Hz, 2H) 7.4 (m, 3H) 7.5 (m, 2H) 7.7 (s, 2H) 7.9 (s, 1H) 8.2 (d, J=0.9 Hz, 1H) 8.4 (s, 1H) 8.8 (d, J=1.3 Hz, 1H) 9.7 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 650 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[S:8][C:4]=2[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:16](Cl)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>ClCCl>[C:16]([C:2]1[S:1][C:5]2[C:6]3[CH:11]=[CH:10][S:9][C:7]=3[S:8][C:4]=2[CH:3]=1)(=[O:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCC(=O)Cl
Reactant: c1cc2c(s1)sc1ccsc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCC(=O)c1cc2sc3sccc3c2s1
Yield: 62.8 %

Procedure:
Dithienothiophene 2 (R1=R2=R3=R4=H) (765 mg, 3.90 mmol) was dissolved in dry dichloromethane (35 cm3) and the solution was ice-cooled before AlCl3 (790 mg, 5.92 mmol) was added in one portion yielding a dark mixture. A solution of octanoyl chloride (1.00 g, 6.02 mmol) in dichloromethane (20 cm3) was added dropwise over a 20 minute period and the mixture was then allowed to stand at room temperature For a further thirty minutes. It was hen added to ice and the mixture was acidified with dilute hydrochloric acid (100 cm3). Additional dichloromethane (100 cm3) was added and the layers separated. The organic layer was washed with water, dried over MgSO4 and concentrated. Column Chromatography (hexane—30% dichloromethane/hexane) afforded 790 mg (63%) of the title compound. An analytical sample may be prepared by recrystallisation from a mixture of dichloromethane and methanol. Rf 0.31 (1:1 dichloromethane/hexane); m.p. 130-131° C.; 1H (250 MHz, CDCl1) δ0.89 (3H, t, J6.5, CH2CH3); 1.25 (8H, br s, CH2CH2CH2); 1.78 (2H, m, CH2CH2CO); 2.93 (2H, t, J7.5, CH2CO); 7.32 (1H, d, J5.0, Dt-H); 7.52 (1H, d, J5.0, Dt-H); 7.91 (1H, s, Dt-H); 13C (100 MHz, CDCl3) δ14.1; 22.6; 25.0; 29.1; 29.3; 30.9; 31.7; 39.0; 120.9; 125.5; 129.0; 141.4; 144.4; 144.9; 193.7; v (cm−1, KBr) 600, 702, 1191, 1364, 1466, 1493, 1644 (C=O), 2925; Calc. for C16H18S3O C: 59.6; H: 5.6; Found: C: 59.2; H: 5.6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][N:12]1[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]1=[O:20])([O-])=O>[Pd].O.CO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][N:12]1[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]1=[O:20]
Reactant: CCCC1CC(=O)N(CNc2ccccc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCC1CC(=O)N(CNc2ccccc2N)C1
Reaction time: 16 h

Procedure:
Palladium on charcoal (10% wt) was added to a solution of (2-nitrophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a28 (1 eq, 2.747 g, 9.905 mmol) and NH4CO2H (5 eq, 49.9 mmol, 3.123 g) in water and methanol (1/1 (v/v), 35 ml). The resulting slurry was kept under agitation during 16 hours at room temperature, then filtration over celite and evaporation of the crude mixture gave (2-aminophenyl){(2-oxo-4-propyl-pyrrolidin-1-yl)methyl}amine a29 (2.232 g, 91%).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[C:19]([OH:26])[CH:18]=2)=[CH:8][CH:7]=1)C.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([C:5](=[O:27])[C:4]([OH:28])=[O:3])=[CH:7][CH:8]=2)=[CH:18][C:19]=1[OH:26])(=[O:25])[CH3:24]
Reactant: CCOC(=O)C(=O)c1ccc(OCCCOc2ccc(C(C)=O)c(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)c1ccc(OCCCOc2ccc(C(=O)C(=O)O)cc2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
As in example 10, 4-[3-(4-acetyl-3-hydroxyphenoxy)propoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.7 g) in methanol (70 mL) was treated with a solution of sodium carbonate (0.42 g) in water and brought just to reflux temperature, then was allowed to cool to room temperature. After 1 hour, most of the methanol was removed in vacuo, then the mixture was diluted with water, acidified with 3N hydrochloric acid and extracted twice with dichloromethane-tetrahydrofuran (1:1). Evaporation of the dried (MgSO4) extracts and crystallization of the solid residue from dichlorornethane-hexane afforded 0.58 g of 4-[3-(4-acetyl-3-hydroxyphenoxy)propoxy]-alpha-oxobenzeneacetic acid, mp 133°-135° C.