Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[CH:36]([N-]C(C)C)(C)C.[Li+].CI.P([O-])([O-])([O-])=O>C1COCC1>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([N:25]([CH3:36])[S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)N(C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 4.8 %

Procedure:
To a stirred solution of 2-ethyl-5,7-dimethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-3H-imidazo[4,5-b]pyridine (Example 1, 200 mg, 0.41 mmol) in THF (10 mL) was added dropwise a solution of lithium diisopropylamide (LDA) (2.0 N in heptane/hexane/ethylbenzene, 0.8 mL, 1.6 mmol) with ice-cooling over a period of 10 min. After completion of the addition, the stirring was continued for an additional 20 min at the same temperature. To the resulting mixture was added dropwise MeI (0.5 mL) at 0° C., and stirred at room temperature for 15 h. The mixture was poured into a solution of phosphate buffer (100 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (10:1) to give 10 mg (5%) of the title compound as a colorless oil: 1H-NMR (CDCl3) δ 7.64 (2H, d, J=8.3 Hz), 7.53–7.25 (7H, m), 6.89 (1H, s), 3.65–3.55 (2H, m), 3.14 (3H, s), 2.96 (2H, t, J=6.7 Hz), 2.82 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.50 (3H, s), 2.40 (3H, s), 1.25 (3H, t, J=7.6 Hz).
Reaction SMILES: Cl.[NH2:2][OH:3].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH:13]=O)[CH:6]=[CH:5]1>N1C=CC=CC=1>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH:13]=[N:2][OH:3])[CH:6]=[CH:5]1
Reactant: NO
Reactant: O=Cc1cccc2cc[nH]c12
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1cccc2cc[nH]c12
Reaction time: 1 h

Procedure:
Hydroxylamine hydrochloride (0.574 g) was added portionwise to a solution of 1H-indole-7-carbaldehyde (1 g) in pyridine (5 ml) at RT. The resulting solution was heated to reflux and kept at that temperature for 1 hour. The solvent was evaporated. Ethyl acetate (50 mL) was added and the resulting solution was washed with aqueous hydrochloric acid (0.5 M, 40 mL). The organic fraction was separated and dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 1H-indole-7-carbaldehyde oxime (D1) as a colorless oil which, upon standing, solidified to give a waxy solid (1.1 g). MS (ES): C9H8N2O requires 160; found 161.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([CH3:21])=[C:19]([Cl:22])[N:18]=[C:17](OS(C(F)(F)F)(=O)=O)[C:16]=1[N+:31]([O-:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[CH:52]=[CH:51][C:39]([CH2:40][NH:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)=[CH:38][CH:37]=1.C(N(CC)CC)C.C(OCC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14][C:15]1[C:20]([CH3:21])=[C:19]([Cl:22])[N:18]=[C:17]([N:41]([CH2:40][C:39]2[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:52][CH:51]=2)[CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:49][CH3:50])=[CH:47][CH:48]=2)[C:16]=1[N+:31]([O-:33])=[O:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Reactant: Cc1c(Cl)nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1NCCOCCNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(Cl)c(C)c(NCCOCCNC(=O)OC(C)(C)C)c2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
A solution of trifluoromethanesulfonic acid 4-[(2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl)amino]-6-chloro-5-methyl-3-nitropyridin-2-yl ester (14.3 g, 27.4 mmol), bis(4-methoxybenzyl)amine (7.00 g, 27.4 mmol), and triethylamine (3.82 mL, 27.4 mmol) in toluene (250 mL) was heated at 90° C. for two hours and then allowed to cool to room temperature overnight. Diethyl ether (300 mL) was added, and the solution was washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified twice by column chromatography on silica gel (eluting sequentially with 80:20 hexanes:ethyl acetate and 70:30 hexanes:ethyl acetate) to provide 8.73 g of {2-[2-(2-[bis{4-methoxybenzyl}amino]-6-chloro-5-methyl-3-nitropyridin-4-ylamino)ethoxy]ethyl}carbamic acid tert-butyl ester.
Reaction SMILES: C(C1C=CC(NCC([C:16]2[CH:25]=[CH:24][C:23]3[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=3[CH:17]=2)O)=CC=1)(OCC)=O.P([O-])([O-])O.[Na+].[Na+].C=O.[O:38]1[CH2:43][CH2:42]OCC1>>[CH3:27][C:22]1([CH3:26])[CH2:21][CH2:20][C:19]([CH3:28])([CH3:29])[C:18]2[CH:17]=[C:16]([CH:42]3[CH2:43][O:38]3)[CH:25]=[CH:24][C:23]1=2
Reactant: CCOC(=O)c1ccc(NCC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: C1COCCO1
Agent: C=O
Agent: [Na+]
Agent: [O-]P([O-])O
Product: CC1(C)CCC(C)(C)c2cc(C3CO3)ccc21

Procedure:
1.58 g (4 millimoles) of N-(4-carbethoxyphenyl)-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-aminoethanol were stirred with 20 ml of 1N sodium hydrogen phosphite solution and 2 ml (20 millimoles) of formalin solution in 20 ml of dioxane for 1 hour at 60° C. The mixture was then poured onto water and extracted with ether, and the organic phase was washed with 2N sodium hydroxide solution and water, dried over magnesium sulfate and evaporated down. Recrystallization from methanol gave 1.0 g of the title compound, RF =0.51 (thin layer chromatography, silica gel; 7:1 n-heptaneethyl acetate).
Reaction SMILES: Cl.[CH:2]1[C:14]2[CH:13]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[C:32]([O:36][C:37](=[O:43])[NH:38][CH2:39][CH2:40][CH:41]=O)([CH3:35])([CH3:34])[CH3:33].C([BH3-])#N.[Na+]>CO>[CH:2]1[C:14]2[CH:13]([CH2:15][O:16][C:17]([N:19]3[CH2:24][CH2:23][N:22]([CH2:41][CH2:40][CH2:39][NH:38][C:37]([O:36][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:43])[CH2:21][CH2:20]3)=[O:18])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCC=O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCN1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
Piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester hydrochloride (0.67 g, 1.93 mmole) was dissolved in methanol (5 ml), treated with diisopropylamine (0.34 m], 1.93 mmole) and allowed to stir at room temperature for 5 minutes. The product from Step 1 (0.50 g, 2.89 mmole) and sodium cyanoborohydride (133 mg, 2.12 mmole) were added and the mixture stirred under argon for 18 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1:1) to afford the title compound (0.71 g). 1H NMR (CDCl3) δ 7.78-7.75 (2H, d), 7.59-7.56 (2H, d), 7.41-7.31 (4H, m), 4.52-4.43 (2H, d), 4.27-4.20 (1H, t), 3.51-3.42 (4H, br m), 3.25-3.15 (2H, m), 2.45-2.35 (6H, m), 1.72-1.60 (2H, m), 1.45 (9H, s).
Reaction SMILES: [CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]([O:11]C)=[O:10])[CH:4]=1)=[O:2].[OH-].[Na+].Cl>CO>[CH:1]([C:3]1[N:7]([CH3:8])[CH:6]=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=1)=[O:2]
Reactant: COC(=O)c1cc(C=O)n(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C(=O)O)cc1C=O
Yield: 87.3 %

Procedure:
methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate (0.5 g) dissolved in methanol (5 ml) was treated with 10% aqueous sodium hydroxide (5 ml) at 50° C. for 2 hours. Reaction cooled, acidified with 10% aqueous hydrochloric acid, and extracted with ethyl acetate. Ethyl acetate layer dried, and concentrated to give pure desired acid (0.4 g).
Reaction SMILES: [OH-].[Na+].[C:3]([SH:7])([CH3:6])([CH3:5])[CH3:4].Cl[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1>CO>[Cl:16][C:11]1[CH:10]=[C:9]([CH2:4][C:3]([S:7][C:3]([CH3:6])([CH3:5])[CH2:4][C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=2)([CH3:6])[CH3:5])[CH:14]=[C:13]([Cl:15])[CH:12]=1
Reactant: Clc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Cc1cc(Cl)cc(Cl)c1)SC(C)(C)Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
To a solution of sodium hydroxide (120 mg, 3 mmol, in oil, 60% cont.) in anhydrous methanol (5 ml) was added tert-butyl mercaptan (0.406 ml). The mixture was stirred for 20 minutes at room temperature. The reaction mixture was concentrated dryness under reduced pressure. The obtained sodium isopropylmercaptan was dissolved in HMPT (2 ml). 1,3,5-trichlorobenzene (1) (1.8 g, 10 mmol) was added thereto. The mixture was stirred for 2 hours and 50 minutes at 80° C. The reaction mixture was poured into ice-water. The mixture was extracted with ethylacetate, washed with water, dried over sodium sulphate, filtrated and concentrated under reduced pressure. The obtained residue was chromatographed twice on silica gel (SiO2 15 g, elution: n-hexane) to yield the objective (4) (293 mg). Yield 41%.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)N1CCc2cc(N)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1CCc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.6 %

Procedure:
To a suspension of 1-acetyl-5-aminoindoline (130 mg, 0.74 mmol) in anhydrous THF (10 mL) was added LiAlH4 (42 mg, 1.11 mmol). The mixture was stirred at rt for 6 h, quenched with saturated NH4Cl and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulphate and concentrated in vacuo to give a purple residue (80 mg, 67%) that was used without further purification. 1H NMR (270 MHz, DMSO): δ 6.56 (1H, s, ArH), 6.47 (1H, d broad, J=8.1 Hz, ArH), 6.37 (1H, d, J=8.0 Hz, ArH), 3.29 (2H, s, NH2), 3.20 (2H, t, J=7.6 Hz, CH2), 3.02 (2H, q, J=6.9 Hz, CH2), 2.86 (2H, t, J=7.6 Hz, CH2), 1.17 (3H, t, J=6.9 Hz, CH3).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:11]([O:12][CH3:13])=[C:10]([C:14]2[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=2)[C:9]([N:23](COC)[S:24]([CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:26])=[O:25])=[N:8]1)(=O)C.C(O)(=O)C(O)=O>O.CO>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:10]3[C:9]([NH:23][S:24]([CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:26])=[O:25])=[N:8][N:7]([CH2:6][CH2:5][OH:4])[C:11]=3[O:12][CH3:13])=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: COCN(c1nn(CCOC(C)=O)c(OC)c1-c1ccc2c(c1)OCO2)S(=O)(=O)CCc1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: COc1c(-c2ccc3c(c2)OCO3)c(NS(=O)(=O)CCc2ccccc2)nn1CCO
Yield: 54.5 %

Procedure:
2-{4-(1,3-Benzodioxol-5-yl)-5-methoxy-3-[(methoxymethyl)(phenethylsulfonyl)amino]-1H-pyrazol-1-yl}ethyl acetate (Preparation 54) (70 mg), oxalic acid (200 mg) were dissolved in a mixture of water (2 ml) and methanol (2 ml) and refluxed for two days. The reaction was diluted with water (10 ml) and the mixture was then extracted with dichloromethane (3×8 ml). The combined organic fractions were dried over sodium sulfate, concentrated under reduced pressure to yield a pale yellow oil which was purified by column chromatography (Sep-Pak™, 10 g) eluted with dichloromethane:methanol (97:3) to yield the title compound as a colourless oil (32 mg).
Reaction SMILES: O[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][OH:15])[CH2:6][CH2:5][N:4]([CH3:7])[CH2:3]1.Cl>>[CH3:7][N:4]1[CH2:5][CH2:6][C:2]2([C:8]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:14][O:15]2)[CH2:3]1
Reactant: CN1CCC(O)(c2ccccc2CO)C1
Agent: Cl
Product: CN1CCC2(C1)OCc1ccccc12

Procedure:
Treatment of 3-hydroxy-3-(α-hydroxy-2-tolyl)-1-methylpyrrolidine with hydrochloric acid by the method described in Example 16d provides 1,3-dihydro-1'-methylspiro[isobenzofuran-1,3'-pyrrolidine].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([Cl:15])[CH:14]=1)=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[C:13]([Cl:15])[CH:14]=1)=[O:4]
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(Cl)cc2c1CC(C)(C)C(c1cccc(Br)c1)N2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1cc(Cl)cc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-7-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (1.2 g, 2.94 mmol), morpholine (1.3 mL, 14.7 mmol), copper(I) iodide (140 mg, 0.7 mmol), N,N-dimethylglycine hydrochloride (206 mg, 1.5 mmol) and potassium carbonate (1.2 g, 8.8 mmol) in dimethyl sulfoxide (15 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 7-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (973 mg, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C23H27ClN2O3 (M+H)+: 415.94, observed: 415.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.C(N(C(C)C)CC)(C)C.[CH3:50][C:51]([CH3:65])([CH3:64])[CH2:52][NH:53][CH2:54][C:55]([N:58]1[CH:62]=[C:61]([NH2:63])[N:60]=[CH:59]1)([CH3:57])[CH3:56]>CN(C=O)C.C(Cl)Cl>[CH3:50][C:51]([CH3:65])([CH3:64])[CH2:52][NH:53][CH2:54][C:55]([N:58]1[CH:62]=[C:61]([NH:63][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:60]=[CH:59]1)([CH3:56])[CH3:57]
Reactant: CC(C)(C)CNCC(C)(C)n1cnc(N)c1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CNCC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (1 equiv) derived from diasteromer #2 above, TPTU (1 equiv), diisopropylethylamine (2 equiv) in DMF followed by 1-[2-(2,2-dimethyl-propylamino)-1,1-dimethyl-ethyl]-1H-imidazol-4-ylamine (2 equiv) in methylene chloride. The reaction is stirred overnight at rt, quenched with aq. sodium bicarbonate, and extracted with methylene chloride. The solvent is dried, concentrated, and purified by silica gel chromatography to afford diastereomer #2 of the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.5, 26.4, 27.8, 28.2, 28.9, 29.8, 32.1, 36.6, 38.8, 52.8, 59.1, 60.9, 61.3, 63.0, 100.8, 101.0, 101.3, 104.5, 110.6, 110.8, 110.9, 131.2, 137.6, 139.8, 159.8, 172.4; MS m/z 490.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=1>C(OCC)(=O)C.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]2)=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2C#N)cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(N)cc2C#N)cn1
Yield: 79.9 %

Procedure:
2-(4-Methyl-imidazol-1-yl)-5-nitro-benzonitrile (650 mg, 2.84 mmol) dissolved in ethyl acetate (10 mL) was hydrogenated under an atmosphere of hydrogen at room temperature for 5 hours in the presence of 10% palladium on charcoal (150 mg). The catalyst was filtered off and washed with ethyl acetate. The solvent of the filtrate was evaporated under reduced pressure and dried to yield the title compound (450 mg, 80%) as a yellow solid. MS ISP (m/e): 199.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.72 (s, 1H), 7.23 (d, 1H), 7.10 (s, 1H), 6.96 (s, 1H), 6.91 (d, 1H), 2.15 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11](=O)[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8]C.C(O)(=O)C.Cl>O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[C:6]([CH3:10])[C:7]=1[OH:8]
Reactant: COc1c(C)cc(C(=O)CCC(=O)O)cc1C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(CCCC(=O)O)cc(C)c1O

Procedure:
A mixture of 4-(3,5-dimethyl-4-methoxyphenyl)-4-oxobutyric acid (13 g), zinc amalgam [prepared from zinc (15 g) and mercuric chloride (1.5 g)], glacial acetic acid (70 ml), water (70 ml) and concentrated hydrochloric acid (170 ml) was heated at reflux for 12 hr. The cooled mixture was filtered and the filtrate was poured into water (1 liter). The mixture was extracted with ethyl acetate and the organic fraction was washed four times with water. The dried (MgSO4) organic fraction was evaporated to give 4-(3,5-dimethyl-4-hydroxyphenyl)butyric acid as a pale yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.79-2.64 (6H,m); 2.22 (6H,s); 6.79 (2H,s); 7.6 (2H,brs).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:16]([O-])([O-])=O.[K+].[K+].IC.CC(O)=O.O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH:9]([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CC(=O)c1ccccc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CC(=O)O
Product: CCOC(=O)C(C)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 3-(2-fluorophenyl)-3-oxopropanoate (4.2 g, 20 mmol) in DMF (30 mL) at 0° C. was added K2CO3 (3.87 g, 28 mmol) portionwise and the mixture was stirred for 30 minutes. After this time iodomethane (1.49 mL, 24 mmol) was added and the reaction mixture was allowed to warm to rt for 2 h. After this time the reaction was treated with 50 mL AcOH/water (5 mL AcOH/45 mL water). The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over Mg2SO4, filtered and evaporated in vacuo to give ethyl 3-(2-fluorophenyl)-2-methyl-3-oxopropanoate. Observed some dimethyl product. Used as crude for the next step. Mass Spectrum (ESI) m/e=225 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=4)[C:11]=3[CH:25]=2)=[N:4][N:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:24]=[CH:23][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=4)[C:11]=3[CH:25]=2)=[N:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nnc(-c2ccc3occ(-c4ccc(CO)cc4)c3c2)o1
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
To a solution of methyl 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoate (408 mg, 1.22 mmol) in tetrahydrofuran (35 mL) was added lithium aluminum hydride (46.3 mg, 1.22 mmol) at room temperature, and the resulting mixture was stirred for 10 min. Sodium sulfate decahydrate (393 mg, 1.22 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from hexane/tetrahydrofuran to give the title compound (321 mg, yield 86%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:3](=[NH:20])[NH:4][C:5](=[O:19])[N:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:27]([N:4]1[C:3](=[NH:20])[C:2]([F:1])=[CH:7][N:6]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[C:5]1=[O:19])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)n2cc(F)c(=N)[nH]c2=O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2cc(F)c(=N)n(Cc3ccccc3)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 20 mL microwave vial, 5-fluoro-4-imino-1-(4-methoxyphenylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one (111 mg, 0.37 mmol) was stirred at room temperature in dimethyl formamide (3 mL) together with anhydrous potassium carbonate (210 mg, 0.55 mmol). Benzylbromide (89 μL, 0.75 mmol) was added. The reaction was capped and placed on a Biotage Initiator microwave reactor for 20 min at 130° C., with external IR-sensor temperature monitoring from the side of the vessel. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (EtOAc; 250 mL), and washed with water (H2O; 3×100 mL). The organic phase was dried over magnesium sulfate (MgSO4), filtered, and the solvent evaporated under reduced pressure. Purification by flash chromatography (SiO2, EtOAc/Hexanes gradient) afforded 3-benzyl-5-fluoro-4-imino-1-(4-methoxyphenylsulfonyl)-3,4-dihydropyrimidin-2(1H)-one as a pale yellow oil (15 mg; 11%): 1H NMR (400 MHz, CDCl3) δ 8.09-8.02 (m, 3H), 7.38-7.27 (m, 6H), 7.00-6.96 (m, 2H), 4.65 (d, J=5.7 Hz, 2H), 3.87 (s, 3H). ESIMS m/z 391 ([M+H]+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.[CH2:39]([O:45][C:46](Cl)=[O:47])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].O>ClCCl>[C:46](=[O:47])([O:45][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:31][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:6]4[C:3]5[CH:4]=[CH:5][S:1][C:2]=5[CH:9]=[CH:8][CH:7]=4)[CH2:15][CH2:14]3)=[CH:22][CH:23]=2)[N:28]=1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Reactant: CCCCCCOC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCOC(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2n1
Yield: 105.2 %

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) synthesized in the same manner as in WO2006/112464 (Example 1) in dichloromethane (20 ml) was added triethylamine (0.65 ml), with stirring under ice-cooling, hexylchloroformate (0.6 g) was added at room temperature overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl hexyl carbonate (1.09 g).