Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[PH2:11]([OH:13])=[O:12]>>[OH:10][C:8]([P:11]([OH:13])[OH:12])([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:9]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: O=[PH2]O
Product: Cc1ccc(C(C)(O)P(O)O)cc1
Temperature: 0 °C

Procedure:
A mixture of p-methylacetophenone (2.68 g. 0.02M) and hypophosphorous acid (90%, 1.45 g. 0.02M) is heated on a steam bath for 12 hours. The reaction mixture is poured into ice-water and the organic material is extracted with ethyl acetate. Evaporation and co-evaporation with toluene gives a white solid which is crystallised from chloroform/hexane. There is obtained 1-hydroxy-1-p-tolylethylphosphonous acid, m.p. 115° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[CH:13]=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.CCCCCC.CN(C)[CH:32]=[O:33]>O1CCCC1>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH:32]=[O:33])=[N:12][C:11]=2[CH:16]([CH3:18])[CH3:17])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)ncn2C)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C=O)n2C)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72 %

Procedure:
In 16 ml of dry tetrahydrofuran was dissolved 800 mg (3.1 mmol) of 5-(3,5-dimethylphenylthio)-4-isopropyl-1-methyl-1H-imidazole (X=Y=Me) (10). This solution was cooled to -78° C. and 2.2 ml of n-butyllithium-n-hexane (1.66 molar) was added dropwise under nitrogen. After 5 minutes, 680 mg (9.3 mmol) of dry N,N-dimethylformamide was added and the reaction was further conducted at the same temperature for 15 minutes. This reaction mixture was poured in ice-water and extracted with diethyl ether. The organic layer was washed with water and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:5) to provide 644 mg (yield 73%) of Compound I-6. mp 93 to 94° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Br[C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[C:4]([C:14]([C:16]([F:19])([F:18])[F:17])=[CH2:15])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: C=C(c1cc(F)c(F)c(F)c1)C(F)(F)F
Temperature: 75 °C

Procedure:
A mixture of (3,4,5-trifluorophenyl)boronic acid (0.5 g, 2.84 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (596 mg, 3.41 mmol, 1.2 eq), Na2CO3 (0.90 g, 8.52 mmol, 3 eq) and Pd(dppf)Cl2 (232 mg, 10% mol) in DME (20 mL) and water (2 mL) was heated at 70 to 80° C. for 2 h. The mixture was cooled to 0° C. with ice-water bath, and then used to next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH:17]([NH2:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.CCCCCC.C(=O)=O>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][C:7]([NH:20][CH:17]([CH3:19])[CH3:18])=[O:8])=[O:5]
Reactant: CC(C)N
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)N=C=O
Agent: O=C=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)NC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
2-Chloro-6-trimethylsilylbenzoyl isocyanate (1.3 g, 5 mmol) was dissolved in 40 mL toluene and isopropyl amine (1 g) added over a period of 30 seconds. After stirring 30 min, the solvent was removed to yield an oil. The oil was dissolved in hexane and cooled in dry ice to yield 1.2 g of crystals of the title compound. m.p. 113-116° C.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:32])[C@@H:15]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH-].[Li+].OO.S(S([O-])=O)([O-])=[O:38].[Na+].[Na+]>CO>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@H:15]([O:24][C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)[C:14]([OH:32])=[O:38])=[CH:22][CH:21]=1
Reactant: O=S([O-])S(=O)[O-]
Reactant: Cc1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(O[C@@H](Cc2ccc(O)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a suspension of (S)-4-benzyl-3-[(S)-3-(4-hydroxyphenyl)-2-(4-methylphenoxy)propionyl]oxazolidin-2-one (6.50 g) obtained from Reference example 20(d) in methanol (80 ml) was added dropwise a mixed solution of an aqueous solution of lithium hydroxide (1N, 37.7 ml) and an aqueous solution of hydrogen peroxide (31%, 4.14 ml). The reaction solution was stirred for 1 hour at room temperature, then an aqueous solution (20 ml) of sodium hydrosulfite (6.56 g) was added thereto followed by stirring for 1 hour, and the resulting reaction solution was concentrated under reduced pressure. To the residue was added an aqueous solution of sodium hydroxide (1N), then the resulting alkaline solution was washed with dichloromethane and acidified by addition of hydrochloric acid. Ethyl acetate was added thereto, and the resulting solution was stirred and partitioned between ethyl acetate and water. The separated ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized by addition of isopropyl ether and hexane to yield (S)-3-(4-hydroxyphenyl)-2-(4-methylphenoxy)propionic acid (3.38 g) as a white powder.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]#[C:25][C:26]([OH:28])=O)[CH2:19][CH2:18]1.[Br:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([NH2:47])[CH:45]=3)[N:40]=[CH:39][N:38]=2)[CH:33]=[CH:34][CH:35]=1>N1C=CC=CC=1.O1CCCC1>[Br:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([NH:47][C:26](=[O:28])[C:25]#[C:24][CH2:23][N:20]4[CH2:19][CH2:18][N:17]([CH3:16])[CH2:22][CH2:21]4)[CH:45]=3)[N:40]=[CH:39][N:38]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: CN1CCN(CC#CC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN1CCN(CC#CC(=O)Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
Isobutyl chloroformate (0.905 g, 6.6 mmol) and N-methylmorpholine (1.550 g, 15.3 mmol) were added to an ice cold solution of 1.900 g (10.71 mmol) of 4-(4-methyl-piperazin-1-yl)-but-2-ynoic acid in l50 mL of tetrahydrofuran under nitrogen. After stirring for 30 min, a solution of 1.500 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 12 mL of pyridine was added and the mixture was stirred for 2 hr at 0° C. The reaction was then quenched with ice water, then it was poured into saturated sodium bicarbonate, and the product was extracted with ethyl acetate. Chromatography of the extract on silica gel, eluting with methanol/ethyl acetate (30:70), gave 0.590 g of 4-(4-methyl-piperazin-1-yl) -but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide: mass spectrum (m/e): M+H 479.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>ClCCl>[Br:11][C:7]1[CH:8]=[C:9]([CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH2:6]
Reactant: [Br-]
Reactant: COc1cc(N)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(N)c(Br)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.6 %

Procedure:
To a solution of 3-methoxy-4-methyl-aniline (8.19 g, 59.71 mmol) in dichloromethane (200 mL), was added tetrabutylammonium tribromide (28.79 g, 59.71 mmol) and the reaction mixture was stirred at room temperature for 2.5 hrs. Aqueous NaHCO3 was added and the layers separated. The aqueous layer was further extracted with dichloromethane and the combined organics washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (20% ethyl acetate in hexane) to give 11.05 g of 2-bromo-5-methoxy-4-methyl-aniline (85% yield). 1H NMR (300 MHz; CDCl3): 2.09 (s, 3 H), 3.75 (s, 3 H), 3.95 (br s, 1 H), 6.27 (s, 1 H), 7.13 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].N.[CH:15](O)=O>C=O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([CH3:15])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2ccncc2c1
Reactant: O=CO
Agent: C=O
Agent: N
Product: CN1CCc2ccc([N+](=O)[O-])cc2C1

Procedure:
A solution of 4.00 g (18.7 mmol) of 7-nitroisoquinoline in 10 ml of formic acid and 17 ml of 38% aqueous formaldehyde was heated at reflux for 1 h. The reaction mixture was cooled, poured onto ice and basified with aqueous ammonia. The gummy residue which precipitated was extracted twice with methylene chloride. The dried (magnesium sulfate) organic phase was concentrated to give crude 7-nitro-2-methyl-1,2,3,4-tetrahydroisoquinoline as a thick oil. This oil was immediately taken up in ethanol (50 ml) and a solution of hydrochloric acid in ethanol was added until the solution was distinctly acidic to litmus. Ether was added to induce precipitation and the resulting solid was collected to give 3.99 g (93%) of the title compound as a yellow solid, m.p. 236-8° C. (dec).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[N:23]=[C:22]([C:24]([O:26]C)=[O:25])[CH:21]=[CH:20][CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-].[Na+].C(O)C.Cl>O.C(OCC)(=O)C>[CH3:12][CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([C:24]([OH:26])=[O:25])[N:23]=3)[N:17]=2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cccc(C(=O)OC)n3)cs2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOc1ccc(-c2nc(-c3cccc(C(=O)O)n3)cs2)cc1OCC
Reaction time: 4 h

Procedure:
First, methyl 6-[2-(3,4-diethoxyphenyl)thiazol-4-yl]pyridin-2-carboxylate (49 g; 127 mmol) and 10% sodium hydroxide (100 ml) were added to ethanol (1.4 L), and the obtained mixture was then stirred for 4 hours under heating to reflux. A majority of solvent was eliminated from the obtained solution, and water and ethyl acetate were then added to the residue for separation. The water layer obtained as a result of the separation was changed to acidic by addition of 10% hydrochloric acid, followed by extraction with ethyl acetate. Thereafter, the extract was quickly washed with a saturated sodium chloride aqueous solution, and was then dried over an excessive amount of magnesium sulfate. The obtained mixture was recrystallized from ethyl acetate, so as to obtain an anhydrous tetomilast type B crystal.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]([CH3:30])[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1.C(#N)C.N>ClCCl.C1CCCCC1.CO>[CH3:30][N:21]([CH3:20])[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3]
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CN(C)CCC1CCCCN1
Agent: N
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CC#N
Product: CN(C)CCC1CCCCN1C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 37 %

Procedure:
Prepared analogously to Example 1 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-(dimethylamino)ethyl]piperidine in a yield of 37% of theory. Colourless crystals, m.p. 188°-190° C. (from acetonitrile), Rf 0.6 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC; eluant: dichloromethane/cyclohexane/ methanol/conc. ammonia 68/15/15/2, v/v/v/v).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:48]1([NH:51][C:52]([C@@H:54]2[CH2:58][C@@H:57]([OH:59])[CH2:56][NH:55]2)=[O:53])[CH2:50][CH2:49]1>CN(C=O)C.C(Cl)Cl>[CH:48]1([NH:51][C:52]([C@@H:54]2[CH2:58][C@@H:57]([OH:59])[CH2:56][N:55]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])=[O:53])[CH2:50][CH2:49]1
Reactant: O=C(NC1CC1)[C@@H]1C[C@@H](O)CN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (232 mg, 0.46 mmol), HOBt (68 mg, 0.51 mmol) and EDC (105 mg, 0.55 mmol) in DMF (8 mL) was added (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide (excess) and TEA (0.95 mL, 0.6 mmol). The mixture was stirred at rt for 3 days. The reaction was diluted with DCM (200 mL), washed with NH4Cl, NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 92 mg of the titled compound. MS m/z 671 [M−1].
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)(=O)=O.[CH3:16][O:17][CH2:18][CH2:19][CH2:20][NH2:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][NH:21][CH2:20][CH2:19][CH2:18][O:17][CH3:16])=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)OCCCc1ccc(Br)cc1
Reactant: COCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCNCCCc1ccc(Br)cc1
Temperature: 85 °C

Procedure:
3-(4-bromophenyl)propyl methanesulfonate (418 g) and acetonitrile (2 L) were charged into reactor 1. 3-methoxypropylamine (305 g) and potassium carbonate (394 g) were added to reactor 1 and the mixture was warmed to 80-90° C. for 4-16 h. The mixture was analysed for completion (3-(4-bromophenyl)propyl methanesulfonate <0.5%). The reaction was cooled to 25° C. and the suspension was filtered to remove the white solids. The filtrate was concentrated to dryness on a rotary evaporator. The crude product from the rotary evaporator, MTBE (2 L) and water (1.5 L) were charged into reactor 2. After phase separation, the organic layer was collected and washed with 1N HCl (2 L) until pH=4-5. After phase separation, the aqueous phase was basified by 2.5N NaOH solution to pH=9-10 and the resulting aqueous solution was used in the next step without further treatment.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[C:2]([CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][N:4]=1
Reactant: COc1ccnc(OC)c1Br
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ccnc1OC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) yellow solution of commercially available 3-bromo-2,4-dimethoxypyridine (1.490 g; 6.83 mmol) in anh. THF (42 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (4.3 ml; 6.88 mmol). The resulting orange solution was further stirred at −78° C. for 10 min. A yellow solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (1.450 g; 6.21 mmol) in anh. THF (5 ml) was then added to the cooled reaction mixture, and stirring at −78° C. was continued for 65 min. The resulting orange reaction mixture was treated successively with aq. sat. NH4Cl (22 ml), Et2O (75 ml) and water (20 ml). The separated orange organic layer was then washed with brine (30 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded methyl 5-(2,4-dimethoxypyridin-3-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate as a yellow oil. LC-MS (conditions B): tR=0.75 min.; [M+H]+: 372.82 g/mol.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=O)C.C[Al](C)C.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:11][C:10]1[C:6]2[C:4](=[O:3])[N:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12][C:7]=2[NH:8][CH:9]=1
Reactant: CCOC(=O)c1c(C)c[nH]c1CCNCCN1CCCCC1
Agent: C[Al](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A stirred solution of 4-methyl-2-[2-(2-piperidin-1-yl-ethylamino)-ethyl]-1H-pyrrole-3-carb oxylic acid ethyl ester (3.07 g, 10 mmol) in toluene (50 ml) was added dropwise slowly with 2M trimethyl aluminum in toluene (10 ml, 20 mmol) under an argon atmosphere. The mixture was stirred for 1 hour at room temperature and heated to reflux for another 4 hours. The reaction mixture was cooled down to 0° C. in ice/water bath, added with cold water (50 ml) and stirred for 5 minutes. The mixture was adjusted to pH12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (40 ml×3). The combined organic extracts were washed with brine (15 ml), filtered through a pad of Celite. The filtrate was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (2.29 g) as a red oil which was used as such.
Reaction SMILES: [CH3:1]OC(=O)CC1C=CC=CC=1OCC1C=CC=CC=1.CC(C)([O-])C.[K+].[CH3:26][O:27][C:28](=[O:45])[CH:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:30].C([N-]C(C)C)(C)C.[Li+]>>[CH3:26][O:27][C:28](=[O:45])[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([CH3:1])[CH3:30]
Reactant: COC(=O)Cc1ccccc1OCc1ccccc1
Reactant: COC(=O)C(C)c1ccccc1OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC(C)[N-]C(C)C
Agent: [K+]
Product: COC(=O)C(C)(C)c1ccccc1OCc1ccccc1
Yield: 70 %

Procedure:
Using 2-benzyloxyphenylacetic acid methyl ester as a starting material and also using potassium t-butoxide as a base, the same procedure of Example la gave 2-(2-benzyloxyphenyl)propioic acid methyl ester. Using lithium diisopropylamide as a base, the resulting 2-(2-benzyloxyphenyl)propionic acid methyl ester was further treated as in Example la to give 4.72 g of the titled compound (yield, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]2=[O:20].[C:26]([O:29][CH2:30][CH2:31]Br)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O>[C:26]([O:29][CH2:30][CH2:31][N:11]1[C:12]2[C:7](=[CH:6][C:5]([CH2:4][C:3]3[CH:21]=[CH:22][CH:23]=[C:24]([Cl:25])[C:2]=3[Cl:1])=[CH:14][CH:13]=2)[C:8](=[O:20])[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10]1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)c1c[nH]c2ccc(Cc3cccc(Cl)c3Cl)cc2c1=O
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCOC(C)=O)c2ccc(Cc3cccc(Cl)c3Cl)cc2c1=O
Temperature: 80 °C
Yield: 92 %

Procedure:
Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate obtained in Step 3 (400 mg, 1.1 mmol) was suspended in dimethylformamide (DMF; 8 ml) and 2-bromoethyl acetate (152 μl, 1.4 mmol) and potassium carbonate (440 mg, 3.2 mmol) were added. The mixture was stirred with heating at 80° C. During the stirring, 2-bromoethyl acetate (152 μl, 1.4 mmol) was added twice and the mixture was stirred with heating at 80° C. for the total of 1.5 hrs. After allowing the mixture to cool, saturated aqueous ammonium chloride was added to the reaction solution, and the precipitate was collected by filtration, washed with water and vacuum-dried to give an object product (468 mg, yield 95%) as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[C@H:11]2[C@H:9]([O:10]2)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:6]1.[NH4+].[Cl-].[N-:18]=[N+:19]=[N-:20].[Na+].CCO>CN(C=O)C.CCO.O>[N:18]([C@@H:9]1[C@@H:11]([OH:10])[C@H:5]([O:4][CH2:3][O:2][CH3:1])[CH2:6][C:7]([C:12]([O:14][CH3:15])=[O:13])=[CH:8]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: COCO[C@@H]1CC(C(=O)OC)=C[C@H]2O[C@H]21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: COCO[C@@H]1CC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1O
Temperature: 25 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
To a solution of cyclic epoxy ester 14 (107 mg, 0.5 mmol) in DMF/EtOH/H2O (1:1:0.5 mL) were added NH4Cl (160.5 g, 3 mmol) and NaN3 (197.4 g, 3 mmol) at 0° C. The mixture was then stirred at 25° C. for 10 h. After completion of reaction (monitored by TLC), EtOH was removed by rotary evaporation. The remaining solution was extracted with EtOAc (100 mL×3). The combined organic layers were washed with, brine (20 mL×6) and dried (Na2SO4). After evaporation of the solvent, the residue was purified by chromatography (petroleum ether/ethyl acetate (7/3 v/v) to obtain compound 15.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH:15]=O)[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1.[CH3:30][S:31][CH2:32][CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>ClCCCl>[CH3:29][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:18])([CH3:17])[CH2:15][NH:34][CH2:33][CH2:32][S:31][CH3:30])[CH:11]=[CH:10][C:9]=2[NH:19][C:20]([C:22]2[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=2)=[O:21])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)C=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CSCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CSCCNCC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1,1-dimethyl-2-oxo-ethyl)-phenyl]-amide (as prepared in the previous step, 60.0 mg, 0.154 mmol) and 2-methylsulfanyl-ethylamine (84 mg, 0.92 mmol) in 2 mL of 1,2-dichloroethane was added sodium triacetoxyborohydride (49.0 mg, 0.231 mmol). After stirring at RT for 3 h, the mixture was treated with EtOAc (40 mL) and washed with aqueous saturated NaHCO3 (10 mL), H2O (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1-3% MeOH/DCM) to afford the title compound (45.0 mg, 63%) as a white solid. 1H-NMR (1:1 CD3OD/CDCl3; 400 MHz): δ 8.22 (d, 1H, J=8.6 Hz), 7.78 (s, 1H), 7.27 (dd, 1H, J=8.6, 2.0 Hz), 7.14 (d, 1H, J=2.0 Hz), 5.73 (m, 1H), 2.77 (s, 2H), 2.68 (t, 2H, J=6.3 Hz), 2.55 (t, 2H, J=6.3 Hz), 2.27 (m, 2H), 2.06 (m, 2H), 1.92 (s, 3H), 1.57 (t, 2H, J=6.3 Hz), 1.35 (s, 6H), 1.07 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H35N5OS, 466.3 (M+H). found 466.2.