Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=S)Nc2cc3sc(C(C)(C)C)nc3cc2N2CCN(C)CC2)CC1

Procedure:
Using the procedure described in Example 1 by reaction of 2-tert-butyl-6-isothiocyanato-5-(4-methyl-piperazin-1-yl)benzothiazole with 4-methylpiperazine is obtained 2-tert-butyl-6[(4-methylpiperazin-1-yl)thiocarbonylamino]-5-(4-methyl-piperazin-1-yl)benzothiazole, melting at 190°-193°.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][C:17](=[CH2:20])[CH2:16][CH2:15]4)[C:11]3=[O:21])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:30])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:15][CH2:16][C:17]5([O:30][CH2:20]5)[CH2:18][CH2:19]4)[C:11]3=[O:21])=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C=C1CCC2(CC1)CCN(c1ccc(C3CC3)cc1)C2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCC1(CC2)CO1
Temperature: 25 °C

Procedure:
A solution of 0.251 g (0.89 mmol) 2-(4-cyclopropyl-phenyl)-8-methylene-2-aza-spiro[4.5]decan-1-one in 3 mL DCM was added at 0° C. to a solution of 0.157 g (0.91 mmol) m-chloroperbenzoic acid and 0.098 mg (1.1 mmol) NaHCO3 in 3 mL DCM and allowed to stir to room temperature and continued for another hour at room temperature. The mixture was poured onto water and extracted with DCM. The combined organic phases were dried with MgSO4, filtered and evaporated. The title compound (0.312 g) was used in the consecutive step without further purification. MS (m/e): 298.8 [MH+].
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].Cl.[CH3:12]O>>[O:1]([CH3:12])[C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: CO
Agent: Cl
Product: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
D-ribose (2.0 g) was dissolved in methanol (40 ml), to which was added 1N methanolic HCl solution (4 ml) and the mixture was allowed to stand at 5° C to produce methyl β-D-ribofuranoside. The compound formed was dissolved in pyridine (50 ml) and the solution was subjected to action of nitrobenzoyl chloride 8.2 g at room temperature. The solvent was distilled off and the residue was dissolved in chloroform. The solution was washed with saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and distilled to remove the solvent therefrom. Methyl 2,3,5-tri-O-(p-nitrobenzoyl)-β-D-ribofuranoside (4.2 g) thus obtained was dissolved in anhydrous dichloromethane (20 ml). To the solution was added acetic acid (20 ml) which had been saturated with hydrogen bromide under ice-cooling and the mixture was allowed to stand in the dark for 1 hour. The reaction solution was concentrated under a reduced pressure and the resulting sprupy concentrate was dissolved in dichloromethane. The solution was washed with a sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and distilled to remove the solvent therefrom. The residue was recrystallized from anhydrous benzene to obtain the titled compound. Yield 3.4 g.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:22][C@H:21]1[CH:33]1[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:35](=[O:45])[CH2:34]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(C)C=CC(S([N:55]=[N+:56]=[N-:57])(=O)=O)=CC=1.C[Si](Cl)(C)C>O1CCCC1>[N:55]([CH:34]1[CH:33]([C@@H:21]2[CH2:22][C@@H:23]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:24][N:20]2[C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:37][N:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:35]1=[O:45])=[N+:56]=[N-:57]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(C)(C)OC(=O)N1CC([C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)CC1=O
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC([C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)C(N=[N+]=[N-])C1=O
Reaction time: 0.75 h
Yield: 68.5 %

Procedure:
1.6M n-butyllithium (2.5 ml, 4 mmol) was dropwise added to a solution of diisopropylamine (0.64 ml, 4.6 mmol) in tetrahydrofuran (40 ml) under a nitrogen stream at -78° C., and the reaction solution was stirred for 45 minutes. A solution of (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(N-tert-butoxycarbonyl-2-pyrrolidon-4-yl)pyrrolidine (986 mg, 2 mmol, compound of Reference Example 5-1) in tetrahydrofuran (10 ml) was dropwise added to this solution, and the mixture was stirred at the same temperature for 2 hours. Then, p-toluenesulfonyl azide (945 mg, 4.8 mmol) was added thereto, and the mixture was stirred further for 1 hour. Then, trimethylsilyl chloride (1.29 ml, 10 mmol) was added to this reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. A saturated sodium hydrogen carbonate aqueous solution was added to the residue, and then the mixture was extracted with methylene chloride (50 ml). The organic layer was washed with a saturated sodium chloride aqueous solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, chloroform) to obtain (2S,4R)-2-(3-azido-N-tert-butoxycarbonyl-2-pyrrolidon-4-yl)-N-tert-butoxycarbonyl-4-(tert-butyldimethylsiloxy)pyrrolidine (720 mg, yield: 68.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1OC.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:14]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccccc1Br
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
60.6 g (324.2 mmol) of 2-bromoanisole was added dropwise to a dichloromethane solution (350 ml) containing 51.8 g (388.6 mmol) of aluminum chloride and 45.6 g (324.3 mmol) of benzoyl chloride which was cooled to 0° C. After addition, the resulting mixture was stirred for 2 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (21) as 61.3 g (210.7 mmol, yield of 75%) of a yellow solid.
Reaction SMILES: [CH:1]12[N:7]([S:8]([CH2:11][C:12]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH3:23])[C:15]([Br:24])=[CH:14][CH:13]=3)(=[O:10])=[O:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Na+].Br[C:27]1C=CC(CS([O-])(=O)=O)=C(C(OC)=O)C=1OC.C12NC(CC1)CCC2>>[CH:1]12[N:7]([S:8]([CH2:11][C:12]3[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH3:23])[C:15]([Br:24])=[CH:14][CH:13]=3)(=[O:9])=[O:10])[CH:4]([CH2:3][CH2:2]1)[CH2:27][CH2:5][CH2:6]2
Reactant: COC(=O)c1c(CS(=O)(=O)[O-])ccc(Br)c1OC
Reactant: COC(=O)c1c(CS(=O)(=O)N2C3CCC2CC3)ccc(Br)c1OC
Agent: C1CC2CCC(C1)N2
Agent: [Na+]
Product: COC(=O)c1c(CS(=O)(=O)N2C3CCCC2CC3)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 177, starting from methyl (4-bromo-3-methoxy-2-methoxycarbonylphenyl)-methanesulphonic acid sodium salt (Intermediate 148) and 8-azabicyclo[3.2.1]octane, as a white solid.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]([C:15](=[O:25])[NH:16][C:17]([C:22](=[O:24])[NH2:23])([CH3:21])[CH:18]([CH3:20])[CH3:19])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:4])[CH3:3].[CH3:27]O>>[CH3:27][O:12][C:11](=[O:13])[C:10]1[CH:14]=[C:6]([O:5][C:2](=[O:4])[CH3:3])[C:7]([CH3:26])=[N:8][C:9]=1[C:15](=[O:25])[NH:16][C:17]([C:22](=[O:24])[NH2:23])([CH3:21])[CH:18]([CH3:19])[CH3:20]
Reactant: CC(=O)Oc1cc(C(=O)O)c(C(=O)NC(C)(C(N)=O)C(C)C)nc1C
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(OC(C)=O)c(C)nc1C(=O)NC(C)(C(N)=O)C(C)C

Procedure:
Hydrochloric acid gas is led for 3 hours through a solution of 53 g (0.151 mol) 5-acetoxy-2-(1-carbamoyl-1,2-dimethylpropyl-carbamoyl)-6-methyl-nicotinic acid in 500 ml absolute methanol boiling under reflux. Then, the solvent is evaporated and the product is dried in a vacuum.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:11][S:12](O)(=[O:14])=[O:13]>C(Cl)Cl>[CH3:10][O:9][C:4]1[CH:5]=[C:6]([CH3:8])[C:7]([S:12]([Cl:11])(=[O:14])=[O:13])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1cc(C)cc(C)c1
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1

Procedure:
A solution of 3,5-dimethylanisole (102.5 g, 753 mmol) in DCM (1000 ml) was cooled to 0° C. A solution of chlorosulfonic acid (251 ml, 3763 mmol) in DCM (250 ml) was added dropwise to this solution. After a reaction time of 10 min, the reaction solution was added to an ice bath (1000 ml), and the phases were separated and extracted again with DCM (250 ml). The combined organic phases were washed with water (1000 ml) and saturated sodium chloride solution (1000 ml), dried over Na2SO4 and concentrated. The product was purified by column chromatography on silica gel (heptane/DCM 5:1). Yield: 63.5 g, 36%
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].[CH3:10][C:11]([CH3:13])=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:4]([CH:11]([CH3:13])[CH3:10])[CH3:5]
Reactant: CC(C)=O
Reactant: CNc1ccccc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)N(C)c1ccccc1Br
Reaction time: 72 h

Procedure:
To a solution of 2-bromo-N-methylaniline (2.07 g, 11.22 mmol), in dichloroethane (45 mL) was added acetone (1.31 g, 22.5 mmol), AcOH (4.04 g, 67.32 mmol) and Na(OAc)3BH (7.14 g, 33.66 mmol) sequentially at RT. The mixture was stirred for 72 h. The reaction was cooled with ice bath, and 2M NaOH (100 mL) was added slowly, then stirred for 5 min. The organic layer was separated, washed with brine dried and solvent removed. The crude product contained a mixture of 2:1 ratio of Compound 219 and starting material. This mixture was used as is in the next step.
Reaction SMILES: [S:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[C:4](=[O:14])[CH:3]=[CH:2]1.[CH:15](Br)([CH3:17])[CH3:16]>>[CH:15]([N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[C:13]2[S:1][CH:2]=[CH:3][C:4](=[O:14])[C:5]1=2)([CH3:17])[CH3:16]
Reactant: CC(C)Br
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Product: CC(C)n1c2ccccc2c2sccc(=O)c21

Procedure:
-- By the same method as described in Example 7, 4.8 g of thiopyrano[3,2-b]indol-4(5H)-one is alkylated with isopropyl bromide to give 2.4 g of product, mp 154°-6° C, after recrystallization from methylene chloride-hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.Cl.[O:11]=[C:12]1[C@@H:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:22][CH:23]=2)[CH2:15][CH2:14][N:13]1[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([N:31]2[CH2:32][CH2:33][CH:28]([N:13]3[CH2:14][CH2:15][C@H:16]([O:17][C:18]4[CH:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:22][CH:23]=4)[C:12]3=[O:11])[CH2:29][CH2:30]2)=[N:6][CH:7]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: COC(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(c4ncc(Cl)cc4F)CC3)C2=O)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
5-Chloro-2,3-difluoropyridine (0.20 g, 1.3 mmol) was added to a mixture of (S)-methyl 5-(2-oxo-1-(piperidin-4-yl)pyrrolidin-3-yloxy)picolinate hydrochloride (0.17 g, 0.44 mmol) and DIEA (0.38 mL, 2.2 mmol) in DMF (1.5 mL). The mixture was stirred at 100° C. overnight and then cooled to ambient temperature. The mixture was partitioned between saturated aqueous NH4Cl (20 mL) and EtOAc (50 mL). The organic phase was washed successively with water (20 mL), water (20 mL) and then brine (20 mL). The combined organic phases were dried over MgSO4, filtered and concentrated. The residue was purified on silica (eluting with EtOAc) to afford (S)-methyl 5-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)picolinate (0.17 g, 0.38 mmol, 86%).
Reaction SMILES: [O:1]1[C@@:15]23[C@:6]4([CH2:18][CH2:17][NH:16][C@@H:14]2[CH2:13][C:12]2[CH:11]=[CH:10][C:9]([O:19][CH3:20])=[CH:8][C:7]4=2)[CH2:5][CH2:4][CH2:3][CH:2]13.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:1][C@:15]12[C@@H:14]3[NH:16][CH2:17][CH2:18][C@:6]1([C:7]1[CH:8]=[C:9]([O:19][CH3:20])[CH:10]=[CH:11][C:12]=1[CH2:13]3)[CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: COc1ccc2c(c1)[C@@]13CCCC4O[C@@]41[C@@H](C2)NCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)NCC3

Procedure:
A solution of 800 mg. of the amine-epoxide (XX) in 10 ml. of tetrahydrofuran was added dropwise at room temperature, to a suspension of 50 mg. of lithium aluminum hydride in 5 ml. of dry tetrahydrofuran. After the addition had been completed, the reaction mixture was stirred and refluxed during fifteen minutes. Work up as usual yielded 700 mg. of an oil which was dissolved in ether and the resulting solution was filtered through a celitecharcoal mixture. The filtrate was treated with a saturated solution of hydrochloric acid in ether to yield 720 mg. of a white hydrochloride salt which after recrystallization from methanol melted at 243°-44° C.(dec.). The IR and NMR were consistent with the structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CCN(CC2)C1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[CH2:19][O:20][S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccoc2CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCc2occc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
4-(2-Hydroxymethylfuran-3-yl)piperidine-1-carboxylic acid t-butyl ester (0.3 g, 1.1 mmol, 1.0 eq.) was dissolved in DCM (5.7 mL). The mixture was cooled to 0° C. and DABCO (132 mg, 1.2 mmol, 1.1 eq.) was added, followed by TsCl (224 mg, 1.2 mmol, 1.1 eq.). The mixture was stirred at 0° C. for 90 minutes, then diluted with EtOAc (500 ml) and washed with water (2×250 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to yield the title compound (340 mg), which was used without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH2:8]Cl)(=[O:3])[CH3:2].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)[OH:22]>O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:10])[CH:8]=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)CCl
Reactant: O=S(=O)(O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(=O)OCC=C(C)C=O
Temperature: 35 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
Crude 1-acetoxy-4-chloro-3-methyl-2-butene (194 g, Purity: 83.8%, 1 mol) was added to hexamine (168 g, 1.2 mol)/water (1 liter), and the mixture was stirred at 35° C. for 4 hours and then separated into aqueous and organic layers. 1,2-Dichloroethane (1 liter) was added to the aqueous layer, and the mixture was subjected to reaction at 72° C. for 6 hours while adjusting the pH with 1N sulfuric acid. The 1,2-dichloroethane layer was separated, 1,2-dichloroethane (1 liter) was added to the aqueous layer, and the reaction was carried out again. The 1,2-dichloroethane layers were combined and concentrated. The residue was distilled under reduced pressure to give 4-acetoxy-2-methyl-2-buten-1-al (98 g, 69%). bp.0.2-0.3 mmHg: 58°-66° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:6]([CH3:27])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+].Cl>ClCCl.O1CCOCC1.O>[CH3:27][C:6]1[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[C:9]([CH3:10])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[N:7]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(C(O)Cc3ccccc3)cc2)c1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nn(Cc2ccc(C(=O)Cc3ccccc3)cc2)c(C)c1CC(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Oxidation: {1-[4-(1-Hydroxy-2-phenyl-ethyl)-benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-acetic acid methyl ester (intermediate 15.1.2, 100 mg, 0.26 mmol) was dissolved in 4 ml dichloromethane, cooled to 0° C. and Dess-Martin periodinane (135 mg, 0.32 mmol) was added to the solution. After warming to room temperature, the mixture was stirred for 3 h. The solvent was evaporated under reduced pressure. Saponification: The ester intermediate (70 mg, 0.19 mmol) was dissolved in 2 ml dioxane and aqueous NaOH solution (0.37 ml, 1 M). After stirring for 2.5 h at 60° C. and dilution with water, aqueous HCl solution (0.39 ml, 1 M) was added. The mixture was extracted with ethyl acetate, and the organic layer was dried with MgSO4 and evaporated under reduced pressure. The residue was purified by preparative reversed phase HPLC (gradient of methanol in water+0.1% NH3).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:12])[C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8].[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:41])[C:20]2[CH:25]=[N:24][C:23](S(C)(=O)=O)=[N:22][C:21]=2[N:30]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[CH:31]=1)=[O:17])[CH3:14].C(N(CC)CC)C>>[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:41])[C:20]2[CH:25]=[N:24][C:23]([NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[C:5]([N:4]([CH3:12])[CH3:3])[CH:6]=3)=[N:22][C:21]=2[N:30]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[CH2:37][CH2:36][CH2:35]3)[CH:31]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(N(C)C)c3)ncc2c1=O
Yield: 39 %

Procedure:
Using the procedure outlined in Example 1(g) the title compound was prepared from 3-dimethylaminoaniline dihydrochloride (7.6 mg, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(e) above, 15 mg, 0.036 mmol) at the presence of triethylamine (11 μL, 0.072 mmol). 6.6 mg of 2-(3-dimethylamino-phenylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a yellow solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.41 (br, 1H), 8.53 (s, 1H), 7.47 (br, 1H), 7.40 (d, 1H), 7.29 (s, 1H), 7.18 (d, 1H), 6.90 (m, 2H), 6.50 (m, 2H), 4.39 (q, 2H), 3.00 (m, 4H), 2.80 (s, 6H), 2.21 (m, 2H), 1.37 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H27N5O3: 470.21 (M+H), Found: 470.4.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)[OH:12])=[O:10])[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.N1C=CC=CC=1>O>[C:13]1([C:11]([C:9]([C:1]2[CH:2]=[CH:3][C:4]([O:5][CH3:6])=[CH:7][CH:8]=2)=[O:10])=[O:12])[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A reaction mixture was prepared containing 1.2 kg. of anisoin, 3 kg. of cupric sulfate pentahydrate, 4.9 l. of pyridine and 1.2 l. of water. The mixture was heated with stirring overnight at a temperature of about 85° C. The resulting green suspension was poured over 20 kg. of ice and the mixture stirred until the ice had dissolved. Anisil, formed in the above reaction was collected by filtration. The filter cake was washed thoroughly with water to remove all traces of copper sulfate. Yield of anisil was 1167 g. melting at 125°-127° C.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[O:3].S(Cl)(Cl)=O.[C:11]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])#[N:12]>CC(N(C)C)=O.CCOCC>[C:11]([C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:1](=[O:6])[C:2](=[O:3])[CH3:4])=[CH:15][C:14]=1[C:20]([F:21])([F:22])[F:23])#[N:12]
Reactant: CC(=O)C(=O)O
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CC(=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
Pyruvic acid (3.0 mL; 43 mmol) and thionyl chloride (3.1 mL; 43 mmol) were added simultaneously via syringes to a stirring solution of 4-cyano-3-trifluoromethyl-aniline (1.00 g; 5.38 mmol) in 20 mL of dry DMA at room temperature. After 10 minutes, the reaction mixture was diluted with ether and extracted 3 times with saturated NaHCO3 and 4 times with cold saturated brine. The organic layer was dried with MgSO4 and concentrated by rotary evaporation. The product was purified by silica gel chromatography (ethyl acetate/hexanes [1/1]). Yield 1.11 g (81%); mp 147-148° C.; MS (FAB+) 257 (M+1); 1H NMR δ 9.12 (s, 1H), 8.15 (s, 1 H), 8.01 (d, J=8.5), 7.84 (d, J=8.5, 1 H), 2.59 (s, 3 H); 13C NMR δ 195.66, 157.71, 140.29, 135.90, 134.2, 122.01, 121.85, 117.44, 115.12, 105.55,23.92; 19F NMR δ-62.76. IR: 3330, 3112, 3065, 1719, 1540. UV: λmax 214, 248, 288. Anal. Calculated for C11H7F3N2O2: C, 51.57; H, 2.75; N, 10.94. Found: C, 51.69; H, 2.81; N, 10.86.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19]O)[C:14]=1[CH3:21])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[CH2:1]([N:8]([CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][Cl:24])[C:14]=1[CH3:21])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(SCCN(C)Cc2ccccc2)ccnc1CO
Product: Cc1c(SCCN(C)Cc2ccccc2)ccnc1CCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Thionyl chloride (10 ml) was dropwise added to 4-(2-(N-benzyl-N-methylamino)ethylthio)-2-hydroxymethyl-3-methylpyridine (1.8 g) under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, thionyl chloride was distilled away. The residue was alkali-oversaturated with potassium carbonate and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 1.7 g of 4-(2-(N-benzyl-N-methylamino)ethylthio)-2-chloromethyl-3-methylpyridine. The product was added to ethanol (30 ml) containing a solution of 2-mercaptobenzimidazole (0.9 g) and sodium hydroxide (0.5 g) in water (10 ml) and the mixture was refluxed under heating for 7 hours. After the completion of the reaction, the ethanol was distilled away and water was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away. Acetone was added to the residue to allow crystallization. The obtained crystals were recrystallized from a mixed solvent of acetone-isopropyl ether to give 2-((4-(2-(N-benzyl-N-methylamino)ethylthio)-3-methyl-2-pyridyl)methylthio)-1H-benzimidazole as crystals, melting point 110°-112° C.