Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.C[O:26][C:27]1[CH:28]=[C:29]([C:33]2[C:34]3[CH2:47][CH2:46][N:45]([C:48]4[CH:49]=[C:50]([N:54]([CH3:56])[CH3:55])[CH:51]=[CH:52][CH:53]=4)[C:35]=3[N:36]=[C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[N:38]=2)[CH:30]=[CH:31][CH:32]=1>>[CH3:55][N:54]([CH3:56])[C:50]1[CH:49]=[C:48]([N:45]2[C:35]3[N:36]=[C:37]([N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)[N:38]=[C:33]([C:29]4[CH:28]=[C:27]([OH:26])[CH:32]=[CH:31][CH:30]=4)[C:34]=3[CH2:47][CH2:46]2)[CH:53]=[CH:52][CH:51]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccc(N(C)C)c2)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: CN(C)c1cccc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 3-N,N-dimethylaminoaniline, {3-[4-(3-methoxy-phenyl)-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-dimethyl-amine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([NH:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[C:17]1=[O:34])(=[O:14])=[O:13])[CH:6]=[CH:5]2.[C:35](=O)([O-])[O-].[Na+].[Na+]>C=O.C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([N:21]([CH3:35])[CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[CH2:26][CH2:27]3)[C:17]1=[O:34])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C1[C@@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1NC1CCN(c2ccncc2)CC1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Solvent: O=CO
Product: CN(C1CCN(c2ccncc2)CC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O

Procedure:
(3S)-3-(6-Chloronaphthalene-2-sulfonylamino)-1-[1-(4-pyridyl)-4-piperidinylamino}-2-pyrrolidone (400 mg) was dissolved in a 37% aqueous solution of formaldehyde (11 ml) and formic acid (5 ml) and refluxed for 3 hours. The reaction mixture was cooled and made alkaline by adding an aqueous solution of sodium carbonate, extracted with dichloromethane, dried and concentrated. The residue was purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) and crystallized from dichloromethane to obtain the title compound (180 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])=[CH:5][CH:4]=1.[NH:20]([C:22]([C:24]1[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:25]=1)=[O:23])[NH2:21].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:21][NH:20][C:22]([C:24]3[S:28][C:27]([C:29]([O:31][CH3:32])=[O:30])=[CH:26][CH:25]=3)=[O:23])[CH3:17])[C:13]=2[OH:14])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(F)(F)F)cc3)c2O)s1
Yield: 72.6 %

Procedure:
From 2-(4-trifluoromethylphenyl)-3-hydroxy-4-methylcarbonylthiophene (57.3 mg, 0.2 mmol), methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (40.0 mg, 0.2 mmol) and tosylic acid monohydrate (11.4 mg, 0.06 mmol), 68.0 mg of the desired product was obtained in the same manner as in Synthetic Example 65 as a pale yellow solid (yield 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl.Cl[CH2:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH3:20]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:13][CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH3:20]
Reactant: CN1CCCC1CCCl
Reactant: Nc1cccc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC1CCOc1cccc(N)c1

Procedure:
3-aminophenol (0.74 g, 6.8 mmol) in DMF (10 ml) was added dropwise to 95% NaH (0.49 g, 20.4 mmol) in 10 ml DMF at 0° C., under nitrogen. The reaction was stirred until H2(g) evolution ceased. 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (1.25 g, 6.8 mmol) was then added portionwise. The mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with 1N NaOH (50 ml) and the desired product extracted into ether (3×50 ml). The combined ether layers were washed (2×50 ml) with water, dried over MgSO4, and evaporated to dryness in vacuo. The residue was purified on silica gel by flash chromatography using 2% TEA in ethyl acetate to give an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:11]2[CH2:16][C@@H:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]2)=[O:9])=[CH:6][N:5]=[C:4]2[CH:36]=[CH:37][S:38][C:3]=12.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][NH2:44].C(N(C(C)C)CC)(C)C.O>CC(O)C>[CH3:39][O:40][CH2:41][CH2:42][CH2:43][NH:44][C:2]1[C:7]([C:8]([N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:11]2[CH2:16][C@@H:15]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:14][N:13]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:12]2)=[O:9])=[CH:6][N:5]=[C:4]2[CH:36]=[CH:37][S:38][C:3]=12
Reactant: CC(C)CN(C(=O)c1cnc2ccsc2c1Cl)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(C)O
Product: COCCCNc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)cnc2ccsc12
Temperature: 60 °C
Reaction time: 12 h
Yield: 68.6 %

Procedure:
tert-Butyl (3S,5R)-3-{[(7-chlorothieno[3,2-b]pyridin-6-yl)carbonyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (120 mg), 3-methoxypropan-1-amine (113 mg) and diisopropylethylamine (0.22 ml) were dissolved in 2-propanol (5 ml), and the mixture was stirred at 60° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-methanol (1:0-9:1) was concentrated under reduced pressure to give the object compound (90 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(N(CC)CC)C.ClC(OCC)=O.[CH2:29]([C:36]1([OH:42])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][C:13]([N:39]1[CH2:38][CH2:37][C:36]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([OH:42])[CH2:41][CH2:40]1)=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: Cc1[nH]c2ccccc2c1CCC(=O)O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1[nH]c2ccccc2c1CCC(=O)N1CCC(O)(Cc2ccccc2)CC1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5.0 g of β-(2-methyl-3-indolyl)propionic acid and 2.5 g of triethylamine in 100 ml of chloroform was added dropwise 2.7 g of ethyl chloroformate at a temperature below 0° C. After the addition was complete, stirring was continued for additional 15 minutes and thereto was added 4.7 g of 4-benzyl-4-hydroxypiperidine in several portions. The reaction mixture was stirred for 4 hours at room temperature and allowed to stand overnight. The reaction product was washed thoroughly with water and concentrated to dryness. The residue was recrystallized from ethanol to give 1-[β-(2-methyl-3-indolyl)propionyl]-4-benzyl-4-hydroxypiperidine, melting at 117°-119° C.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[Cl:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][O:17][C:18]3[CH:33]=[CH:32][C:21]4[O:22][CH2:23][C:24]5[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=5[CH:26](O)[C:20]=4[CH:19]=3)=[N:13]2)=[CH:8][CH:7]=1>FC(F)(F)C(O)=O.C(Cl)Cl>[C:1]([S:3][CH:26]1[C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[CH2:23][O:22][C:21]2[CH:32]=[CH:33][C:18]([O:17][CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([Cl:5])=[CH:7][CH:8]=4)[N:13]=3)=[CH:19][C:20]1=2)(=[O:4])[CH3:2]
Reactant: CC(O)=S
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)SC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Temperature: 0 °C

Procedure:
Under ice cooling and stirring, 1.25 ml of thioacetic acid was added to 7.03 g of 2-(7-chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine obtained in Reference example 36 dissolved in a mixed solution of 58 ml of trifluoroacetic acid and 30 ml of methylene chloride and the mixture was stirred at the same temperature for 3 hours. 300 ml of ice water was added to the reaction mixture, crystals precipitated by neutralization with a 1N-sodium hydroxide aqueous solution were collected by filtration and these crystals were dissolved in methylene chloride. Then, this organic layer was washed with water and dried over anhydrous sodium sulfate and then the solvent was removed. The resulting residue was applied to silica gel column chromatography to obtain 4.6 g of the title compound as white powder.
Reaction SMILES: C[O-].[Na+].C(=O)(O)O.[NH2:8][C:9]([NH2:11])=[NH:10].C([O:14][C:15](=O)[C:16]([O:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=1[CH:30]([CH3:32])[CH3:31])=[CH:17]OC)C>CS(C)=O>[NH2:10][C:9]1[NH:11][C:15](=[O:14])[C:16]([O:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=2[CH:30]([CH3:32])[CH3:31])=[CH:17][N:8]=1
Reactant: CCOC(=O)C(=COC)Oc1cc(C)c(OC)cc1C(C)C
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(C(C)C)c(Oc2cnc(N)[nH]c2=O)cc1C
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 22 %

Procedure:
To a solution of NaOMe [prepared from sodium (0.05 g, 2.17 mmol) in anhydrous methanol (5 ml)], was added guanidine carbonate. After 5 minutes, a solution of 2-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-3-methoxy-acrylic acid ethyl ester (0.22 g, 0.713 mmol) in anhydrous DMSO (10 ml) was added. The mixture was heated at 120° C. for 3 hours and was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure. The residue was purified with silica gel chromatography (5% methanol in methylene chloride/0.1% concentrated NH4OH) to yield 2-amino-5-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-3H-pyrimidin-4-one as pale yellow solid (0.045 g, 22%). MS M+H=290.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCOCC>[OH:17][CH2:16][C:15]1[CH:14]=[C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a suspension of 100 mg of lithium aluminum hydride in 20 mL of ether was added 500 mg 3-phenylbenzoic acid. The reaction mixture was stirred at room temperature overnight. After any excess lithium aluminum hydride was destroyed with water, the organic layer was washed successively with 25 mL aliquots of dilute hydrochloric acid, dilute sodium hydroxide and brine. The organic phase was dried over anhydrous sodium sulfate and the solvent removed by evaporation under reduced pressure to yield 360 mg of 3-hydroxymethylbiphenyl as a crystalline solid. This material was used in the next step without further purification.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH:14]([P:19](=[O:22])([OH:21])[OH:20])[P:15](=[O:18])([OH:17])[OH:16].[OH-].[Na+:24]>O>[OH2:8].[Na+:24].[Na+:24].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH:14]([P:19](=[O:20])([O-:21])[O-:22])[P:15](=[O:16])([OH:17])[OH:18]
Reactant: O=P(O)(O)C(NCCCCOc1ccccn1)P(=O)(O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=P([O-])([O-])C(NCCCCOc1ccccn1)P(=O)(O)O
Yield: 62 %

Procedure:
4-(2-Pyridyloxy)butylaminomethylenebisphosphonic acid hydrochloride (2.0 g) was dissolved in water (50 ml), to which was added an aqueous solution of sodium hydroxide (1N, 15.9 ml). The reaction mixture was concentrated and then dissolved in water (50 ml). To the solution was added methanol to cause precipitation of a solid matter. The solid matter was collected by filtration and washed with methanol to give 4-(2-pyridyloxy)butylaminomethylenebisphosphonic acid disodium salt monohydrate (1.3 g, 62%) as colorless crystals, m.p.>300° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[O:3].[N:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1.[OH-].C[N+](C)(C)C.[OH-].[Na+]>CO>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:17][C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)=[CH:5][CH:6]=1
Reactant: O=Cc1ccncc1
Reactant: CC(=O)c1ccc(F)cc1
Agent: C[N+](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccncc1)c1ccc(F)cc1

Procedure:
The procedure is as in Example 11 starting from 2.9 g of 4-fluoroacetophenone and 3 g of pyridine-4-carbaldehyde, but using a solution of tetramethylammonium hydroxide in methanol instead of the aqueous solution of sodium hydroxide. 1-(4-fluorophenyl) 3-(4-pyridyl) 2-propene-1-one which melts at 157° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:14])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[CH:5]=[O:6].ClC1C=CC=C(C(OO)=[O:23])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:14])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[C:5]([OH:23])=[O:6]
Reactant: C#CCOc1c(F)cc(C=O)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C#CCOc1c(F)cc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 184.9 %

Procedure:
To 100 ml of chloroform were added 20 g of 3,5-difluoro-4-(2-propynyloxy)benzaldehyde and 25 g of 3-chloroperbenzoic acid and the mixture obtained was stirred at room temperature overnight. Then, aqueous sodium sulfite solution was added to the reaction mixture and extracted with chloroform and ethyl acetate in order. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure to obtain 40 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid.
Reaction SMILES: C([NH:4][C:5]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:8]2[O:9][C:10]([CH3:21])([CH3:20])[C@@H:11]([OH:19])[C@H:12]([N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[C:7]=2[CH:6]=1)(=O)C.Cl.C(O)C>O.[OH-].[Na+]>[NH2:4][C:5]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:8]2[O:9][C:10]([CH3:20])([CH3:21])[C@@H:11]([OH:19])[C@H:12]([N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[C:7]=2[CH:6]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H](O)[C@@H]2N1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)Oc2cc([N+](=O)[O-])c(N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Yield: 113.1 %

Procedure:
The compound of Example 1 (130 mg), 5N HCl (5 ml) and ethanol (9 ml) were heated under reflux for 3 h. After cooling, the reaction mixture was diluted with water and basified with dilute sodium hydroxide solution, extracted with ethyl acetate, and dried with anhydrous magnesium sulphate. Removal of drying agent and evaporation gave a red solid (130 mg). Recrystallisation from ethyl acetate-pentane gave the nitroamine (40 mg) as brick red crystals of m.p. 244°-245° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[O:26]([CH2:33][CH:34]=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:34][CH2:33][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=CCOc1ccccc1
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Product: CC1=C(CCON=CCOc2ccccc2)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with phenoxyacetaldehyde by the method of Example 1.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.ON1C2C=CC=CC=2N=N1.N=C=N.C(N(CC)C(C)C)(C)C.[CH3:51][O:52][CH2:53][CH2:54][O:55][CH2:56][C:57](O)=[O:58]>CN(C)C=O>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:57](=[O:58])[CH2:56][O:55][CH2:54][CH2:53][O:52][CH3:51])[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Reactant: COCCOCC(=O)O
Agent: Cl
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCC(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (138.0 mg, 0.2984 mmol), 1-hydroxybenzotriazole (40.8 mg, 0.302 mmol), and PS-Carbodiimide (1.37 mmol/g loading; 873 mg, 1.20 mmol) in anhydrous N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (260 μL, 1.5 mmol) was added. A small amount of sonication was used to get majority of solid into solution. 2-(2-Methoxyethoxy)acetic acid (45.7 mg, 0.334 mmol) in anhydrous DMF (1 mL) was added, and the reaction was vigorously shaken at rt for 5.5 h. An additional 0.2 eq of 2-(2-methoxyethoxy)acetic acid (8.1 mg, 0.060 mmol) in anhydrous N,N-dimethylformamide (0.5 mL) was added (after 7 h), and the reaction was shaken overnight at rt. The resin was filtered off (M-size frit) and rinsed several times with DMF. The filtrate was concentrated in vacuo at medium temp (bath temp: max 43° C.), redissolved in MeOH and DCM, and concentrated again under reduced pressure. The crude material was adsorbed onto Hydromatrix, dry loaded, and purified by chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with MeOH:DCM 2%→5%→10%]. Fractions containing product were combined and concentrated in vacuo, affording the title compound, as an off-white solid. The material was further purified by trituration in MeOH/sonication, affording the title compound, as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ=2.36-2.56 (s, br, rotamers, 2H), 3.19 (s, 3H), 2.38-2.45 (m, 2H), 3.49-3.55 (m, 2H), 3.58 & 3.64 (t, J=5.2 Hz, rotamers, 2H), 4.08 & 4.10 (s, br, rotamers, 2H), 4.14 & 4.18 (s, rotamers, 2H), 6.37 (s, br, 1H), 6.77 & 6.78 (s, rotamers, 1H), 7.80 (dd, J=8.8, 2.0 Hz, 1H), 7.97 (d, J=8.8 Hz, 1H), 8.28 (s, 1H), 8.85 (s, 1H), 9.17 (s, 1H), 9.54 (s, —NH), 11.95 (d, J=9.2 Hz, —NH). MS (ES+): m/z 465.01 (100) [MH+]. HPLC: tR=2.24 min (ZQ2000, polar—5 min).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[Br:43][C:44]1[C:45]([CH3:53])=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47](O)=[O:48]>C(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Br:43][C:44]1[C:45]([CH3:53])=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:48]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: COC(=O)CCCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: COC(=O)CCCCCNC(=O)c1cccc(Br)c1C
Reaction time: 24 h
Yield: 31.2 %

Procedure:
1.27 g of methyl 6-aminohexanoate hydrochloride (6.98 mmol) was dissolved in 25 ml of CH2Cl2 with stirring. 941 mg of triethylamine (9.3 mmol, 1.3 ml) was added to the mixture, and dicyclohexylcarbodiimide (DCC; 1.15 g, 5.58 mmol), dimethylaminopyridine (DMAP; 56.8 mg, 10 mol %), and 3-bromo-2-methylbenzoic acid (1.00 g, 4.65 mmol) was added thereto and stirred under a nitrogen atmosphere. After 24 hrs, the resulting mixture was subjected to thin layer chromatography to monitor the amount of the starting materials consumed, and the reaction was terminated by adding H2O thereto and extracted with CH2Cl2. The separated organic layer was dried over MgSO4 and removed the solvent under a reduced pressure. The residue thus obtained was subjected to a column chromatography (hexane:ethyl acetate=1:1, v/v) to obtain the title compound (497 mg, 31%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].[N+](N[C:24]1[NH:29][C:28](=[O:30])[C:27]([CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[CH:26][N:25]=1)([O-])=O>N1C=CC=CC=1>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:24]1[NH:29][C:28](=[O:30])[C:27]([CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[CH:26][N:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: NCCCN(Cc1ccccc1Cl)c1ccccn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCN(Cc3ccccc3Cl)c3ccccn3)[nH]c2=O)cn1

Procedure:
2-[N-(3-aminopropyl)-N-(2-chlorobenzyl)amino]pyridine (1 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (0.78 g) were heated together under reflux in pyridine (10 ml) for 20 hr. After stripping, the residue was triturated with ether and recrystallised twice from ethanol/water to give 2-[3-[N-(2-chlorobenzyl)-N-pyrid-2-ylamino]propylamino]-5-(6-methylpyrid-3-ylmethyl)-pyrimid-4-one 0.4H2O, 0.34 g (20%) mp softens 94°-102° C. melts 120°-26° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:13])[C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:4]1[C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([CH:14]=[CH2:15])[CH:3]=1
Reactant: N#CC1(c2ncc(Br)cc2Cl)CC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cnc(C2(C#N)CC2)c(Cl)c1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
4.7 g of 1-(5-Bromo-3-chloro-pyridin-2-yl)-cyclopropanecarbonitrile (step 2 of PREPARATION EXAMPLE 3) was dissolved in 40 ml anhydrous toluene, then 700 mg of tetrakis(triphenylphosphine)palladium(0) and 9.0 g vinyltributylstannane were added under a nitrogen atmosphere. The reaction mixture was heated on reflux for 3 hours. After cooling to ambient temperature, the reaction mixture was filtered, the filtrate was diluted with 100 ml of ethyl acetate, then washed with water and with saturated potassium fluoride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. Crude material was obtained as a dark oil, which was purified by flash chromatography on silica gel with heptane/ethyl acetate as a solvent. Thus, 1.9 g of 1-(3-chloro-5-vinyl-2-pyridyl)cyclopropanecarbonitrile was obtained as a yellow oil. 1H-NMR (CDCl3): 8.40 ppm (s, 1H), 7.78 ppm (s, 1H), 6.67 ppm (dd, 1H), 5.87 ppm (d, 1H), 5.50 ppm (d, 1H), 1.77 ppm (m, 2H), 1.63 ppm (m, 2H).