Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([O:29]C)=[O:28])=[CH:20][C:19]=2[CH:31]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=2[CH:31]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1CCCOc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1ccccc1CCCOc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 58.8 %

Procedure:
To methyl 7-[3-(2-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (832 mg) dissolved in THF-methanol (15-7.5 ml) was added a 2 M aqueous solution of potassium carbonate (1.5 ml), and the resulting mixture was stirred at 60° C. for 20 hours. The reaction mixture was treated with 1 N hydrochloric acid to bring the pH to 2. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the precipitated crystals were washed with ethyl acetate to obtain 7-[3-(2-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (474 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[CH2:4][CH2:5][C:6]#[CH:7].N[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12]C=1O>ClC(Cl)C>[CH2:4]([C:3]1[O:2][C:1]2[CH:10]=[CH:15][C:14]([Cl:16])=[CH:13][C:12]=2[N:8]=1)[CH2:5][C:6]#[CH:7]
Reactant: C#CCCC(=N)OC
Reactant: Nc1cc(Cl)ccc1O
Solvent: CC(Cl)Cl
Product: C#CCCc1nc2cc(Cl)ccc2o1
Reaction time: 48 h
Yield: 6.8 %

Procedure:
A mixture of pent-4-ynimidic acid methyl ester (142 mg, 1.28 mmol) and 2-amino-4-chlorophenol (227 mg, 1.53 mmol) in dichloroethane (10 mL) was stirred for 2 days under reflux. The solvent was evaporated, the residue was partly dissolved in MeOH and filtered. The filtrate was concentrated, and the resulting crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 18 mg (87 μmol, 7%) of 2-(but-3-ynyl)-5-chlorobenzo[d]oxazole.
Reaction SMILES: [S-:1][S-:2].[Na+].[Na+].O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[S].Br[CH2:19][CH2:20][CH:21]=[C:22]([F:24])[F:23]>C(O)C>[F:23][C:22]([F:24])=[CH:21][CH2:20][CH2:19][S:1][S:2][CH2:19][CH2:20][CH:21]=[C:22]([F:24])[F:23]
Reactant: [S-][S-]
Reactant: FC(F)=CCCBr
Agent: [Na+]
Agent: [S-2]
Agent: [S]
Solvent: CCO
Solvent: O
Product: FC(F)=CCCSSCCC=C(F)F

Procedure:
A solution of sodium disulfide (previously prepared from sodium sulfide nonahydrate (53 g) and sulfur (7.0 g) in ethanol (250 cm3)) was added to 1-bromo4,4-difluorobut-3-ene (50 g) in ethanol (100 cm3). The mixture was gradually heated and stirred under reflux for 2 hours, then cooled and evaporated under reduced pressure. The residue was extracted with diethyl ether, the organic phase filtered to remove sodium bromide and the ether evaporated under reduced pressure to give a liquid which was distilled at 16 mm Hg, bp 120° C. to give the bis-(4,4-difluorobut-3-enyl)disulfide (24 g) as a colourless liquid.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:11]2[C:12](=O)[NH:13][CH2:14][CH2:15][CH2:16][C:10]=2[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[CH2:1]([O:4][C:5]([C:7]1[C:11]2[C:12](=[S:19])[NH:13][CH2:14][CH2:15][CH2:16][C:10]=2[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCOC(=O)c1c[nH]c2c1C(=O)NCCC2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CCCOC(=O)c1c[nH]c2c1C(=S)NCCC2
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.5 %

Procedure:
A mixture of compound (500 mg) from Step 1 and P4S10 (2.0 g) in 20 mL of pyridine is heated at 80° C. with stirring overnight. It is cooled and evaporated under vacuum, then diluted with water and stirred. The insoluble material is filtered and the mother liquid is extracted with CH2Cl2/EtOAc (1:4). The combined extract is washed with brine, dried and concentrated to give 120 mg of 4-thioxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-3-carboxylic acid propyl ester.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[C:25]([CH3:31])=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[C:25]([CH3:31])[CH:26]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Reactant: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Product: CC(=O)Oc1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2c1
Yield: 35 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloroquinazoline was reacted with 5-amino-2-tolyl 2-pyridylmethyl ether to give 6-acetoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline in 35% yield, m.p. 149°-151° C.;
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[CH:24][CH:23]=3)=[N:16][CH:17]=2)[N:12]1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[N:36]=1)[CH:9]=[CH2:10]>N1C=CC=CC=1>[CH2:8]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[N:16][CH:17]=2)[N:12]1[C:35]1[N:36]=[C:37]([NH:41][C:5](=[O:7])[CH3:6])[CH:38]=[CH:39][CH:40]=1)[CH:9]=[CH2:10]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(N)n1
Solvent: c1ccncc1
Product: C=CCn1c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc2n1-c1cccc(NC(C)=O)n1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
0.2 mL of acetic anhydride was added to pyridine (2 mL) solution of 50 mg of 2-allyl-1-(6-aminopyridin-2-yl)-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one obtained in Example 50, and stirred at 50° C. for 6 hours. After this was concentrated under reduced pressure, saturated sodium hydrogencarbonate solution was added thereto, extracted with chloroform, and the organic layer was washed with saturated saline water and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through preparative basic thin-layer chromatography (chloroform/methanol=40/1) to obtain 47 mg of the entitled compound as a yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.S(Cl)(Cl)=O.[C:18]1(C)C=CC=C[CH:19]=1>>[CH2:18]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:5]([CH2:4][CH2:3][CH2:2][Br:1])=[CH:6][CH:7]=1)[CH3:19]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1ccc(CCCBr)cc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(CCCBr)cc1

Procedure:
100 g 4-(3-Bromo-propyl)-benzoic acid (JACS 65, 2281 (1943) , 400 ml of toluene and 80 ml of thionyl chloride were refluxed for 4 hours. The solvent and the thionyl chloride in excess were removed under reduced pressure and after addition of 400 ml of absolute ethanol to the residue the mixture was heated for one hour to the boiling point. It was evaporated under reduced pressure, the residue was taken up in benzene and washed neutral with a saturated NaHCO3 -solution. The organic phase was distilled off after drying with MgSO4. Boiling point0.1 : 105° - 107° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][CH3:19])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1.C([O-])(=O)C.[K+].[Br:26]Br>C(O)(=O)C.O>[Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][CH3:19])=[N:13][CH:14]=[C:15]([Br:26])[CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1
Reactant: BrBr
Reactant: CCNc1ncccc1C(=O)Nc1ccc(Cl)nc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCNc1ncc(Br)cc1C(=O)Nc1ccc(Cl)nc1Cl
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
To a solution of N-(2,6-dichloro-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide (7.4 g, 24 mmol) and potassium acetate (2.8 g, 28 mmol) in 90 mL of acetic acid was added bromine (1.2 mL, 23 mmol). After 15 min, the reaction mixture was diluted with water and the precipitate was collected by suction filtration to give 8.2 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN1C(=O)CCC1.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19](Br)[CH:20]=1>C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[C:19]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:18]=[N:17][CH:16]=1
Reactant: C1COCCN1
Reactant: Brc1cncc(Br)c1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: Brc1cncc(N2CCOCC2)c1
Temperature: 180 °C
Yield: 19.5 %

Procedure:
To a solution of morpholine (3.67 g, 4.23 mmol), NMP (2 mL) and toluene (4 mL) was added 3,5-dibromopyridine (1.00 g, 4.20 mmol) and the mixture was heated under microwave conditions at 180° C. for 1 h. The solution was partitioned between DCM and water, the organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography eluting with (EtOAc: PE=1:5). (200 mg, yield 19.5%) MS (ESI+) e/z: 243.0 [M+1]+ LCMS.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.I[CH3:21]>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH3:21])[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCc1ccc(F)cc1
Reactant: CI
Product: CN(Cc1ccc(F)cc1)c1nc(Cl)ccc1[N+](=O)[O-]
Yield: 65 %

Procedure:
In accordance with the same procedures as in Step 2 of Preparation 4, except for using (6-chloro-3-nitropyridin-2-yl)-(4-fluorobenzyl)-amine prepared in Step 1 and iodomethane, the titled compound was obtained as yellow solid. (Yield: 65%)
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([N:6]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.C1CCCCC1.[Br:27]Br>O1CCCC1>[Br:27][C:10]1[N:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[N:7]=[C:8]([C:11]([F:14])([F:12])[F:13])[CH:9]=1
Reactant: BrBr
Reactant: CN(C)S(=O)(=O)n1ccc(C(F)(F)F)n1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1nc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of N,N-dimethyl-3-(trifluoromethyl)-1H-pyrazole-1-sulfonamide (i.e. the product of Example 10, Step A) (4.25 g, 17.5 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C., and then 2 M n-butyllithium in cyclohexane (10.0 mL, 20.0 mmol) was added dropwise. The reaction mixture was stirred a further 30 minutes, and then bromine (1.0 mL, 3.1 g, 18.7 mmol) was added dropwise. The reaction mixture was stirred for 10 minutes, warmed to room temperature, and quenched with brine (50 mL). The resulting solution was extracted with diethyl ether, dried (MgSO4), and concentrated under reduced pressure to give 6.77 g of title compound as a light yellow oil. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.P(Cl)(Cl)Cl.[NH2:19][C:20]1[S:21][C:22]([C:25]2[S:26][C:27]([Br:30])=[CH:28][CH:29]=2)=[CH:23][N:24]=1>O>[Br:30][C:27]1[S:26][C:25]([C:22]2[S:21][C:20]([NH:19][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])=[N:24][CH:23]=2)=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: Nc1ncc(-c2ccc(Br)s2)s1
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=C(Nc1ncc(-c2ccc(Br)s2)s1)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.43 g) of Preparation 1 in 80 mL xylenes is heated to reflux. PCl3 (0.12 mL) is added dropwise and the mixture stirred for 20 minutes. 2-Amino-5-(5-bromothien-2-yl)thiazole (0.62 g) is added in one portion and the reaction refluxed overnight. The reaction is cooled to room temperature and H2O is added to quench excess PCl3. The solvents are removed and the residue is dissolved in acetic acid. A dark orange solid precipitates upon addition of hexanes (0.28 g) to yield the title product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[C:20]([O:1][CH2:2][CH2:3][C:4]1[C:5]2[N:6]([N:17]=[CH:18][N:19]=2)[C:7]([NH2:16])=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC(=O)Cl
Reactant: Nc1nc(-c2ccccc2)c(CCO)c2ncnn12
Product: CCCCCCCC(=O)OCCc1c(-c2ccccc2)nc(N)n2ncnc12

Procedure:
The title compound, m.p. 89°-91°, was prepared by the method of Example 2 using 5.1 g (0.02 mole) of the product compound of Example 1 and 3.25 g (0.02 mole) of octanoyl chloride, except that the solution was not divided before purification.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:22])=[O:21]
Reactant: CCOC(=O)CCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 6-hydroxyhexanoate (5 g, 31.2 mmol) in anhydrous dichloromethane (115 mL) under nitrogen at −10° C. was added triethylamine (8.7 mL, 62.5 mmol) followed by methanesulfonyl chloride (4.8 mL, 62.5 mmol) dropwise over 1 hour. The resulting solution was stirred at room temperature for 6 hours and then diluted to 300 mL using dichloromethane. The solution was washed with twice saturated NaHCO3, and the aqueous layers backextracted with dichloromethane. The combined organics were dried over MgSO4, filtered, and concentrated. The resulting dark orange oil was purified by column chromatography (column 5″L×2″W; eluted with a gradient of 100% hexanes→10%→20% ethyl acetate in hexanes) to afford the product as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([NH:14][C:15](=[N:18][CH3:19])SC)#[N:13]>C(#N)C>[C:12]([NH:14][C:15]([NH:18][CH3:19])=[N:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CN=C(NC#N)SC
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (17.0 g.) and N-cyano-N',S-dimethylisothiourea (11.2 g.) in acetonitrile (500 ml.) was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was finally recrystallised from acetonitrile-ether to yield N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 141°-2°. (Found: C, 47.2; H, 6.4; N, 33.4; S, 12.4. C10H16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:4]#[CH:5].C(=O)([O-])[O-].[K+].[K+].C([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1)(=O)C.O>CN(C=O)C>[OH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:16]2[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]3/[C:7]([NH:6][CH2:3][C:4]#[CH:5])=[N:8][C:9](=[O:19])[S:10]/3)[CH2:14][CH2:15]2)=[C:32]([C:38]([F:39])([F:40])[F:41])[CH:31]=1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: CC(=O)Oc1ccc(CBr)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of (5Z)-4-(prop-2-yn-1-ylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (2 g) in DMF (20 mL) were added potassium carbonate (3.45 g) and 4-(bromomethyl)-3-(trifluoromethyl)phenyl acetate (1.84 g). The reaction mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue in methanol (20 mL) was added potassium carbonate (858 mg), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the solid was recrystallized from ethyl acetate/heptane to give the title compound (0.75 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8].[SH:9][CH2:10][CH2:11][CH2:12][Si:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].CC[O-].[Na+]>>[Si:13]([CH2:12][CH2:11][CH2:10][S:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Cl:8])([O:17][CH2:18][CH3:19])([O:20][CH2:21][CH3:22])[O:14][CH2:15][CH3:16]
Reactant: ClCCCCCCCl
Reactant: CCO[Si](CCCS)(OCC)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCO[Si](CCCSCCCCCCCl)(OCC)OCC
Temperature: 80 °C

Procedure:
A 1-liter separable flask equipped with a nitrogen gas inlet, thermometer, Dimroth condenser and dropping funnel was charged with 310.0 g (2.0 mol) of 1,6-dichlorohexane and heated at 80° C. With stirring, the reaction product of 3-mercaptopropyltriethoxysilane with sodium ethylate was slowly added dropwise. After the completion of dropwise addition, the solution was continuously stirred at 80° C. for 5 hours, and then cooled. From the solution, the salt was filtered off and the ethanol and excess 1,6-dichlorohexane were distilled off in vacuum. The residual solution was subjected to vacuum distillation, collecting 64.2 g of a colorless clear liquid at a boiling point of 148–150° C./0.005 Torr. On analysis by IR, 1H-NMR and MS, the liquid was identified to be a compound of the following formula. (CH3CH2O)3Si(CH2)3S(CH2)6Cl Analysis by gas chromatography gave a purity of 98.7%.
Reaction SMILES: Cl[C:2]1[C:3]([Cl:9])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:5]2[N:6]=[C:7]([N:14]3[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]3)[CH:2]=[C:3]([Cl:9])[N:4]=2)[CH2:13][CH2:12]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cc(Cl)nc(N3CCN(C)CC3)n2)CC1
Temperature: 0 °C

Procedure:
Trichloropyrimidine is added in portions to an ice cooled solution of N-methylpiperazine (40 g) in alcohol (200 ml). The mixture is then heated at 60° for 2 hr. The mixture is concentrated and chromatographed on silica gel with 2 to 5% methanol in methylene chloride to give 2,4-bis-[4-methylpiperazino]-6-chloropyrimidine. This material is heated at 130° in water (30 ml) with piperazine (32 g) in a Parr bomb for 20 hr. The product is partitioned between methylene chloride and aqueous sodium carbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give 2,4-bis[1-(4-methylpiperazino)]-6-piperazinopyrimidine. This triamine is stirred in acetonitrile (200 ml) with 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (7.18 g) and potassium carbonate (2 g) for 20 hr. The mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated and the organic phase is concentrated and chromatographed on silica gel (methylene chloride to 5% methanol and 0.5% ammonium hydroxide/methylene chloride) to give the free base corresponding to the title compound. The free base is dissolved in ethyl acetate and treated with methane sulfonic acid (2.22 g). The product is triturated with ether to give the title compound, bubbled at 110° without obvious decomp.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]3)[CH2:7][C:6]2=1.[O:25]=[C:26]1[NH:31][C:30]2[CH:32]=[C:33]([CH:36]=O)[CH:34]=[CH:35][C:29]=2[S:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([NH:24][CH2:36][C:33]4[CH:34]=[CH:35][C:29]5[S:28][CH2:27][C:26](=[O:25])[NH:31][C:30]=5[CH:32]=4)[CH2:20][CH2:19]3)[CH2:7][C:6]2=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: COc1ccc2ncc3c(c2c1)CC(CN1CCC(N)CC1)CO3
Product: COc1ccc2ncc3c(c2c1)CC(CN1CCC(NCc2ccc4c(c2)NC(=O)CS4)CC1)CO3

Procedure:
The titled compound is prepared as an off-white lyophilized powder following Scheme 1 and in analogy to Example 18 using 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-piperidin-4-ylamine and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde as starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[C:23]2[CH2:22][CH2:21][NH:20][CH:19]([CH3:24])[C:18]=2[O:17][CH:16]=1>>[Cl:14][C:15]1[C:23]2[CH2:22][CH2:21][N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:19]([CH3:24])[C:18]=2[O:17][CH:16]=1
Reactant: CC1NCCc2c(Cl)coc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2occ(Cl)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-chloro-7-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine to provide the title compound.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH:14]([CH3:16])[CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:4].[NH3:17]>CO>[NH2:17][CH2:2][C:3]([N:5]([CH:14]([CH3:16])[CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: N
Solvent: CO
Product: COc1ccc(N(C(=O)CN)C(C)C)cc1
Reaction time: 72 h

Procedure:
A solution of 2.86 g of 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (10 mmol) in 100 mL methanol is saturated with ammonia at 0° C. and left for 3 days at ambient temperature in a sealed flask. Methanol and ammonia were removed in vacuo and the residue is dissolved in 100 mL of chloroform and washed with water (2×50 mL). The organic layer is dried over anhydrous MgSO4, filtered, concentrated in vacuo and dried under high vacuum to afford 2.7 g of 2-Amino-N-isopropyl-N-(4-methoxy-phenyl)-acetamide as an oil: 1H NMR (300 MHz, CDCl3) δ6.96 (m, 4H), 4.99 (m, 1H), 3.84 (s, 3H), 2.97 (s, 2H), 1.58 (s, 2H), 1.05 (d, 6H, J=6.6); low resolution MS (ESI)m/e 223 (MH+).