Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C([Li])CCC.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:19](N1CCOCC1)=[O:20]>C1COCC1.CCOCC>[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]([C:5]1[O:1][CH2:2][CH2:3][CH:4]=1)=[O:20]
Reactant: Cc1cccc(C(=O)N2CCOCC2)c1Br
Reactant: C1=COCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)C2=CCCO2)c1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 2,3-dihydrofuran (0.70 mL, 9.25 mmol) in THF (9.0 mL) under inert atmosphere was cooled to −78° C. A solution of n-butyllithium, 1.7 M in pentanes (5.98 mL, 10.17 mmol), was added dropwise over 10 min. The reaction was maintained at that temperature for 30 min, and allowed to warm to 0° C. for 30 min. It was cooled back down to −78° C. and then added via cannula to a solution of (2-bromo-3-methylphenyl)(morpholino)methanone (2.02 g, 7.12 mmol) in Et2O (17.92 mL), also at −78° C. The solution was stirred at that temperature for 10 min and then allowed to warm to 0° C. The mixture was partitioned between Et2O and water and the organics were washed with water and brine. The solution was dried over Na2SO4 and concentrated. The crude material was absorbed onto a plug of silica gel and purified by column chromatography eluting with a gradient of Et2O in hexane, to provide (2-bromo-3-methylphenyl)(4,5-dihydrofuran-2-yl)methanone as a colorless oil. This oil was immediately re-dissolved in Et2O and placed under nitrogen before storing in the freezer for further use.
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[Cl:15][C:16](Cl)([O:18]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[C:16]([Cl:15])(=[O:18])[O:5][CH2:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: C[Si](C)(C)CCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)Cl
Reaction time: 0.25 h

Procedure:
To a solution of 2-trimethylsilylethanol (5.0 g, 42.3 mmol) in dichloromethane (35 mL) at 0° C. was added triethylamine (4.7 g, 46.5 mmol). To this stirred solution was added dropwise a solution of triphosgene (4.40 g, 14.8 mmol) in dichloromethane (15 mL); a white precipitant was formed immediately. The mixture was stirred at low temperature for 15 minutes, the ice bath removed, and the mixture was stirred for an additional 1 hour at room temperature. After 1 hour, the white precipitant was filtered and washed with dichloromethane (˜60 mL). The combined filtrate and washings were concentrated. The resultant oily carbonochloridate was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:31]=[CH:30][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=3[O:27][CH3:28])[CH2:14][CH2:15][C:9]=2[CH:8]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:31]=[CH:30][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][NH:18][C:19](=[O:29])[C:20]3[CH:25]=[CH:24][C:23]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:22][C:21]=3[O:27][CH3:28])[CH2:14][CH2:15][C:9]=2[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N)ccc1C(=O)NCCN1CCc2ccc(N)cc2CC1
Solvent: c1ccncc1
Product: COc1cc(NS(C)(=O)=O)ccc1C(=O)NCCN1CCc2ccc(NS(C)(=O)=O)cc2CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulphonyl chloride (0.155 ml) was added dropwise to a solution of 7-amino-3-[2-(4-amino-2-methoxybenzamido)ethyl]-1,2,4,5-tetrahydro-3H-3-benzazepine in pyridine cooled to 0°, and the reaction mixture was stirred for a further 18 hours at room temperature. The solvent was evaporated in vacuo and the residue taken up in methylene chloride, washed three times with aqueous sodium bicarbonate and three times with brine. The organic layer was dried (Na2SO4), filtered and evaporated to give an oil, in which thin layer chromatography detected the presence of some unreacted starting material. The oil was therefore taken up in pyridine and treated with methanesulphonyl chloride (0.05 ml), and the reaction mixture was stirred at room temperature for 72 hours. The solvent was then evaporated in vacuo and the residue taken up in methylene chloride, washed three times with aqueous sodium bicarbonate and three times with brine. The organic layer was dried (Na2SO4), filtered and evaporated to give an oil. The resulting oil was then purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 5%) and the product-containing fractions were combined and evaporated in vacuo to give the title compound as a colourless foam, yield 0.32 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Nc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
4-Chloro-3-nitrobenzenesulfonyl chloride (460 mg, 1.8 mmol) was added to a colorless solution of aniline (250 mg, 2.7 mmol) in CH2Cl2 (10 mL) followed by pyridine (0.80 mL, 10.0 mmol). The resulting orange solution was stirred at room temperature for 30 minutes, after which time the mixture was concentrated under vacuum. Acidification with 2M aq. HCl followed by extraction using EtOAc and drying with Na2SO4 followed by filtration through a plug of silica, gave 500 mg (62%) of 4-chloro-3-nitro-N-phenylbenzenesulfonamide. 1H NMR (CDCl3) δ 8.30 (d, 1H), 7.80 (dd, 2H), 7.55 (d, 1H), 7.20 (m, 5H). MS(negESI) m/z=311(M-H+). 1-Methylhomopiperazine (258 mg, 2.3 mmol) was added to a solution of 4-chloro-3-nitro-N-phenylbenzenesulfonamide obtained as above (500 mg, 1.6 mmol) in CH2Cl2 (20 mL) followed by addition of K2CO3 (310 mg, 2.3 mmol) The reaction mixture was heated to reflux. After 2.5 h, the solution was concentrated under vacuum. After adjusting to pH=6, the product was extracted using EtOAc to give, after drying with Na2SO4 and concentration, 450 mg (72%) of 4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide as an orange oil. 1H NMR (CDCl3) δ 8.15 (d, 1H), 7.60 (dd, 1H), 7.15 (m), 6.95 (d, 1H), 3.45 (m, 2H), 3.30 (m, 2H), 2.75 (m, 2H), 2.60 (m, 2H), 2.35 (s, 3H), 1.95 (m, 2H). MS (posESI) m/z=391(M+H+). To a solution of 4-(4-methyl-1,4-diazepan-1-yl)-3-nitro-N-phenylbenzenesulfonamide (225 mg, 0.58 mmol) in EtOH/THF (4/1, 25 mL) activated Raney-Ni (slurry in EtOH) and hydrazine monohydrate (142 μL, 2.9 mmol) were added. After stirring for 30 minutes at room temperature, the mixture was filtered and the yellow solution concentrated to give yellow oil. The oil was dissolved in a mixture diethyl ether/EtOAc followed by addition of excess of HCl/ether. The resulting precipitate was filtered and washed with ether to give, after drying under vacuum at 40° C., 88 mg (38%) of 3-amino-4-(4-methyl-1,4-diazepan-1-yl)-N-phenylbenzenesulfonamide as a beige solid. Mp 84-85° C. MS (posESI m/z=361 (M+H+). 1H NMR (MeOH-d3) δ7.85 (d, 2H), 7.60 (d, 1H), 7.15 (m, 5H), 3.50 (m, 7H), 3.15 (m, 2H), 3.00 (s, 3H), 2.30 (m, 1H), 2.20 (m, 1H). Anal. (C18H24N4SO2.2HCl) C,H,N,S.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[N:3]=1.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[OH-].[Na+]>ClC(Cl)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)[N:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1ncnc2c1c(I)nn2C1CCCNC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: CN1CCCC(n2nc(I)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
To a mixture of 3-iodo-1-(3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.4 g, 0.00116 mol) and sodium triacetoxyborohydride (0.34 g, 0.00162 mol) in dichloroethane (30 mL) was added formaldehyde solution (37% in water, 0.035 mL, 0.00128 mol, 1.1 eq.) at room temperature. The mixture was stirred at room temperature under an atmosphere of nitrogen for 18 hours. Additional formaldehyde solution (37% in water, 0.035 mL, 0.00128 mol, 1.1 eq.) was added, and the mixture was stirred at room temperature for 2 hours. A 5 N aqueous solution of sodium hydroxide (5 mL) was added to the mixture. The solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure, and the mixture was lyophilized to yield 3-iodo-1-(1-methyl-3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.41 g, 0.0011 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 6.0 min. MS: MH+ 359
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25](C)(C)C)=[O:23])[C:12]([O:14]C(C)(C)C)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)CCCC(CSc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)CCCC(CSc1ccc(Cl)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.1 %

Procedure:
To a solution of di-tert-butyl 2-(3,4-dichlorophenylthiomethyl)adipate (550 mg) in benzene (7 ml) was added p-toluenesulfonic acid (40 mg), and the mixture was refluxed for 45 minutes. After the reaction mixture was cooled to room temperature, methanol (7 ml) was added, and the solution was stirred at 40° C. for 2.5 hours. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica by eluting with chloroform/methanol (10:1) to give 340 mg of 3-(3,4-dichlorophenylthio)-2-(3-methoxycarbonylpropyl)propionic acid as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]2)=[O:10])[CH:7]=1.[N+](C1C=C(S(O[CH2:31][C@@H:32]2[CH2:34][O:33]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:31][C@@H:32]2[CH2:34][O:33]2)=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12]2)=[O:10])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: O=C(Nc1cc(Cl)ccc1O)N1CC[C@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Cl)ccc1OC[C@@H]1CO1)N1CC[C@H](O)C1
Yield: 29.1 %

Procedure:
A solution of (3S)-N-(5-chloro-2-hydroxyphenyl)-3-hydroxypyrrolidine-1-carboxamide (232 mg, 0.90 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (234 mg, 0.90 mmol) and caesium carbonate (369 mg, 1.13 mmol) in dimethylformamide (9 mL) was stirred at room temperature, over night. The mixture was partitioned between water and ethyl acetate, and the organic phase was washed twice with water and once with brine, and finally concentrated. The crude material was purified by HPLC on C 18 (“Kromasil” column, 10 um, acetonitrile/water 35/65 to 85/15 over 30 min), yielding the titled compound (82 mg, 29%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:22]([O:24][C:25](=[O:32])[CH:26]([CH2:30][CH3:31])[C:27](O)=[O:28])[CH3:23]>>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1)[C:27](=[O:28])[CH:26]([C:25]([O:24][CH2:22][CH3:23])=[O:32])[CH2:30][CH3:31])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)C(CC)C(=O)O
Reactant: CCCCNCc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Product: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)C(CC)C(=O)OCC

Procedure:
The starting material can be prepared, for example, as follows: Analogously to Example 4b) and using 2.64 g of N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amine and 2.68 g of ethylmalonic acid monoethyl ester monochloride as starting materials, there is obtained 2-ethoxycarbonylbutanoic acid N-butyl-N-(2'-cyano-biphenyl-4-ylmethyl)-amide that has an Rf value of 0.65 [CH2Cl2 /CH3OH (95:5)].
Reaction SMILES: [I-:1].[I-].[I-].[C:4]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[C:20]([CH2:33][CH3:34])[C:21]3[C:30]([CH:31]=2)=[S+:29][C:28]2[C:23](=[C:24]([CH3:32])[CH:25]=[CH:26][CH:27]=2)[N:22]=3)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N1CCCN(C2C=C(CC)C3C(C=2)=[S+][C:59]2[C:54](=C(C)C=[CH:57][CH:58]=2)[N:53]=3)CC1)(OC(C)(C)C)=O.C(N1CCCN(C2C=C(CC)C3C(C=2)=[S+]C2C(=C(C)C=CC=2)N=3)CC1)(OC(C)(C)C)=O.N1CCCC1>CO>[I-:1].[C:4]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[CH:19]=[C:20]([CH2:33][CH3:34])[C:21]3[C:30]([CH:31]=2)=[S+:29][C:28]2[C:23](=[C:24]([CH3:32])[CH:25]=[C:26]([N:53]4[CH2:54][CH2:59][CH2:58][CH2:57]4)[CH:27]=2)[N:22]=3)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc2[s+]c3cccc(C)c3nc12
Agent: [I-]
Solvent: CO
Solvent: C1CCNC1
Product: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc2[s+]c3cc(N4CCCC4)cc(C)c3nc12

Procedure:
a solution of 3-(4-Boc-1,4-diazepan-1-yl)-1-ethyl-9-methyl-phenothiazin-5-ium triiodide (100 mg, 0.12 mmol) in methanol (10 mL) and pyrrolidine (71 mg, 1.0 mmol) was stirred for 4 h at room temperature. The resulting mixture was concentrated to dryness and purified by flash chromatography using the methanol-chloroform gradient to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1C
Reactant: Cc1ncc[nH]1
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccccc3)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[N:10]1[C:17]([Cl:18])=[N:16][C:14](Cl)=[N:13][C:11]=1[Cl:12].C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:12][C:11]1[N:10]=[C:17]([Cl:18])[N:16]=[C:14]([NH:2][N:3]2[CH2:9][C:7](=[O:8])[NH:6][C:4]2=[O:5])[N:13]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CN(Nc2nc(Cl)nc(Cl)n2)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 107.2 %

Procedure:
An ice-cold suspension of 1-aminohydantoin hydrochloride (457 mg, 3.0 mmol), cyanuric chloride (500 mg, 2.73 mmol) and sodium bicarbonate (505 mg, 6 mmol) in acetonitrile (5 mL) was stirred under an atmosphere of nitrogen for 2 h and then stirred at room temperature for 20 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extracted with ethyl acetate and the ethyl acetate was separated and dried (MgSO4). The crude product (770 mg) gave a single spot on thin layer chromatography [silica; CH2Cl2/MeOH (10:1)] and was used in the next step without further purification. NMR (CD3CN): δ=4.11 (s, 2H); 8.71 (s, 1H); 8.85 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][CH3:30])[CH2:25][CH2:24]2)[CH:3]=1.[NH3:31]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:31])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][CH3:30])[CH2:25][CH2:24]2)[CH:3]=1
Reactant: CO[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)CC1
Reactant: N
Product: CO[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)CC1

Procedure:
Prepared analogously to 1.4 from 0.1 g 4-[4-fluoro-2-(trans-4-methoxycyclohexyloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid and ammonia (7M in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=2)[N:7]=1.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]1.Cl>CCOCC>[ClH:1].[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][NH:22][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][OH:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:15][CH2:14]1
Reactant: NCCCN1CCOCC1
Reactant: OCc1cnc2ccc(Cl)nn12
Agent: Cl
Solvent: CCOCC
Product: OCc1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 65 %

Procedure:
Prepared from (6-chloroimidazo[1,2-b]pyridazin-3-yl)methanol (7) and and 3-morpholinopropylamine according to general procedure 4 (StepB). The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (174 mg, 65%) as a yellow solid; 1H NMR (500 MHz, CD3OD) δ 7.58 (d, J=9.7 Hz, 1H), 7.63 (s, 1H), 6.98 (d, J=9.7 Hz, 1H), 4.89 (s, 2H), 3.93-3.91 (m, 4H), 3.55-3.52 (t, J=6.6 Hz, 2H), 3.34-3.25 (m, 6H), 2.22-2.16 (m, 2H); 13C NMR 75 MHz, CD3OD) δ 156.3, 135.7, 130.7, 124.7, 123.5, 118.0, 65.1, 56.7, 53.5, 53.3, 39.6, 24.3; HPLC tR=7.4 min (Synergi), 98.9%; ES-MS: (M+H)=292 m/z.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[F:23])=[C:13]([CH3:24])[C:12](=[O:25])[N:11]2[CH2:26][CH2:27][N:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]=12.C(OC(=O)C)C>N1C=CC=CC=1>[CH2:29]([N:28]1[C:10]2=[C:9]([NH:8][S:4]([CH:1]3[CH2:3][CH2:2]3)(=[O:6])=[O:5])[C:14]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=3[F:23])=[C:13]([CH3:24])[C:12](=[O:25])[N:11]2[CH2:26][CH2:27]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(N)c2n(c1=O)CCN2Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27.4 %

Procedure:
Cyclopropanesulfonyl chloride (254 mg, 0.0002 mol) was added to a stirred solution of 8-amino-1-benzyl-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (400 mg, 0.001 mol) in pyridine (4 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was concentrated to afford the crude product. Purification by column chromatography on silica gel (80% ethylacetate in hexane), followed by preparative HPLC afforded 30 mg of the product (6% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:8][CH2:9][C:10](Cl)=[O:11]>CCOCC>[Cl:8][CH2:9][C:10]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:11]
Reactant: O=C(Cl)CCl
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)CNC(=O)CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Glycine (1.5 g, 20 mmol) was dissolved in 2N NaOH (25 ml, 50 mmol) and ether (20 ml) was added. Chloroacetyl chloride (2.26 g) dissolved in Et2O (20 ml) was added dropwise at 0° C. The mixture was stirred at 0° for 30 minutes and at room temperature 1 hour. The layers were separated and the water layer was washed with Et2O (2×20 ml). The water layer was then acidified to pH 2 with concentrated HCl and the product was extracted into EtOAc (3×50 ml). The combined EtOAc extracts were washed with brine, dried (MgSO4), and freed of solvent in vacuo to give title acid compound as a solid (2.56 g, 84%) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([OH:12])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=1.[CH3:13]O>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)C(C(=O)O)CC2
Reactant: CO
Product: COC(=O)C1CCc2cc(C)sc21
Yield: 74 %

Procedure:
A solution of 9.4 g (0.051 mole) of 2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylic acid and 0.4 g of paratoluenesulfonic acid monohydrate in 400 cc of methanol was stirred at ambient temperature for 20 hours then concentrated dry under reduced pressure. The residue was picked up with ethyl acetate. The resulting solution was washed with an aqueous solution of sodium bicarbonate then water. It was dried on sodium sulfate. After evaporation of the solvent under reduced pressure, the residue was distilled. 7.5 g (yield=74%) of methyl 2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylate was obtained. Bp0.6=107° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br.Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[C:5]([N:12]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[C:29]([C:28]([F:27])([F:37])[F:38])[CH:30]=2)[C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCOC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(Cc1cccc(C(F)(F)F)c1)c1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of ethyl 4-bromo-2-nitro-6-(trifluoromethyl)phenylcarbamate (275.3 mg) and potassium carbonate (108.3 mg) in N,N-dimethylformamide (5 ml) was added 3-trifluoromethylbenzyl bromide (0.180 ml). After the mixture was stirred at room temperature for 1 hour, 1N hydrochloric acid (ca. 30 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated brine, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (35 g, hexane:ethyl acetate=20:1) to give the title compound (345.3 mg, 82%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14][NH:15][NH:16][C:17](OC(C)(C)C)=O)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.CN(C=[C:30]([C:36](=O)[C:37]([F:40])([F:39])[F:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32])C.C(N(CC)CC)C>C(O)C>[F:38][C:37]([F:39])([F:40])[C:36]1[N:15]([CH2:14][C:11]2[S:12][CH:13]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=3)[N:10]=2)[N:16]=[CH:17][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NNCc1nc(-c2cccc(C(F)(F)F)c2)cs1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)cs2)c1C(F)(F)F
Yield: 69.2 %

Procedure:
A mixture of the compound (0.16 g) obtained in Example 103c, ethyl 2-[(dimethylamino)methylidene]-4,4,4-trifluoro-3-oxobutanoate (0.10 g), triethylamine (0.21 mL) and ethanol (4 mL) was heated under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and saturated brine. The ethyl acetate layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.13 g) as a colorless oil.