Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.NC1C=C(Cl)C=CC=1CO.C(N(CC)CC)C.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29]>CN(C=O)C>[NH2:1][C:2]1[C:3](/[CH:29]=[CH:28]/[C:27]([O:31][CH3:32])=[O:30])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: C=CC(=O)OC
Agent: Nc1cc(Cl)ccc1CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ncc(Cl)cc1N
Yield: 63.6 %

Procedure:
A solution of 3-amino-2-bromo-5-chloropyridine (2.257 ml, 19.96 mmol), Reactant 2 (0.283 g, 0.399 mmol), triethylamine (3.03 g, 29.9 mmol) and methyl acrylate (3.44 g, 39.9 mmol) in 5 mL of DMF was heated at 145° C. under microwave irradiation for 35 min. The reaction mixture was evaporated to dryness and was loaded to flash column (DCM to DCM/EA=10:1) to give 1.98 g of pure (E)-methyl 3-(3-amino-5-chloropyridin-2-yl)acrylate (2.7 g, 12.70 mmol, 63.6% yield) as a light yellow solid and 820 mg of less pure product. 1H NMR (400 MHz, chloroFORM-d) δ ppm=8.01 (d, J=1.8 Hz, 1 H), 7.72 (d, J=15.1 Hz, 1 H), 7.01 (d, J=2.0 Hz, 1 H), 6.92 (d, J=15.3 Hz, 1 H), 4.02 (br. s., 2 H), 3.81 (s, 3 H).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[NH:28][CH:27]=[C:26]2[S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[NH:28][CH:27]=[C:26]2[S:34]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=c1[nH]cc(S(=O)(=O)Cl)c2cc(Br)ccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2c[nH]c(=O)c3ccc(Br)cc23)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
To a solution of tert-butyl 1,4-diazepane-1-carboxylate (0.621 g) and triethylamine (0.864 mL) in THF (12 mL) was added dropwise a solution of 6-bromo-1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (Example 46a, 1 g) in THF (20 mL). The reaction was stirred at room temperature for 20 min. The resulting solution was concentrated under reduced pressure, acidified with 2 M HCl, and extracted into ethyl acetate. The combined organics were dried (MgSO4), filtered and evaporated under reduced pressure to give the subtitle compound (1.097 g) that was used without further purification.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10]Cl)[N:6]=1)([CH3:4])[CH3:3].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:2]([C:5]1[CH:9]=[CH:8][N:7]([CH2:10][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[N:6]=1)([CH3:4])[CH3:3]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)c1ccn(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 37.4 %

Procedure:
0.77 g of 3-i-propyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.64 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 8 ml of N,N-dimethylformamide. 1.54 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then recrystallized from hexane-ethyl acetate to obtain 0.42 g of [(3-i-propyl-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (2), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].[O:14]1C=CC=[CH:16][CH:15]1OCCBr.Cl>CO.CC(N(C)C)=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH2:15][OH:14])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: BrCCOC1C=CC=CO1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(OCCO)cc1
Yield: 37.9 %

Procedure:
A mixture of 4-methanesulfonylphenol (1.72 g, 10 mmol), DMA (25 ml) and 4 N sodium hydroxide (7 ml) was stirred under an atmosphere of nitrogen. 2-(2-Pyranyloxy)ethylbromide (2.8 g, 14 mmol) was added dropwise and then the mixture was stirred overnight at ambient temperature. The solvent was evaporated in vacuo and the residue was taken up in water (100 ml). The aqueous mixture was extracted with ethyl acetate (2×100 ml) and the combined organic extracts were washed with a 0.5 N sodium hydroxide solution and brine. The organic phase was concentrated to give an oily residue that was dissolved in methanol (50 ml). A solution of 5 N HCl (20 ml) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated and a small portion of ice was added followed by 4 N sodium hydroxide until approximately pH 10. The alkaline mixture was extracted with ethyl acetate (3×75 ml) and the combined organic extracts were washed with water and dried (MgSO4). The solvent was evaporated to give 0.82 g (38%) of 2-(4-methanesulfonylphenoxy)ethanol. M.p. 89–90° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C#N)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C#N)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J28) (302 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (420 mg, 79%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[N:12]1)=[O:5])[CH3:2].[CH2:30]([CH2:32][NH2:33])[OH:31].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]1[CH:29]=[CH:28][CH:27]=[C:9]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[CH:26]=[CH:25][C:21]([C:22](=[O:23])[NH:33][CH2:32][CH2:30][OH:31])=[CH:20][CH:19]=3)=[N:12]2)[CH:8]=1)[CH3:2]
Reactant: NCCO
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C(=O)O)cc3)ccc2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C(=O)NCCO)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
197 mg (0.5 mmol) of 4-[1-(3-ethoxycarbonylaminobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzoic acid are suspended in 2 ml of DMF, and 30 μl (0.5 mmol) of ethanolamine, 112 μl (1 mmol) of 4-methylmorpholine, 70 mg (0.5 mmol) of 1-hydroxybenzotriazole and 194 (1 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 24 h and purified by means of prep. HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:13]=[CH:12][C:11]([OH:14])=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1)[CH3:2].CI.[C:18](=O)([O-])O.[Na+]>CN(C=O)C>[CH3:18][O:9][C:8](=[O:10])[C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][C:11]=1[OH:14])[C:4]([O:3][CH2:1][CH3:2])=[O:15]
Reactant: CCOC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(O)c(C(=O)OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 4-hydroxyisophthalic acid 1-ethyl ester (4.51 g) in DMF (36 mL) were added methyl iodide (3.66 g) and sodium hydrogen carbonate (2.16 g). The mixture was stirred at 60° C. for 2 hours and then allowed to stand for cooling down to room temperature. The resulting precipitated solid formed upon addition of water was filtered off to give the title compound (4.20 g).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Cl.O1CCOCC1>C(O)CCC>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[S:3][C:4]3[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc2nc(Cl)sc2c1
Reactant: Nc1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Product: Fc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Temperature: 65 °C

Procedure:
A mixture of 2-chloro-6-fluoro-benzothiazole (0.65 g, 3.5 mmol) and 4-bromoaniline (0.61 g, 3.5 mmol) in n-butanol (6 mL) was heated at 60-70° C. under nitrogen to obtain a solution, to which 4 M HCl in dioxane (0.43 mL, 1.73 mmol) was slowly added dropwise. The reaction mixture was then heated at 90° C. for 18 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The resulting solid was triturated with ethanol and collected by filtration. This yielded 0.98 g (88%) of the title compound. LC/MS m/z 323.0 (MH+); retention time 3.74 min. 1H NMR (CD3OD) δ 7.10-7.30 (m, 1H), 7.39 (d, 1H), 7.45 (d, 2H), 7.58-7.61 (m, 3H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[N+:13]([CH3:16])([O-:15])=[O:14].C([O-])(=O)C.[NH4+].O>C(O)(=O)C>[N+:13]([CH:16]=[CH:11][C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][O:4][C:5]=2[CH:10]=1)([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])C=Cc1ccc2c(c1)OCCO2
Temperature: 110 °C
Yield: 61 %

Procedure:
To 1,4-benzodioxane-6-carboxaldehyde (10.0 g, 60 mmol) in acetic acid (50 mL) was added nitromethane (6.3 mL, 1.9 eq.) and ammonium acetate (5.1 g, 1.1 eq.). After heating at 110° C. for 4 hours the mixture was cooled to ambient temperature, water (150 mL) was added, and the solid precipitate was collected by filtration. The solid was crystallized from methylene chloride-hexane (1:1, 45 mL) to obtain 7.6 g (61%) of 6-(2-nitroethenyl)-1,4-benzodioxane. To a portion of the solid (3.58 g) dissolved in MeOH-EtOH-AcOEt (1:1:1, 450 mL) was added 10% Pd/C (1.7 g) and concentrated HCl (3.3 mL, 2.3 eq). After shaking on a Parr hydrogenator at 45 psi for 5 hours, the catalyst was removed by filtration through Celite and washed with methanol. Evaporation of the filtrate gave 3.59 g (96%) of 1,4-benzodioxan-6-ethanamine, hydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].[CH3:11]S(C)=O.CI>O>[CH3:11][O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CS(C)=O
Reactant: OCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCc1ccccn1
Temperature: 25 °C

Procedure:
Also, 2-(methoxymethyl)pyridine is prepared by the following alternative procedure. A mixture of 10.9 g. of 2-pyridinemethanol and 2.4 g. of sodium hydride in 50 ml. of dimethylsulfoxide is warmed on a steam bath for 15 minutes, then cooled to room temperature. Methyl iodide (14.2 g.) is added and then the mixture is heated at 40°C. for 1 hour. Water (150 ml.) is then added and the mixture is extracted with ether. The extracts are dried, concentrated and distilled to give 2-(methoxymethyl)pyridine.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.O1CCOCC1.CC(C)([O-])C.[K+].Cl[C:27]1[N:28]=[C:29]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][CH:49]([N:52]4[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]4)[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)[C:30]([C:36]([NH2:38])=[O:37])=[N:31][C:32]=1[CH:33]1[CH2:35][CH2:34]1>O>[C:36]([C:30]1[N:31]=[C:32]([CH:33]2[CH2:35][CH2:34]2)[C:27]([O:1][C@@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[N:28][C:29]=1[NH:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:47][CH2:48][CH:49]([N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]3)[CH2:50][CH2:51]2)=[CH:42][CH:41]=1)(=[O:37])[NH2:38]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CN1CCN(C2CCN(c3ccc(Nc4nc(Cl)c(C5CC5)nc4C(N)=O)cc3)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(C2CCN(c3ccc(Nc4nc(O[C@@H]5CCN(C(=O)OC(C)(C)C)C5)c(C5CC5)nc4C(N)=O)cc3)CC2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (151 mg) and dioxane (4 mL) were added potassium tert-butoxide (91 mg) and 5-chloro-6-cyclopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (190 mg), followed by stirring at 100° C. for 16 hours. After leaving to be cooled, water was added thereto, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-cyclopropyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]oxy}pyrrolidine-1-carboxylate (189 mg) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][N:12]([CH2:16][C:17](OC)=[O:18])[C:11]2[N:21]([CH3:30])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:10]1=2.[C-]#[N:32].[K+].N>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[S:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]([NH2:32])=[O:18])[C:11]2[N:21]([CH3:30])[N:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:10]1=2
Reactant: [C-]#N
Reactant: COC(=O)CN1CCSC(c2ccc(Cl)cc2Cl)c2c(-c3ccccn3)nn(C)c21
Agent: N
Agent: [K+]
Solvent: CO
Product: Cn1nc(-c2ccccn2)c2c1N(CC(N)=O)CCSC2c1ccc(Cl)cc1Cl
Temperature: 140 °C
Yield: 47.4 %

Procedure:
A mixture of methyl 2-[4-(2,4-dichlorophenyl)-1-methyl-3-(2-pyridyl)-6,7-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepin-8-yl]acetate (0.350 g, 0.76 mmol, Preparation #12 step A), KCN (0.050 g, 0.77 mmol), and ammonia (10 mL, 7 M in MeOH, 70 mmol) in methanol (10 mL) was heated, in a sealed flask, for about 50 min at about 140° C. in a microwave. After cooling to rt the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/methanol 95:5) to give 2-[4-(2,4-dichlorophenyl)-1-methyl-3-(2-pyridyl)-6,7-dihydro-4H-pyrazolo[3,4-e][1,4]thiazepin-8-yl]acetamide (0.16 g, 0.36 mmol, 47%) as a beige solid: LC-MS (Table 1, Method b) Rt=5.49 min; m/z 448 (M+H)+.
Reaction SMILES: [Br-].[C:2]([N:5]([CH:23]1[CH2:25][CH2:24]1)[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N+:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)(=[O:4])[CH3:3].[CH3:26][Mg]Cl.[Cl-].[NH4+]>O1CCCC1.CO>[CH2:16]([N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([N:5]([CH:23]2[CH2:25][CH2:24]2)[C:2](=[O:4])[CH3:3])=[CH:7][CH:8]1[CH3:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[Mg]Cl
Reactant: CC(=O)N(c1cc[n+](Cc2ccccc2)c2ccccc12)C1CC1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N(C1=CC(C)N(Cc2ccccc2)c2ccccc21)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a mixture of 4-(acetyl-cyclopropyl-amino)-1-benzyl-quinolinium bromide (9.6 g) in tetrahydrofuran (200 ml), under nitrogen and under cooling at 0° C., a solution of methyl magnesium chloride 1 Mol/l (12 ml) was added during 15 minutes. After 2 hours, a solution of ammonium chloride in methanol (100 ml) was added. The solvent was removed under reduce pressure and then washed with dichloromethane and water. The organic layer was separated and the solvent was removed under reduce pressure. The crude compound was purified by flash chromatography on silicagel with an eluent of dichloromethane/methanol (98/2) to give the N-(1-benzyl-2-methyl-1,2-dihydro-quinolin-4-yl)-N-cyclopropyl-acetamide (7.9 g, 98.6% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]([CH3:44])([CH3:43])[C:20]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]3[C:34](=[O:41])[NH:35][NH:36][C:37]=3[CH:38]([CH3:40])[CH3:39])=[C:28]([CH3:42])[CH:27]=2)=[O:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:45][C:46]([O:48][CH2:49][C@H:50]1[O:55][C@H:54](Br)[C@H:53]([O:57][C:58]([CH3:60])=[O:59])[C@@H:52]([O:61][C:62]([CH3:64])=[O:63])[C@H:51]1[O:65][C:66]([CH3:68])=[O:67])=[O:47].CC(OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O)=O>>[C:58]([O:57][C@@H:53]1[C@@H:52]([O:61][C:62](=[O:63])[CH3:64])[C@@H:51]([O:65][C:66](=[O:67])[CH3:68])[C@@H:50]([CH2:49][O:48][C:46](=[O:47])[CH3:45])[O:55][C@H:54]1[O:41][C:34]1[C:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]([C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH2:16][CH2:15]3)=[O:18])([CH3:44])[CH3:43])=[CH:27][C:28]=2[CH3:42])=[C:37]([CH:38]([CH3:39])[CH3:40])[NH:36][N:35]=1)(=[O:59])[CH3:60]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCN(C(=O)OCc3ccccc3)CC2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Agent: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCNC(=O)C(C)(C)C(=O)N3CCN(C(=O)OCc4ccccc4)CC3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 17 using 4-[(4-{2-[2-{[4-(benzyloxycarbonyl)piperazin-1-yl]carbonyl}-2-(methyl)-propionylamino]ethoxy}-2-methylphenyl)methyl]-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-galactose instead of 4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one and acetobromo-α-D-glucose, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=O)[CH:11](Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([NH2:20])(=[S:19])[CH3:18].C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[S:19][C:17]([CH3:18])=[N:20][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2

Procedure:
The title compound was prepared by the following reaction sequence: i) treatment of the 5-bromo-azepan-4-one hydrobromide (1:1) [Ger. Offen. (1989), DE 38207751] with di-t-butyldicarbonate in dioxane/aq. sodium hydrogen carbonate solution to yield the 4-bromo-5-oxo-azepane-1-carboxylic acid tert-butyl ester; ii) treatment of the 4-bromo-5-oxo-azepane-1-carboxylic acid tert-butyl ester with thioacetamide in ethanol in the presence of triethylamine at reflux to give the 2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylic acid tert-butyl ester; iii) conversion of the 2-methyl-4,5,7,8-tetrahydro-thiazolo[5-d]azepine-6-carboxylic acid tert-butyl ester into the 2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine by removal of the tert-butyloxycarbonyl function with hydrogen chloride (aqueous, 37%) in methanol at room temperature.
Reaction SMILES: [Cl-:1].[P+]=O.N1C2C(=CC=CC=2)C=CC=1.[Br:14][C:15]1[C:16](=O)[NH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[CH3:21]>O>[Br:14][C:15]1[C:16]([Cl:1])=[N:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[CH3:21]
Reactant: Cc1c([N+](=O)[O-])c[nH]c(=O)c1Br
Reactant: [Cl-]
Agent: O=[P+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: Cc1c([N+](=O)[O-])cnc(Cl)c1Br
Temperature: 120 °C
Reaction time: 2 h

Procedure:
In a 25 ml single-necked round-bottomed flask, to 1.72 ml phosphorous oxide chloride kept at a temperature of 5° C., 0.857 ml quinoline and 3.40 g of 3-bromo-4-methyl-5-nitro-1H-pyridin-2-one are added consecutively. The resulting beige suspension is stirred under heating to 120° C. whereupon a brown solution is obtained. Stirring is continued for 2 hours. Afterwards, the solution is cooled down to an ambient temperature and poured into water. The resulting precipitate is collected by filtration, the filter cake washed with water (4×) and dried to give 3.15 g of the title compound in the form of a brown solid (MP: 60-62° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:24][NH:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Product: CS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(Br)cc32)cc1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from 5-bromo-1H-indole-2,3-dione (Meth-Cohn and Goon, Tetrahedron Letters 1996, 37, 9381-4) and 4-methylsulfonylphenylhydrazine according to Procedure G: 1H NMR (DMSO-d6): δ12.7 (s, 1H), 11.3 (s, 1H), 7.9 (d, 2H), 7.7-7.8 (m, 3H), 7.4 (dd, 1H), 6.9 (d, 1H), 3.2 (s, 3H); ESI−MS m/z 392 (M−H)−.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28](C)[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].[CH3:32][O:33][C@H]1CC[C@H](N)CC1.C1(CCBr)C=CC=CC=1>C(OC(=O)C)C>[CH3:32][O:33][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:16]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH2:26][CH2:27]1
Reactant: CO[C@H]1CC[C@H](N)CC1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: BrCCc1ccccc1
Solvent: CCOC(C)=O
Product: CO[C@H]1CC[C@H](N(CCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using trans-4-methoxy-cyclohexylamine (prepared as described in J. Med. Chem. 1977, 20, 279-290), 2-phenylethylbromide and 2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[N:5]2[CH:13]=[CH:14][N:15]=[C:4]2[CH:3]=1.[CH:16]1([CH:19]=[CH:20][C:21]#[N:22])[CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[N:11][N:10]([CH:19]([CH:16]3[CH2:18][CH2:17]3)[CH2:20][C:21]#[N:22])[CH:9]=2)[N:5]2[CH:13]=[CH:14][N:15]=[C:4]2[CH:3]=1
Reactant: N#CC=CC1CC1
Reactant: Clc1cc2nccn2c(-c2cn[nH]c2)n1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC(C1CC1)n1cc(-c2nc(Cl)cc3nccn23)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
To a solution of 7-chloro-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.107 g, 0.4872 mmol) and 3-cyclopropylacrylonitrile (Preparation B; 0.3403 g, 3.654 mmol) in 2 mL of acetonitrile was added DBU (0.1457 mL, 0.9744 mmol). The reaction mixture was sealed and heated to 50° C. and stirred overnight. To the reaction mixture was added more 3-cyclopropylacrylonitrile (0.100 g, 0.107 mmol) and DBU (0.072 mL, 0.448 mmol) and the reaction mixture was sealed and heated to 60° C. for 4 hours. The reaction mixture was loaded onto directly onto a column of silica gel and eluted with a gradient of 50-75% ethyl acetate in hexanes with 0.5% ammonium hydroxide to afford the title compound (0.119 g, 0.3729 mmol, 76.54% yield). MS (apci) m/z=313.1 (M+H).