Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2N(O)N=N[C:5]=2[CH:6]=1.[C:11]([O:14]C(=O)C)(=O)[CH3:12].[N:18]1C=CC=C[CH:19]=1>C(Cl)Cl>[CH2:19]([NH:18][C:11](=[O:14])[CH3:12])[C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: On1nnc2ccccc21
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1ccccc1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a suspension of P-HOBT 1 (0.212 g, 0.125 mmol) in CH2Cl2 (5 mL) was added acetic anhydride (0.216 g, 0.200 mL, 2.12 mmol, 17 equiv.) and pyridine (0.234 g, 0.240 mL, 2.96 mmol, 24 equiv.). The suspension was subsequently rocked for 60 minutes at 25° C. The polymer was then filtered, washed with CH2Cl2 (3×5 mL), NMP (3×5 mL), CH2Cl2 (3×5 mL), and anhydrous Et2O (3×5 mL). The polymer was re-suspended in CH2Cl2 (5 mL) and benzylamine (0.0098 g, 0.010 mL, 0.91 mmol, 0.73 equiv. based on P-HOBT 1) was added. The suspension was rocked at 25° C. for 4 h. The polymer was then filtered and washed with CH2Cl2 (4×5 mL). The filtrate and washings were combined and concentrated to yield 0.014 g (100%) of N-benzylacetamide as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:4].[H][H].Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][N:14]=1.Cl>CN(C=O)C.O.CO>[Cl:19][C:18]1[C:13]([CH:5]([C:3]#[N:4])[C:6]([O:8][CH3:9])=[O:7])=[N:14][CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: [H][H]
Reactant: COC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C#N)c1ncc(C(F)(F)F)cc1Cl

Procedure:
Under argon, 116 g of sodium hydride 60% in dispersion in oil (2.91 mol, 1.8 eq.) was suspended in 3 L of DMF. The suspension was cooled down in an ice-water bath. 160 g (1.616 mol, 1.0 eq) of methyl cyanoacetate in solution in 200 mL of DMF was added dropwise under stirring. Temperature rose to 50° C. and hydrogen was released. Once bubbling was over, 350 g (1.616 mol, 1.0 eq) of 2,3-dichloro-5-(trifluoromethyl)-pyridine was added under stirring. The mixture was stirred overnight at room temperature. 50 mL of methanol were added dropwise to quench the reaction. The reaction mixture was poured in 5 L of water. pH was adjusted to 3-4 with concentrated hydrochloric acid.
Reaction SMILES: C([Al](CC(C)C)CC(C)C)C(C)C.[NH2:14][C:15]1[S:16][CH2:17][CH2:18][N:19]=1.[C:20]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([C:34]=1[OH:35])=[CH:32][CH:31]=[CH:30][CH:29]=2)(OCC)=[O:21]>C1(C)C=CC=CC=1>[S:16]1[CH2:17][CH2:18][N:19]=[C:15]1[NH:14][C:20]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([C:34]=1[OH:35])=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:21]
Reactant: NC1=NCCS1
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Product: O=C(NC1=NCCS1)c1cnc2ccccc2c1O
Temperature: 8 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
167 ml of a solution of 25% by weight of triisobutyl aluminum in toluene were added with stirring over 20 minutes at 8° to 10° C. to a mixture of 37.4 g of 2-amino-thiazoline and 800 ml of methylene chlorideand the mixture was stirred at 8° C. for 30 minutes. 15.89 g of 3-carbethoxy-4-hydroxy-quinoline were added to the mixture which was then stirred for 30 minutes and then refluxed for 16 hours. The mixture was evaporated to dryness under reduced pressure and the residue was taken up in 1 liter of N aqueous hydrochloric acid. The solution was filtered and the filtrate was iced for 16 hours and was filtered. The product was washed with water and the filtrate was made alkaline with sodium carbonate. The mixture was filtered and the product was washed with water and dried to obtain 11.7 g of N-(4,5-dihydro-thiazol-2-yl)-4-hydroxy-3-quinoline-carboxamide.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH:8]1(O)[CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([O:1][CH:2]2[NH:6][C:5](=[O:7])[CH:4]=[CH:3]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1C=CC(O)N1
Reactant: OC1CCCC1
Product: O=C1C=CC(OC2CCCC2)N1
Temperature: 60 °C

Procedure:
A mixture of 4.5 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one, 100 cm3 of cyclopentanol and 2.25 g of Amberlite IR 120 H is maintained for 8 hours at 60° C. It is then allowed to cool, is filtered, and evaporated to dryness. The residue is chromatographed on silica (eluent: ethyl acetate-n-hexane, 1--1). 3 g of the expected product is obtained, m.p.=77°-78° C. crystallized from cyclohexane. After recrystallizing from a mixture of isopropyl ether-n-hexane, 1--1, m.p.=81°-82° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[CH:4]=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C(#N)C>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[N:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[CH:4]=2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(Br)cc1
Reactant: FC(F)(F)c1cc(CBr)n(-c2ccccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(COc2ccc(Br)cc2)n(-c2ccccc2Cl)n1

Procedure:
Into a 25 mL flask was weighed 1.52 g (4.48 mmol) of 5-bromomethyl-1-(2-chlorophenyl)-3-trifluoromethyl-1H-pyrazole, 854 mg of 4-bromophenol, 584 mg of sodium carbonate, then 5 mL of DMF, and 5 mL of acetonitrile were added. The resulting suspension was stirred and heated at 80-850C for 20 h then was washed into a separatory funnel with ethyl acetate and water. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Biotage, 80 g Silica gel, gradient elution from 100% hexanes to 40% ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated in vacuo to afford the product as a colorless solid, yield: 1.917 g (99%); 1H NMR (400 MHz, DMSO-d6): δ 7.82 (m, 2H), 7.70 (dt, J=1.5, 7.5 Hz, 1H), 7.62 (dt, J=1.5, 7.5 Hz, 1H), 7.49 (d, J=9 Hz, 2H), 7.27 (s, 1H), 6.92 (d, J=9 Hz, 2H), 5.12 (s, 2H); MS (ES): 431 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:9][CH2:10][C:11]([OH:13])=[O:12])[CH3:8].Cl[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C.O>[CH2:7]([O:9][CH2:10][C:11]([O:13][CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])[CH3:8]
Reactant: ClCSc1ccccc1
Reactant: CCOCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCC(=O)OCSc1ccccc1
Temperature: 70 °C
Yield: 68.7 %

Procedure:
To a mixture of Cs2CO3 (29.5 g, 91 mmol) in DMF (150 mL) at 0° C. was added 2-ethoxyacetic acid (18.0 mL, 191 mmol), and the resulting mixture was heated at 70° C. for 30 min. The reaction was cooled to 0° C., chloromethyl phenylsulfide (10.56 mL, 79 mmol) was added, and the reaction was heated at 70° C. for 90 min. The mixture was cooled to room temperature, and then 0° C., before diluting with H2O (200 mL; an exotherm was observed). The reaction mixture was divided into two equal portions and one portion was further diluted with water (400 mL) and extracted with Et2O (200 mL×2, 100 mL×1). The combined organic extracts were diluted with hexane (100 mL) and washed successively with 1.0 M aqueous NaOH (100 mL) and brine (2×200 mL), dried over anhydrous MgSO4, filtered, and concentrated. The second portion of the reaction mixture from above was processed in an identical fashion and the two lots were combined and concentrated in vacuo to afford the title compound as a yellow oil (12.28 g, 97%): 1H NMR (400 MHz, CDCl3) δ 7.48-7.41 (m, 2H), 7.31 (ddd, J=12.6, 7.9, 6.3 Hz, 3H), 5.51 (s, 2H), 4.11 (s, 2H), 3.59 (q, J=7.0 Hz, 2H), 1.24 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 170.00, 134.35, 130.53, 129.16, 127.55, 68.46, 68.10, 67.32, 14.99; ESIMS: m/z 226 ([M]+).
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:19][CH2:20][O:21][CH3:22].[I-].[Na+]>CN(C=O)C>[CH3:22][O:21][CH2:20][CH2:19][N:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[S:8]([C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)(=[O:9])=[O:10]
Reactant: COCCBr
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(I)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN(C(C)(C)C)S(=O)(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Sodium hydride (71 mg, 1.77 mg) was added to a solution of N-t-butyl-4-iodobenzenesulphonamide (Method 73; 500 mg, 1.47 mmol), in anhydrous DMF (15 ml), under nitrogen at 0° C. The resulting suspension was stirred at 0° C. for 30 minutes. A solution of 1-bromo-2-methoxyethane (167 μl, 1.77 mmol), and sodium iodide (265 mg, 1.77 mmol) in DMF (15 ml) (which had been pre-stirred at ambient temperature for 1 hour), was then added dropwise to the mixture so that the reaction temperature was maintained at 0° C. and the mixture then stirred for 10 minutes. The mixture was allowed to warm to ambient temperature, and then heated at 60° C. for 20 hours and then allowed to cool to ambient temperature. A further solution of 1-bromo-2-methoxyethane (167 μl, 1.77 mmol), and sodium iodide (265 mg, 1.77 mmol), in DMF (15 ml), (pre-stirred at ambient temperature for 1 hour), was then added dropwise and the reaction mixture was heated at 60° C. for a further 20 hours. The mixture was then cooled and solvent removed by evaporation. The residue was dissolved in ether (25 ml), washed with 10% aqueous sodium hydroxide solution (20 ml), water (3×25 ml), and dried. The volatiles were removed by evaporation and the residue purified by flash chromatography on silica gel eluting with DCM to yield the title compound (147 mg, 25%), as a clear oil that crystallised on standing. NMR: 1.23 (s, 9H), 3.24 (s, 3H), 3.48 (s, 4H), 7.57 (d, 2H), 7.94 (d, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.[H-].[Na+].Br[CH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.O>CN(C=O)C.CCOC(C)=O>[CH:36]1([CH2:35][CH2:34][N:23]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:16][O:15][N:14]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:22]=2)[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: Cn1nnnc1C(=NOCc1cccc(NC(=O)OC(C)(C)C)n1)c1ccccc1
Reactant: BrCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nnnc1C(=NOCc1cccc(N(CCC2CCCCC2)C(=O)OC(C)(C)C)n1)c1ccccc1
Reaction time: 1 h
Yield: 106.5 %

Procedure:
A stirred solution of tert-butyl {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (0.2 g, 0.488 mmol, 1 eq.) in 3 ml of dry DMF was treated with NaH (60% dispn in mineral oil, 0.020 g, 0.513 mmol, 1.05 eq.) added in one portion. After 20 mins (2-bromoethyl)cyclohexane (0.098 g, 0.513 mmol, 1.05 eq.) was added and the reaction was stirred for 1 hr. Water was added followed by EtOAc. The aqueous layer was separated and extracted with EtOAc. Then the organics were combined, dried over MgSO4 and evaporated to give tert-butyl (2-cyclohexylethyl){6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (0.27 g, 85%) as a viscous oil
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].Cl[C:31]1[C:32]2[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:33]=2[N:34]=[CH:35][N:36]=1.N12CCCN=C1CCCCC2>CC(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:25][CH2:26][N:27]([C:31]4[C:32]5[C:39]([CH3:40])([CH3:41])[C:38](=[O:42])[NH:37][C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:28][CH2:29]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: CC1(C)C(=O)Nc2ncnc(Cl)c21
Reactant: Fc1ccc(-c2cn(CCN3CCCC3)c(C3CCNCC3)n2)cc1Cl
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: CC1(C)C(=O)Nc2ncnc(N3CCC(c4nc(-c5ccc(F)c(Cl)c5)cn4CCN4CCCC4)CC3)c21
Yield: 13.5 %

Procedure:
Combine 4-[4-(3-Chloro-4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidine tris hydrochloride (0.3 g; 0.00062 mol), 4-chloro-5,5-dimethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.16 g; 0.0008 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.76 mL; 0.0051 mol) into IPA (10 mL) and stir at 120° C. for 16 h; cool and concentrate. Quench the reaction with saturated sodium bicarbonate solution and extract with EA. Evaporate the EA layer and purify by column chromatography using 0-5% MeOH/DCM as eluent to afford the title compound (0.045 g; 13.5%). MS (ES+): m/z=538 (M+1).
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(Cl)Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:24]([O:20][C@@H:5]1[C@@H:4]([O:21][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:3]([O:22][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:2]([CH2:1][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:7][C@@H:6]1[O:8][C@@H:9]1[C@@H:10]([CH2:18][O:19][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:11][CH:12]([O:17][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:13]([O:16][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:14]1[O:15][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)C(OC(=O)c3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 163.2 %

Procedure:
Maltose (2.0 g, 5.84 mmol) was dissolved in dry pyridine (40 mL) at 0° C. DMAP (cat.) was added. Benzoyl chloride (2.5 equiv., 14.6 mmol, 16.4 g, 13.6 mL) was added dropwise and the solution stirred at room temperature overnight. The solution was poured onto a mixture of ice-water and DCM. The organic layer was washed with NaHCO3(sat.) (×7), brine, H2SO4 (5%) (×2), followed by brine. The solution was dried (Na2SO4) and the solvent evaporated. The product was passed through a short silica plug to remove the remaining benzoyl chloride and the solvent was evaporated to yield 3.5 g (51%) of the white solid product which was reacted on without further purification or characterisation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]=2[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:4][CH:3]=1.[CH3:36][N:37]([CH3:41])[CH2:38][C:39]#[CH:40].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.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.[Cu]I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:40]#[C:39][CH2:38][N:37]([CH3:41])[CH3:36])[C:9]=2[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OS(=O)(=O)C(F)(F)F)cccc2-c2ccc(Cl)cc2)CC1
Reactant: C#CCN(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)CC#Cc1cccc(-c2ccc(Cl)cc2)c1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
To a mixture of EXAMPLE 196C (380 mg), N,N-dimethylprop-2-yn-1-amine (0.227 ml), tetrakis(triphenylphosphine)palladium(0) (123 mg) and triethylamine (0.492) in N,N-dimethylformamide (1.5 ml) was added copper(I) iodide (27.1 mg) and tBuNI (394 mg). The reaction mixture was heated at 100° C. for 4 hours, cooled and diluted with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography, eluting with a mixture of methanol, dichloromethane and triethyl amine to provide the title compound.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2Cl)[N:7]([CH3:16])[C:6]1=[O:17])[C:2]#[C:3][CH3:4].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.Cl>C(#N)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:12]2[N:11]=[C:10]([Cl:15])[N:9]=[C:8]3[C:13]=2[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:6](=[O:17])[N:7]3[CH3:16])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC#CCn1c(=O)n(C)c2nc(Cl)nc(Cl)c21
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC#CCn1c(=O)n(C)c2nc(Cl)nc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 60.2 %

Procedure:
7-(2-Butynyl)-2,6-dichloro-9-methyl-7,9-dihydropurin-8-one (334 mg) was dissolved in acetonitrile (5 mL), piperazin-1-carboxylic acid t-butyl ester (300 mg) and triethylamine (190 μL) were added, and this reaction solution was stirred at room temperature for 96 hours. After completion of the reaction, 1 N hydrochloric acid (3 mL) and water (10 mL) were added to the reaction solution, and this was extracted with ethyl acetate. The obtained organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The resulting organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (312 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[F:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH:32][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: NCCOCCCF
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOCCCF)ccc21
Yield: 16.9 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(3-fluoro-propoxy)-ethyl]-amide (12 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (55 mg), 2-(3-fluoro-propoxy)-ethylamine (50 mg), HBTU (60 mg), and DIEA (50 uL) in DMF (800 uL). LC/MS: m/z 463.0.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:26]=[N:27][N:28]([CH3:30])[N:29]=4)[CH:20]=3)[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[N:26]=[N:27][N:28]([CH3:30])[N:29]=4)[CH:20]=3)[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cccc(-c4nnn(C)n4)c3)csc12
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cccc(-c4nnn(C)n4)c3)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-[3-(2-methyl-2H-tetrazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.15 g, 0.35 mmol) (from Example 31 supra) in 2-propanol (15 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-[3-(2-methyl-2H-tetrazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.11 g, 79%).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18].[CH:23]([C:26]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:27]=1[NH2:28])([CH3:25])[CH3:24].C(N(CC)CC)C>O1CCCC1>[CH3:35][CH:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:26]([CH:23]([CH3:25])[CH3:24])[C:27]=1[NH:28][S:17]([NH:20][C:21](=[O:22])[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:19])=[O:18])[CH3:34]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1NS(=O)(=O)NC(=O)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of dibenzylamine (5.0 g, 25.3 mmol) in 75 mL tetrahydrofuran was added dropwise to a solution of chlorosulfonyl isocyanate (2.21 mL, 25.3 mmol) in 75 mL tetrahydrofuran at 0° C. under an atmosphere of nitrogen. The resulting mixture was warmed to room temperature and stirred for 16 hours. A solution of 2,6-diisopropyl aniline (4.08 g, 23 mmol) and triethylamine (3.5 mL, 25 mmol) in 50 mL tetrahydrofuran was added dropwise and the resulting suspension was stirred for 72 hours. Partitioned between 1N HCl and ethyl acetate. The organic layer was dried with MgSO4, filtered, and evaporated to give an orange oil. Chromatography gave the title compound as a white solid, mp 140°-142° C.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)([O-:22])=[O:21].N1C=CC=CC=1>C(#N)C>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:31])[S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCCCS
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCSC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and reflux condenser, n-octadecanethiol (183 g) was dissolved in acetonitrile (1000 ml) in a nitrogen atmosphere. To the solution, p-nitrophenyl isocyanate (100 g) was gradually added and then pyridine (4 ml) was added dropwise, the mixture was stirred at room temperature for 10 minutes and then refluxed for 30 minutes. The reaction mixture was cooled to room temperature to allow crystals to precipitate. The crystals were collected by filtering and washed with acetonitrile, to obtain S-n-octadecyl p-nitrophenylthiocarbamate (272 g) at a yield of 99%.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:11]=[C:10](F)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:5]=1[C:6]#[N:7]>C1COCC1>[Cl:3][C:4]1[CH:11]=[C:10]([NH:2][CH3:1])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CN
Reactant: N#Cc1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: C1CCOC1
Product: CNc1cc(Cl)c(C#N)cc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of MeNH2 in THF (14.9 mL, 2 M, 29.8 mmol) was added dropwise to a solution of 2-chloro-4-fluoro-5-nitrobenzonitrile (3.0 g, 15 mmol) in THF (100 mL) at −20° C. The mixture was stirred at −20° C. for 1 h and thereafter concentrated, washed with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was washed with PE to give the sub-title compound.