Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:13]2[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1.Cl.CCN(C(C)C)C(C)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([N:13]2[CH2:17][CH2:16][CH:15]([NH:18][S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc3cnc4[nH]ccc4n23)C1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NC1CCN(c2ncc3cnc4[nH]ccc4n23)C1)C1CC1
Reaction time: 4 h
Yield: 70.6 %

Procedure:
To a solution of tert-butyl 1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylcarbamate (0.175 g, 0.511 mmol, Example #D.1.42) in DCM (10 mL) was added HCl (4 N in 1,4-dioxane, 1.28 mL, 5.11 mmol). After about 4 h at ambient temperature, the reaction mixture was concd in vacuo. The residue was suspended in DCM (10 mL) and DIEA (0.446 mL, 2.56 mmol) was added to the reaction mixture resulting in a nearly homogeneous mixture. To the mixture was added cyclopropanesulfonyl chloride (0.079 g, 0.56 mmol). After about 2 h at ambient temperature, additional cyclopropane-sulfonyl chloride (0.079 g, 0.56 mmol) was added. After about 6 h at ambient temperature, saturated aqueous NaHCO3 (10 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were concd in vacuo and purified by chromatography on silica gel (40 g) eluting with 50-90% MeCN in DCM to provide N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropane-sulfonamide (0.125 g, 70%) as a tan solid: LC/MS (Table 1, Method a) Rt=1.42 min; MS m/z: 347 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][NH2:25].C(OCC)(=O)C>CS(C)=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][NH:25][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1ccc2nc(Cl)cnc2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cnc3cc(OC)ccc3n2)c(OC)c1
Yield: 94.1 %

Procedure:
2-Chloro-6-methoxyquinoxaline (0.93 g, 4.77 mmol) and (2,4-dimethoxyphenyl)methanamine (2.2 ml, 14.64 mmol) were microwaved in dimethylsulfoxide (5 mL) for 30 min at 150° C. The reaction was diluted into ethyl acetate (250 mL) and extracted with brine (3×100 mL). The crude product was purified by column chromatography (20 to 80% ethyl acetate/hexanes) to afford N-(2,4-dimethoxybenzyl)-6-methoxyquinoxalin-2-amine (1.46 g, 87% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (1H, s), 7.59-7.63 (1H, m), 7.30 (1H, d, J=8.31 Hz), 7.21-7.24 (2H, m), 6.47 (1H, d, J=2.27 Hz), 6.42 (1H, dd, J=8.31, 2.27 Hz), 5.10 (1H, t, J=5.92 Hz), 4.61 (2H, d, J=5.79 Hz), 3.88 (3H, s), 3.84 (3H, s), 3.78 (3H, s). MS (LC/MS) R.T.=1.95; [M+H]+=326.23.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]#[N:16].[Al+3].[Cl-].[Cl-].[Cl-].O>ClC(Cl)C>[Br:1][C:2]1[C:3]([NH:9][C:15]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)=[NH:16])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: N#Cc1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: N=C(Nc1ncc(Br)nc1Br)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A solution of 3,5-dibromo-pyrazin-2-ylamine (608 mg, 2.4 mmol), furan-2-carbonitrile (297 uL, 3.39 mmol) and AlCl3 (320 mg, 2.4 mmol) in dichloroethane (6 ml) was heated at 115° C. overnight. The reaction was cooled to room temperature and water (5 ml) was added. After 30 minutes, the resulting precipitate was collected and purified by column chromatography (SiO2, THF) to afford 595 mg (72%) of N-(3,5-dibromo-pyrazin-2-yl)-furan-2-carboxamidine as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 6.73 (dd, J=3.4, 1.8 Hz, 1H), 7.3 (dd, J=3.1 Hz, 1H), 7.98 (s, 1H), 8.49(s, 1H), 8.69 (br. s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])(C)(C)C.[CH3:13][CH:14]([C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH3:15]>C1COCC1>[CH3:13][CH:14]([C:16]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([OH:20])[CH:17]([CH3:19])[CH3:18])[CH3:15]
Reactant: Cc1ccccn1
Reactant: CC(C)C(=O)C(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)C(O)(Cc1ccccn1)C(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
2-Methyl-pyridine (1.86 g, 20 mmol) is dissolved in THF (20 mL) and cooled to −30° C. tert-Butyl lithium (11.8 mL, 1.7M in pentane, 20 mmol) is added dropwise to the solution, and the reaction is stirred for 30 min at −30° C. 2,4-Dimethyl-pentan-3-one (3.4 mL, 24 mmol) is added and the reaction is warmed to room temperature and stirred for 2 h. Add H2O (30 mL) and extract with EtOAc. Wash combined organics with brine and concentrate in vacuo. The residue is purified by flash chromatography on silica gel (EtOAc/Heptane) to afford 2,4-dimethyl-3-pyridin-2-ylmethyl-pentan-3-ol (4.14 g, quant.).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH:14]([OH:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6])[CH:2]=[CH2:3].C(=O)(O)[O-]>CC(C)=O.[Cl-].[Na+].O>[C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:13]=1)(=[O:16])[CH3:15]
Reactant: C=CCOC(=O)Nc1cc(C(C)O)ccc1CC(=O)OCC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOC(=O)Nc1cc(C(C)=O)ccc1CC(=O)OCC
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
Ethyl [2-{[(allyloxy)carbonyl]amino}-4-(1-hydroxyethyl)phenyl]acetate (10.3 g) prepared by step e) was dissolved in acetone (30 mL) and thereto was added at room temperature Jons' reagent (10 mL), followed by stirring for 30 minutes. To the reaction solution were added saturated bicarbonate solution (50 mL) and saturated brine (100 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The organic layer was combined, dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give a crude product. The crude product was combined with the crude product prepared separately prepared in a scale of 1 g and purified with column chromatography (SiO2 300 g, hexane/ethyl acetate 1:1) to give the object compound (10.3 g, 85%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[CH2:36][C:37]([N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)=[O:38]>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[C:13]([N:15]1[CH2:20][CH2:19][C@H:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:36][C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:38])[CH2:23][CH2:22]2)[C@H:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:14]
Reactant: O=C(CCl)N1CCOCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccccc2)C1
Product: O=C(CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@H]2c2ccccc2)CC1)N1CCOCC1

Procedure:
The title compound, MS: m/e=613.1 (M+H+), was prepared in accordance with the general method of example 35 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-(3-phenyl-4-piperazin-1-yl-piperidin-1-yl)-methanone and 4-(2-chloroacetyl)morpholine.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.O1CCCC1.[H-].[Na+].C1(C)C=CC(S(O[CH:28]([CH3:40])[CH2:29][CH:30]([CH3:39])[CH2:31][CH2:32][CH2:33][C:34]([O:37][CH3:38])([CH3:36])[CH3:35])(=O)=O)=CC=1>CN(C)P(=O)(N(C)C)N(C)C>[CH3:38][O:37][C:34]([CH3:35])([CH3:36])[CH2:33][CH2:32][CH2:31][CH:30]([CH3:39])[CH2:29][CH:28]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1)[CH3:40]
Reactant: Oc1ccc2c(c1)OCC2
Reactant: COC(C)(C)CCCC(C)CC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(C)(C)CCCC(C)CC(C)Oc1ccc2c(c1)OCC2
Temperature: 25 °C

Procedure:
A solution of 2.7 g. of 6-hydroxy-2,3-dihydrobenzofuran in 10 ml. of absolute tetrahydrofuran is allowed to drop at 0° C. and while stirring into a suspension, cooled in ice, of 0.5 g. of sodium hydride in 5 ml. of absolute tetrahydrofuran. The mixture is stirred for 2 hours (during which time it is allowed to warm up to room temperature), again cooled to 0° C. and added dropwise to a solution of 7.13 g. of 7-methoxy-1,3,7-trimethyloctyl p-toluenesulfonate in 10 ml. of absolute tetrahydrofuran. The mixture is then diluted with 4 ml. of absolute hexamethylphosphoric acid triamide and stirred for 20 hours at room temperature. The mixture is then poured onto ice-water, extracted three times with diethyl ether, the ether extracts are washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (19:1 parts by volume) there is obtained pure 2,3-dihydro-6-[(7-methoxy-1,3,7-trimethyloctyl)-oxy]-benzofuran which is distilled in a bulb-tube at 145° C./0.03 mmHg; nD20 = 1.5046.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][O:41][C:39](/[N:3]=[C:1](\[NH2:2])/[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:8][CH:9]=1)=[O:40]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1

Procedure:
Dabigatran etexilate was first described in U.S. Pat. No. 6,087,380, according to which the synthesis of dabigatran etexilate was carried out in three synthetic steps (see Scheme 1). Example 58 describes the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound II) and N-(4-cyanophenyl)glycine (compound III) in the presence of N,N′-carbonyldiimidazole (CDI) in tetrahydrofuran to give the hydrochloride salt of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound IV), which is subsequently reacted with ethanolic hydrochloric acid, ethanol and ammonium carbonate to give the hydrochloride salt of ethyl 3-{[(2-[{(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound V). Finally, example 113 describes the reaction between compound V and n-hexyl chloroformate (compound VI), in the presence of potassium carbonate, in a mixture of tetrahydrofuran and water, to give dabigatran etexilate after work-up and chromatographic purification. However, no information is given about the purity of the isolated dabigatran etexilate.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].N([O-])=O.[Na+].[BrH:20]>O>[Br:20][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1Br
Temperature: -5 °C

Procedure:
Hydrobromic acid (48% wt. in water, 120 ml) is added dropwise to a suspension of 3-amino-4′-chloro-4-methylbiphenyl (21 g, 0.09 mol) in water (80 ml), and the mixture stirred until the solid is dissolved. The mixture is cooled to −5° C. and a solution of sodium nitrite (10.12 g, 0.14 mol) in water (50 ml) is added dropwise, maintaining the temperature at 0-5° C. The reaction mixture is stirred for 1 hour, then added to a pre-cooled solution of cuprous bromide (17.9 g, 0.12 mol) in hydrobromic acid (48% wt. in water, 120 ml) at 0° C. The reaction mixture is stirred and allowed to warm to room temperature overnight. The mixture is extracted with ethyl acetate, and the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with 2% ethyl acetate in hexane to give 3-bromo-4′-chloro-4-methylbiphenyl (15.0 g).
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:27])(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(Cl)(=O)OCC.[C:34](O)(=[O:42])[C:35]1[C:36](=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH2:37]>C(Cl)Cl>[CH2:9]([C:8]1[O:27][C:34](=[O:42])[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: Nc1ccccc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2c(=O)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
Triethylamine (0.46 ml) was added to a suspension of stearic acid (853 mg) in methylene chloride (8.5 ml). Then, ethyl chlorocarbonate (0.32 ml) was dropwise added to the mixture while being cooled with ice. After being stirred for 1 hour at 0° C., the mixture, with a mixed solution of anthranilic acid (411 mg) and triethylamine (0.42 ml) in methylene chloride (2 ml) dropwise added thereto, was stirred for 16 hours at 45C and cooled with ice. The reaction mixture, with triethylamine (0.46 ml) and ethyl chlorocarbonate (0.32 ml) dropwise added thereto, was stirred for 1 hour at 0° C. and for 1.5 hours at room temperature successively, and then concentrated. The residue, with ethyl acetate added thereto, was washed with water, neutralized with diluted hydrochloric acid, and washed with saturated brine. The organic layer was dried over magnesium sulfate anhydride and then concentrated. The residue was purified by silica gel column chromatography (silica gel 35 g, chloroform-methanol), thereby yielding 966 mg of the aimed compound as colorless crystals.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:8])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].Cl.[CH2:10](N(CC)CC)C.CCOCC>CO>[NH2:1][C@@H:2]([CH3:8])[CH:3]([OH:7])[C:4]([O:6][CH3:10])=[O:5]
Reactant: CCN(CC)CC
Reactant: C[C@H](N)C(O)C(=O)O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(O)[C@H](C)N
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Into a suspension of (3S)-3-amino-2-hydroxybutanoic acid (1.0 g, 8.4 mmol) in methanol (25 ml) was bubbled anhydrous hydrogen chloride gas until a solution resulted. After a solution resulted, the reaction was cooled in an ice bath and saturated with hydrogen chloride. The cooling bath was removed and the reaction stirred at room temperature for 3.5 hours. The solvent was removed on a rotary evaporator at ambient temperature and the resultant residue dissolved in methanol (25 ml), cooled in an ice bath and saturated with hydrogen chloride gas. Warming of the reaction solution to room temperature and removal of the solvent on a rotary evaporator gave an oil. To this oil was added triethylamine (15 ml) followed by the minimum amount of methanol (about 15 ml) needed to dissolve the initial gummy solid. The solution was cooled in an ice bath and ether (75 ml) added in portions with stirring. The precipitated triethylamine hydrochloride was filtered and the filtrate evaporated to give methyl (3S)-3-amino-2-hydroxybutanoate.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)=[N:6][CH:5]=1)[CH3:3].[CH3:23][C:24]([CH3:38])([CH3:37])[C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31])=[O:26].C(N(CC)CC)C>CN(C)C=O>[CH3:23][C:24]([CH3:38])([CH3:37])[C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][CH:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][C:11]2[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=2)=[N:6][CH:5]=1)[CH3:3])=[O:31])=[O:26]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: CC(C)(C)C(=O)Nc1ccccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3NC(=O)C(C)(C)C)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 18 (below), 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.050 g, 0.16 mmol) 2-[(2,2-dimethylpropanoyl)amino]benzoic acid (0.040 g, 0.18 mmol), O-(7-azabenzotriazol-1-yl-N,N,N′N′-tetramethyluronium hexafluorophospahte (0.068 g, 0.18 mmol) and triethylamine (0.048 mL, 0.34 mmol) in N,N-dimethylformamide (1.0 mL) gave 2-[(2,2-dimethylpropanoyl)amino]-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.040 g) as a white solid. MS m/z 509 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH:12]([CH3:14])[CH3:13].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[C:22]=[O:23])[CH:16]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:22](=[O:23])[NH:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:3]=1[S:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Sc1cc2c(cc1Cl)NCC2
Reactant: O=C=Nc1cccnc1
Product: CC(C)Sc1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2
Yield: 61 %

Procedure:
6-Chloro-5-isopropylthioindoline (D66) (0.35 g, 1.52 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was recrystallised from ethanol/diethyl ether to give the title compound (0.33 g, 61%) as a white crystalline solid m.p. 199°-201° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of 3,4-difluoronitrobenzene (1.00 mL, 9.03 mmol), imidazole (0.615 g, 9.04 mmol) and K2CO3 (2.50 g, 18.1 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water (20 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give 1-(2-fluoro-4-nitrophenyl)-1H-imidazole as a solid (1.81 g). MS 208.2 (M+H)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].[NH2:10][C:11](N)=[O:12]>>[C:11](=[O:12])([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)[NH2:10]
Reactant: NC(N)=O
Reactant: CCc1ccc(O)cc1
Product: CCc1ccc(OC(N)=O)cc1
Yield: 88 %

Procedure:
The same method as step (6-1) of Example 6 was carried out with the exception of using 39.0 kg of 4-ethyl phenol (Tokyo Chemical Industry Co., Ltd., Japan) instead of 4-phenyl phenol, using 1057 g of urea and carrying out the reaction for 12 hours. When a portion of the reaction liquid was removed and analyzed by liquid chromatography, the formation of (4-ethylphenyl) carbamate was confirmed. The yield was about 88% based on the charged amount of urea.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].Cl[C:12]1[N:13]=[CH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[C:24]([OH:28])=[C:23]([CH3:29])[CH:22]=3)[O:18][C:16]=2[N:17]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:12]1[N:13]=[CH:14][C:15]2[N:20]=[C:19]([C:21]3[CH:22]=[C:23]([CH3:29])[C:24]([OH:28])=[C:25]([CH3:27])[CH:26]=3)[O:18][C:16]=2[N:17]=1
Reactant: Oc1ccccc1F
Reactant: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.48 g of sodium hydride (60% in mineral oil) is added a little at a time to a solution of 1.12 ml of 2-fluorophenol in 40 ml of dry N,N-dimethylacetamide. After 30 min at room temperature, a suspension of 2.78 g of 4-(5-chlorooxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenol (see Ex. 1 (c)) in 60 ml of dry N,N-dimethylacetamide is added, and the reaction is stirred at 60° C. for 1.5 h and at 80° C. for 5.5 h. Another 1.12 ml of 2-fluorophenol in 40 ml of dry N,N-dimethylacetamide were then reacted under argon with 0.48 g of sodium hydride (60% in mineral oil), and this mixture was added to the reaction at room temperature. After a further 9 h at 80° C., the reaction was cooled to room temperature and neutralized with 10% strength aqueous citric acid solution. The precipitated solid was filtered off with suction, washed with water and dried under reduced pressure at 45° C. This gave 3.37 g (96%) of the title compound, which was reacted without any further purification.
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([C:18]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CNCCN1
Reactant: O=C(Cl)C1CCCC1
Solvent: O
Solvent: CCO
Product: O=C(C1CCCC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Piperazine hexahydrate (8.55 g, 44.0 mmol) was dissolved in absolute ethanol (50 ml) and then refluxed for 10 min. Cyclopentanecarbonyl chloride (5.83 g, 44 mmol) was added dropwise at 65° C. and the reaction mixture was refluxed for 30 min and then stirred at room temperature for 18 h. The reaction mixture was cooled, filtered and the filtrate was concentrated in vacuo to give ˜20 ml of solution. The concentrate was cooled and then filtered again. Ethanolic hydrogen chloride was added to the mother liquor, and the reaction mixture was concentrated to give a white solid, which was dissolved in water (15 ml). The solution was basified to pH 14 and the product was extracted with dichloromethane (7×50 ml). The extracts were dried, (Na2SO4) and concentrated to give the title compound as a yellowish residue, which was distilled to give the product (1.28 g, 7.0 mmol, 16%)