Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:22][O:23][C:24](=[O:33])[C@H:25]([CH2:27][C:28]1[N:32]=[CH:31][NH:30][CH:29]=1)[NH2:26].C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C=O>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([NH:26][C@@H:25]([CH2:27][C:28]1[N:32]=[CH:31][NH:30][CH:29]=1)[C:24]([O:23][CH3:22])=[O:33])=[O:12])(=[O:6])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.7 (20 mmol) of (S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamic acid (EPA 0236734) 4.85 g (20 mmol) of L-histidine methyl ester dihydrochloride, 10.3 ml (81.7 mmol) of N-ethylmorpholine and 2.98 g (20 mmol) of HOBT in 85 ml of dimethylformamide is treated portionwise under argon at 0°-2° with 4.23 g (22 mmol) of EDC and subsequently stirred at room temperature overnight. Thereafter, the solvent is evaporated in a high vacuum, the residue is taken up in 100 ml of ethyl acetate and washed in sequence three times with 10 ml of 2N sodium bicarbonate solution, twice with 10 ml of saturated sodium chloride solution, twice with 10 ml of saturated ammonium chloride solution and twice with 5 ml of saturated sodium chloride solution. The aqueous phases are extracted three times with 20 ml of ethyl acetate and the pooled organic phases are dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product obtained (9.4 g) is chromatographed on 300 g of silica gel using a 95:5 mixture of methylene chloride and methanol as the eluent. There are obtained 8.6 g of methyl (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionate as a colourless foam; MS: 436 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]3[NH:14][CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=2)[CH:7]=[N:6][CH:5]=1.[C:21]([N:29]=C=O)(=[O:28])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:21]([N:14]1[C:13]2[N:12]=[CH:11][C:10]([C:8]3[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:20])=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1)(=[O:28])[NH2:29]
Reactant: COC(=O)c1cncc(-c2cnc3c(c2)CCCN3)c1
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: NC(=O)N1CCCc2cc(-c3cncc(C(=O)O)c3)cnc21
Yield: 52.9 %

Procedure:
To the solution of 5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-nicotinic acid methyl ester (205 mg, 0.76 mmol) in 60 mL of anhydrous DCM is added benzoyl isocyanate (170 mg, 1.1 mmol) and the solution is heated to reflux for 3 hrs. Then the solvent is removed in vacuo and to the residue is added 60 mL of MeOH. Then K2CO3 (180 mg, 1.3 mmol) is added and the mixture is heated to reflux for 0.5 hr. After cooling down, the organic solvent is evaporated. The residue is taken up in water and washed with DCM. The aqueous layer is separated and purified by neutral preparative HPLC to give 120 mg of the titled product.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@:10]([OH:32])([C@H:17]([S:19][C@@H:20]1[CH2:25][O:24][C@@H](C2C=CC=CC=2)[O:22][CH2:21]1)[CH3:18])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1>C1(C)C=CC=CC=1>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@:10]([OH:32])([C@H:17]([S:19][CH:20]([CH2:21][OH:22])[CH2:25][OH:24])[CH3:18])[CH2:11][N:12]1[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1cccc(F)c1F
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1cccc(F)c1F
Temperature: 50 °C

Procedure:
30 ml (30 mmol) of 1 N hydrochloric acid were added to a solution of 3.35 g of crude (2R,3R)-2-(2,3-difluorophenyl)-3-[(trans-2-phenyl-1,3-dioxan-5-yl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Step 7(v) above] in 45 ml of toluene. The resulting mixture was heated at 50° C. for 6 hours. At the end of this time, the aqueous layer was separated. The oily layer was then extracted twice with a dilute hydrochloric acid solution. The aqueous layers were then combined and sodium hydrogen carbonate was carefully added in small portions to the solution until the evolution of carbon dioxide gas had ceased. The reaction mixture was then extracted with ethyl acetate and the extract was concentrated under reduced pressure to afford the title compound as a solid. The solid was washed with a 2:1 mixture of ethyl acetate and hexane and 1.54 g [overall yield from Step 7(v) 61%] of the title compound were collected by filtration.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Br:11])[CH:10]=1.[H-].[Na+].Br[CH2:16][CH2:17]Br.O>CN(C)C=O.O1CCCC1>[Br:11][C:9]1[CH:10]=[C:5]([C:4]2([C:3]([O:2][CH3:1])=[O:12])[CH2:17][CH2:16]2)[CH:6]=[N:7][CH:8]=1
Reactant: BrCCBr
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C1(c2cncc(Br)c2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of the title compound from Example 71 Step A (0.50 g, 2.17 mmol) in N,N-dimethylformamide (6.8 mL) and tetrahydrofuran (6.8 mL) was added sodium hydride (60% dispersion in mineral oil, 0.435 g, 10.9 mmol). After stirring for 15 minutes, 1,2-dibromoethane (0.56 ml, 6.5 mmol) was added. After stirring overnight, the reaction was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (20-80% ethyl acetate in hexanes) provided the title compound: LCMS m/z 257.78 [M+2+H]+; 1H NMR (500 MHz, CD3OD) δ 8.53 (s, 1H), 8.49 (s, 1H), 8.02 (s, 1H), 3.63 (s, 3H), 1.64 (m, 2H), 1.29 (m, 2H).
Reaction SMILES: [Br:1]Br.[CH2:3]([N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([CH3:20])=[N:14][C:15]=2[NH2:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CC([O-])=O.[Na+]>CC(O)=O>[CH2:3]([N:10]1[C:18]([Br:1])=[N:17][C:16]2[C:11]1=[N:12][C:13]([CH3:20])=[N:14][C:15]=2[NH2:19])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: Cc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 70 °C
Yield: 16 %

Procedure:
Bromine (0.2 ml) was added to a solution of 9-benzyl-2-methyladenine 60 mg (0.25 mmol) and NaOAc (0.22 g) in AcOH (5 ml), and the mixture was heated at 70° C. for 40 min. The solvent was evaporated under vacuum, and the residue was extracted by EtOAc. The resulting organic layer was evaporated under vacuum, and the residue was purified by column chromatography (CH2Cl2 :MeOH=50:1) to obtain 9-benzyl-8-bromo-2-methyladenine as an orange solid (60 mg). A mixture of the resulting 9-benzyl-8-bromo-2-methyladenine (60 mg) and conc.HCl (5 ml) was refluxed for 3 h. After cooling, aqueous NH3 was added to crystallize the product, and the desired compound was collected by filtration (10 mg, Yield: 16%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:27])=[C:15]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>ClCCl.C1(OC)C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([O:18][S:19]([C:22]([F:24])([F:25])[F:23])(=[O:20])=[O:21])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)C(F)(F)F)CS[C@H]12
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(OS(=O)(=O)C(F)(F)F)CS[C@H]12
Reaction time: 1 h
Yield: 113.8 %

Procedure:
To a solution of benzhydryl 7β-(2-phenylacetamido)-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylate (9.0 g) in a mixture of dichloromethane (27 ml) and anisole (9 ml) was added trifluoroacetic acid (18 ml) under ice-cooling. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into diisopropyl ether (380 ml) The precipitate was collected by filtration and dried to give 7β-(2-phenylacetamido)-3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylic acid (7.55 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([CH3:21])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C([O-])=O.[NH4+].ClCCl>[Pd].O>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([CH3:21])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1cc(OCCOCc2ccccc2)ccc1N
Reaction time: 1 h
Yield: 103.8 %

Procedure:
A 500 ml round bottomed flask fitted with a teflon stirrer bar was charged with 4-(2-(benzyloxy)ethoxy)-2-methyl-1-nitrobenzene (5.15 g) and methanol (200 ml) and stirred to dissolve all material. The reaction mixture was charged with 10% palladium on charcoal (50% water w/w) and stirred at room temperature. Ammonium formate (20.5 g) was added in one lot and the reaction mixture was stirred at room temperature. After 1 hour, additional ammonium formate (20.5 g) was added, and the progress of the reaction was followed by TLC (silica, dichloromethane). After 4 hours, the reaction was found to be complete. The reaction mixture was then filtered through a plug of Celite, which was washed with methanol (2×50 ml). The resulting filtrate was evaporated under reduced pressure to give a solid. This material was dissolved in water (300 ml), extracted with diethylether (3×100 ml). The combined ethereal solutions were washed with water (2×100 ml) and saturated sodium chloride solution (2×100 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 4.79 g of 4-(2-(benzyloxy)ethoxy)-2-methylaniline, 1H-NMR (CDCl3) 7.39 (m, 2H), 7.37 (s, 1H), 7.31 (m, 2H), 6.33 (m, 1H), 6.30 (s, 1H), 6.23 (m, 1H), 5.85 (bs, 2H), 4.63 (s, 2H), 4.11 (m, 2H), 3.79 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[C:5]([Br:8])=[CH:6][CH:7]=1.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-])=O.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[C:3]([N:10]=[N:11][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([NH2:9])[C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: Nc1c(Br)ccc(Br)c1N
Reactant: O=[N+]([O-])c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1c(Br)ccc(Br)c1N=Nc1ccccc1
Temperature: 160 °C
Yield: 3.5 %

Procedure:
3,6-dibromo-1,2-phenylenediamine (1.33 g, 5.0 mmol), nitrobenzene (2.06 mL, 20 mmol), and sodium hydroxide (0.20 g, 5 mmol) were mixed in an 1-neck 100-mL round bottomed flask. The flask was heated in an oil bath at 160° C. for 3 h. The mixture was cooled to room temperature and dichloromethane was added to extract the product. The extract was filtered and the solution concentrated using a rotary evaporator. The solution was chromatographed on a silica gel column using dichloromethane as eluent. The fractions were combined and solvent removed under reduced pressure. The solid was further dried under high vacuum for 1 h. Yield: 3.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.[C:13](Cl)(=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:8]([CH3:11])[C:7]=2[CH:12]=1
Reactant: CCCCCCC(=O)Cl
Reactant: COc1ccc2occ(C)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CCCCCCC(=O)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a mixture of 5-methoxy-3-methyl-1-benzofuran (1.87 g) synthesized in Example A104(2), heptanoyl chloride (2.14 mL) and nitromethane (20 mL) was added aluminum chloride (3.07 g), and the mixture was stirred overnight at room temperature. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (7% ethyl acetate/hexane) to give the title object compound (2.34 g, 74%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]#[N:18])[S:11]3)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH3:16])=[C:12]([C:17]([NH:20][OH:21])=[NH:18])[S:11]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C#N)sc2nc(-c3ccc(F)cc3)cn12
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c(C(=N)NO)sc2nc(-c3ccc(F)cc3)cn12
Yield: 63 %

Procedure:
6-(4-Fluoro-phenyl)-3-methyl-imidazo[2,1-b]thiazole-2-carbonitrile (example 20, 140 mg, 0.54 mmol), hydroxylamine hydrochloride (226.9 mg, 3.26 mmol) and triethylamine (529 μl, 3.8 mmol) were stirred in 10 ml of isopropanol at 90° C. for 2 hours. The solvent was removed in vacuo and water was added. The solid was filtered, washed with diluted hydrochloric acid and water and was dried. Yield: 63%. MS: M+H+=291.15.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[NH3:9].C([O-])(=O)/C=C\C([O-])=O.[NH4+].[NH4+]>O>[NH2:9][C@H:2]([C:1]([O-:8])=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[NH4+:9].[NH4+:9]
Reactant: N
Reactant: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])/C=C\C(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 30 °C
Reaction time: 72 h
Yield: 98.8 %

Procedure:
According to the same procedure of Example 1, 600 g maleic acid was dissolved in deionized water, and 705 g of 25 wt % aqueous ammonia solution (molar ratio to maleic acid was about 2.0) was added thereon. The cells of Alcaligenes faecalis ATCC 8750 were added to 2 L of an ammonium maleate substrate solution (pH 8.4) containing 600 g maleic acid, and the substrate solution were gently stirred at 30° C. for 72 hours. After the reaction, ammonium L-aspartate was formed with a molar yield of 98.8% based on maleic acid. To the reaction solution from which the cells had been removed by centrifugation, was added 610 g maleic acid at 30° C. After the addition, a temperature of the solution was 37.0° C., and pH value thereof was 3.8. L-aspartic acid crystals were separated by filtration, so as to recover 1.5 L of mother liquors. The crude crystals was 769 g (excluding water) (88.0 wt % aspartic acid, 11.4 wt % maleic acid, 250 μm average crystal size). The crystals were washed with about 600 ml of water and dried so as to obtain 675 g of L-aspartic acid crystals (98.8 wt % aspartic acid, 0.77 wt % maleic acid, 100 μm average crystal size).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH2:10][CH2:9]1)[C:2]1C=CC=[CH:4][CH:3]=1.C(=O)C1C=CC=CC=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11](=[CH:14][C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH2:12][CH2:13]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cccc(C#CC=C2CCN(Cc3ccccc3)CC2)n1
Solvent: O=Cc1ccccc1
Product: CCCCN1CCC(=CC#Cc2cccc(C)n2)CC1

Procedure:
The title compound was prepared following the procedure described for the compound of Example 27, but substituting butyraldehyde for benzaldehyde. After the usual work-up procedure, the crude was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with a gradient Petroleum Ether-(EtOAc+1.4 N methanolic ammonia 1:0.1) from 90:10 to 30:70 affording the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][C:16]4=O)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:40])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:37]=[CH:36][C:9]2[N:10]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=[C:16]4[Cl:40])=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3[nH]c(-c4ccccc4)cc(=O)c3c1)n2C1CCCCC1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cc(Cl)c3c1)n2C1CCCCC1
Temperature: 100 °C

Procedure:
1-Cyclohexyl-2-(4-oxo-2-phenyl-1,4-dihydro-quinolin-6-yl)-1H-benzoimidazole-5-carboxylic acid ethyl ester acid (4 g, 8.14 mmol) was dissolved in phosphorous oxy chloride and heated at 100° C. overnight. After evaporation of the solvent the product was recrystallized from methanol/water to give 3.96 g of crude product. Silica gel purification of the title compound proved to be unsatisfactory due to degradation of the product on the column. MS: 510.22 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([O:13]C2C=CC=CC=2)=O)[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:47][C:46]2[CH:48]=[CH:49][CH:50]=[C:44]([O:43][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:45]=2)=[O:13])[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cccc(Oc2ncnc3cc(OCCOC)c(OC)cc23)c1

Procedure:
Using the procedure described in Example 159B, ethyl 2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate described in Example 166A (0.138 g, 0.4 mmol) was reacted with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 7 hours, to afford ethyl 2-[3-tert-butyl-5-(3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}ureido)-1H-pyrazol-1-yl]acetate as solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C[O:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:38]=1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:37]3[CH:36]=[N:35][CH:34]=[C:33]([OH:32])[CH:38]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(OC)c1
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cncc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was made in a similar way as that of the compound of example 89 from of 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate D2a, 804 mg, 1.579 mmol) and 3-methoxy-5-(tributylstannyl)pyridine (1257 mg, 3.16 mmol) at 120° C. overnight. Solvent was removed, and product was purified by Biotage Si 25 g with a gradient of DCM and EtOH affording a as yellow pale solid (500 mg). This material was dissolved in dry DCM (10 mL), 1M BBr3 in DCM (24 ml) was added and the solution was stirred at room temperature for 48 hrs. Then, solution was cooled to 0° C. and dry ethanol (10 ml) was added. Solvent was evaporate and product was straightforward purified via reverse phase chromatography with a Biotage C18 SNAP column (Phase A, water 95%, ACN 5%, formic acid 0.1%); (Phase B ACN 95%, water 5%, formic acid 0.1%) affording the title compound as white solid. Then, product was dissolved in a mixture of DCM (100 ml) and EtOH (5 ml) and the solution was washed with saturated solution of aqueous NaHCO3. aqueous phase was extracted with DCM (5×50 ml). Organic phases were collected, dried and solvent evaporated to dryness affording desired product affording the title compound (331 mg, 0.695 mmol, 68.4% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.[C:30]1([C:36]2([CH2:39]O)[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH2:39][C:36]3([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:38][CH2:37]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: OCC1(c2ccccc2)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2(c3ccccc3)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.4 %

Procedure:
To a solution of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g), (1-phenylcyclopropyl)methanol (0.87 g) and tributylphosphine (2 mL) in THF (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2 g) at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.43 g, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[N:14]([CH2:22][CH:23]3[CH2:25][CH2:24]3)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(Cl)c2)n[nH]c1=O
Reactant: ClCC1CC1
Product: COC(=O)c1cc(-c2ccc(OC)c(Cl)c2)nn(CC2CC2)c1=O
Yield: 72.7 %

Procedure:
Using 6-(3-chloro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedure of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 72.7%.