Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1>>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:33][C:30]2[S:31][CH:32]=[C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[N:29]=2)=[O:18])(=[O:11])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1nc(-c2ccccn2)cs1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Product: O=C(Nc1nc(-c2ccccn2)cs1)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (100 mg, 0.33 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (49 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 75-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 3-(indolin-1-ylsulfonyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a white solid. Yield: 17 mg (13%). 1H-NMR: 8.65-8.61 (m, 1H), 8.60-8.58 (m, 1H), 8.38 (dt, J=8.0, 1.0, 1.0 Hz, 1H), 8.05-7.99 (m, 2H), 7.95-7.88 (m, 2H), 7.74 (t, J=8.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.38-7.33 (m, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H) 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.03 (t, J=8.5 Hz, 2H), 2.93 (t, J=8.5 Hz, 2H).
Reaction SMILES: [NH3:1].[O:2]1[CH:8]2[CH:3]1[C:4]([CH3:27])([CH3:26])[O:5][C:6]1[CH:12]=[CH:11][C:10]([S:13]([C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])(=[O:15])=[O:14])=[CH:9][C:7]=12.O>C(O)C>[NH2:1][C@@H:8]1[C:7]2[CH:9]=[C:10]([S:13]([C:16]([F:25])([F:24])[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])(=[O:14])=[O:15])[CH:11]=[CH:12][C:6]=2[O:5][C:4]([CH3:26])([CH3:27])[C@H:3]1[OH:2]
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)F)cc2C2OC21
Reactant: N
Solvent: CCO
Solvent: O
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reaction time: 72 h

Procedure:
30 ml of 28% v/v aqueous ammonia were added to a solution of 1.086 g of 3,4-epoxy-6-heptafluoropropylsulfonyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (prepared as described in Preparation 3) in 30 ml of ethanol, and the resulting mixture was allowed to stand at room temperature for 3 days. At the end of this time, the reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and then the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the eluent. The fractions containing the desired compound were then recrystallized from a mixture of ethyl acetate and hexane, to afford 0.796 g of the title compound, melting at 176°-177° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH2:6][O:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=2)[CH2:5][CH2:4]1>O1CCCC1.CO>[CH:3]1([CH2:6][O:7][C:8]2[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=2)[CH2:5][CH2:4]1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCC2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCC2CC2)c1
Yield: 78 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10.0 mmol, 4.8 eq) of sodium hydroxide and methyl 3-[2-cyclopropylmethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 426 mg of 3-[2-cyclopropylmethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=64° C.). Yield=78% over the two steps
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C@@H:22]([F:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[F:24][C@H:22]1[CH2:23][C@@:6]2([CH3:7])[C@@H:8]([CH2:9][CH2:10][C@@H:5]2[OH:4])[C@H:11]2[C@H:21]1[C@:19]1([CH3:20])[C:14]([CH2:13][CH2:12]2)=[CH:15][C:16](=[O:25])[CH2:17][CH2:18]1
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
1.2 g. of 17β-acetoxy-11β-fluoro-4-androsten-3-one is stirred in a mixture of 30 ml. of methanol and 5 ml. of water for 10 hours at room temperature with 1 g. of potassium carbonate. The reaction mixture is filtered off from the insoluble matter, the solution is neutralized with glacial acetic acid, concentrated under vacuum, the residue taken up in methylene chloride, and dried. After recrystallization from acetone/hexane, 800 mg. of 11β-fluoro-17β-hydroxy-4-androsten-3-one is obtained; m.p. 161°-162°. UV: ε239 = 16,600 (methanol).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=O.II>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:1]=[C:2]([NH2:4])[S:3][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: NC(N)=S
Agent: II
Product: COc1ccc(-c2csc(N)n2)cc1
Reaction time: 5 h
Yield: 91.7 %

Procedure:
33.5 g of thiourea are added to 30 g of 4-methoxyacetophenone, 56 g of iodine are added and the mixture is kept at 100° C. for 5 hours. The reaction mixture is discharged onto water, powdered, washed several times with ether then with ammonia solution and finally with water, and dried. 37.8 g of 4-(4-methoxyphenyl)-thiazol-2-yl-amine of melting point 194°-205° C. are obtained.
Reaction SMILES: I/[CH:2]=[CH:3]/[C@@H:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17]C2CCCCO2)=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](S([O-])(=O)=O)=[CH:27][CH:26]=1.C1C=C[NH+]=CC=1>CCO>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C@H:4](/[CH:3]=[CH:2]/[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=1
Reactant: CCOC(=O)C[C@@H](/C=C/I)c1ccc(OC2CCCCO2)cc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC(=O)C[C@@H](/C=C/Cc1ccccc1)c1ccc(O)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of 84.4 (156.9 mg, 0.398 mmol, MW 394.50) in EtOH (5 mL) at 23° C. was added PPTS (catalytic). Stirring was continued for 16 hours. The reaction was concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0 to 20% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated providing a colorless oil. The desired product was contaminated (˜5%) with a further olefinic product (believed to contain a terminal double bond) and was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][S:22][CH2:23]Cl.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:21][S:22][CH3:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSCCl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (13 g) in dirnethylformamide (100 ml) was added 60% sodium hydride (2.5 g) under an argon atmosphere, and the mixture was stirred at room temperature for 30 minutes. Then, chloromethyl methyl sulfide (5.2 ml) was dropwise added with ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:acetone=20:1-10:1) and dried under reduced pressure to give the title compound (9.6 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[N:9]=[CH:8][C:7]=1[OH:14].Cl.[Br:16][C:17]1[C:22]([CH2:23]Cl)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:16][C:17]1[C:22]([CH2:23][O:14][C:7]2[C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:11][C:10]([O:12][CH3:13])=[N:9][CH:8]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: ClCc1cccnc1Br
Reactant: COc1cc(C2OCCO2)c(O)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C2OCCO2)c(OCc2cccnc2Br)cn1
Temperature: 70 °C
Yield: 66.8 %

Procedure:
A mixture of 4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-ol (980 mg, 4.97 mmol, 1 eq.), 2-bromo-3-(chloromethyl)pyridine hydrochloride (1.2 g, 4.93 mmol, 1 eq.) and K2CO3 (2.7 g, 19.88 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-bromopyridin-3-yl)methoxy)-4-(1,3-dioxolan-2-yl)-2-methoxypyridine (1.21 g, 66%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.26 (dd, J=4.7, 1.9 Hz, 1H), 7.83 (dd, J=7.6, 1.9 Hz, 1H), 7.74 (s, 1H), 7.25 (dd, J=7.6, 4.8 Hz, 1H), 6.86 (s, 1H), 6.10 (s, 1H), 5.09 (s, 2H), 4.07-3.93 (m, 4H), 3.82 (s, 3H). LRMS (MAT) m/z 367.0.
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:27])[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1.[CH2:29]([NH2:32])[CH:30]=[CH2:31]>CC(O)C>[CH2:29]([NH:32][CH2:28][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:27])[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1)[CH:30]=[CH2:31]
Reactant: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Reactant: C=CCN
Solvent: CC(C)O
Product: C=CCNCC(O)COc1ccc2c(=O)c(-c3ccccc3)c(-c3ccccc3)oc2c1

Procedure:
Using Method B, the reaction of 7-(2,3-epoxypropoxy)-2,3-diphenychromone and allylamine afforded the desired amine as white needles, m.p. 119°-120° (iPrOH); yield, 82%. Its hydrochloride salt had m.p. 140°-142° (iPrOH/phCH3); containing water).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21]([O:23][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[O:22])[CH:18]=3)[N:13]([C:29](=[O:31])[NH2:30])[CH:12]=2)=[C:6]([O:32][CH3:33])[CH:5]=1.O1CCCC1.O.[OH-].[Li+]>O>[C:29]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([NH:20][C:21]([O:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:22])=[CH:16][CH:15]=2)[C:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:34])=[O:2])=[CH:5][C:6]=2[O:32][CH3:33])=[CH:12]1)(=[O:31])[NH2:30]
Reactant: COC(=O)c1ccc(Cc2cn(C(N)=O)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)ccc1Cc1cn(C(N)=O)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 46 h
Yield: 93.3 %

Procedure:
To a solution of 4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid methylester (1.15 grams, 2.47 mmol) in a 6:1 ratio tetrahydrofuran:water (70 mL) was added lithium hydroxide monohydrate (0.21 grams, 4.94 mmol) and the resulting solution was stirred, at room temperature, for 46 hours. The reaction mixture was concentrated in vacuo to a volume of 15 mL, then diluted with water (300 mL). The aqueous solution was acidified by addition of 1 M hydrochloric acid (aq), and the resulting precipitate was collected via filtration to give 4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (1.04 grams, 93% yield).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[NH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[N:36]=[CH:35]2>CC(O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[NH:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[N:36]=[CH:35]2)(=[O:3])[CH3:2]
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Cl)c2cc1OC(C)=O
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Solvent: CC(C)O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Temperature: 95 °C
Yield: 58.8 %

Procedure:
A mixture of 4-chloro-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-6-yl acetate (3.14 g, 7.42 mmol) and tert-butyl 5-amino-1H-indazole-1-carboxylate (1.85 g, 7.93 mmol) in IPA (180 mL) was heated at 95° C. for 5 h. The mixture was allowed to cool to RT and the solid was collected via filtration. The solid was subjected to flash chromatography (SiO2, CH2Cl2/MeOH) to give the desired compound tert-butyl 5-(6-acetoxy-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (2.70 g, 4.36 mmol, 59%). MS 620.4 (M+1). HPLC retention time 8.10 mins (5-95-13 method).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[C:37]1([CH2:43][CH2:44][CH2:45]Cl)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O>[CH2:1]([C:4]1[C:12]2[N:11]=[C:10]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:9]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:26][CH2:27][N:28]([CH2:45][CH2:44][CH2:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:29][CH2:30]3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: ClCCCc1ccccc1
Reactant: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCCC1CCN(CCCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In a 50 ml round bottom flask, under a nitrogen atmosphere, were added 4-(prop-2-enyl)-2-[(4-chlorophenoxy)methyl]-1-[3-(piperidin-4-yl)propyl]benzimidazole (898 mg, 2.12 mmol), potassium carbonate (1.46 g, 10.58 mmol), 3-(phenyl)propyl chloride (0.2 ml, 506 mg, 2.54 mmol) and N,N-dimethylformamide (7 ml). The resulting mixture was heated to 60° C. and maintained at this temperature overnight. The progress of the reaction was monitored by thin layer chromatography. An additional 1 equivalent of potassium carbonate and 0.2 ml of 3-(phenyl)propyl chloride were added and the resulting contents were stirred at 60° C. for an additional two hours. The reaction was quenched by the addition of water. The aqueous fraction was extracted wtih ethyl acetate. The organic fractions were combined, washed with water, and then dried over sodium sulfate. The solvents were removed in vacuo. The desired title product was further purified by radial chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:10][C@H:9]1[C:36]([OH:38])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1CCOCC1.CN>C1COCC1.C(Cl)Cl>[Cl:34][C:30]1[C:29]([F:35])=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][C@H:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:36]([NH:40][CH3:39])=[O:38])[CH2:10]4)[CH:16]=3)[N:21]=[CH:20][N:19]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CN1CCOCC1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C1
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 100.2 %

Procedure:
A stirred solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-({-4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylic acid (4 g, 7.31 mmol, prepared as described in Example 1) in THF (50 ml) was cooled to −15° C. (acetone/ice). NMM (1.21 ml, 11.0 mmol) was added to the solution followed by IBCF (1.24 ml, 9.51 mmol). The reaction mixture was held at −15° C. (the formation of the mixed anhydride was monitored by TLC (THF)). After 5-10 minutes, the reaction mixture was treated with a 2.0M solution of methylamine in THF (10 ml) at −15° C. and allowed to warm to room temperature. The reaction mixture was diluted with DCM (250 ml), washed with water (2×20 ml) and concentrated to give tert-butyl (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-1-carboxylate (4.1 g, 100%) as pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 560.1.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C:35]1([O:38]C(=O)C)[CH2:37][CH2:36]1)=[O:34]>>[OH:38][C:35]1([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:34])[CH2:37][CH2:36]1
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: O=C(N[C@H]1CC[C@H](NC(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C1(C)C=CC=CC=1>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]([Cl:24])[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)Cc1ccc(C(O)c2ccc(Cl)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)Cc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Yield: 75 %

Procedure:
4-chloro-4'-ethane sulfonylmethylbenzhydrol (6.0 g), thionyl chloride (5.4 g), toluene (200 ml) and a catalytic amount of N,N-dimethylformamide were mixed and gradually heated with stirring to a refluxing temperature. The mixture was stirred for 4 hours under reflux and then left to cool. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the desired product as a slight yellow viscous substance (4.6 g, nD20 : 1.6044, yield: 75%).
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([OH:20])=O)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:21]3[CH:26]=[C:25]([C:27](=[O:32])[NH:28][CH:29]4[CH2:31][CH2:30]4)[CH:24]=[CH:23][C:22]=3[CH3:33])[CH:14]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([NH:39][CH2:38][CH2:37][N:36]([CH3:40])[CH3:35])=[O:20])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:21]3[CH:26]=[C:25]([C:27](=[O:32])[NH:28][CH:29]4[CH2:31][CH2:30]4)[CH:24]=[CH:23][C:22]=3[CH3:33])[CH:14]=2)[C:9]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C(=O)O)c2c1
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C(=O)NCCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of step iii) (0.48 g) and N,N-dimethylethane-1,2-diamine (0.17 mL) in THF (20 mL) was added N,N-diisopropylethylamine (0.56 mL) followed by HATU (0.60 g) and the reaction stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and the crude product purified by SiO2 chromatography (eluting with 90:10:0.1 dichloromethane:methanol:triethylamine). The fractions containing product were concentrated to dryness and the residue triturated with acetonitrile to give the title compound as a solid (0.35 g).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19]1([CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCCCc1ccccc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CCCCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.67 h
Yield: 109.2 %

Procedure:
To a tetrahydrofuran (300 ml) solution of (4S)-4-benzyl-1,3-oxazolidin-2-one (26.58 g), 1.58 M of n-butyl lithium (tetrahydrofuran solution; 100 ml) was added under argon atmosphere at −78° C., and the mixture was stirred at the same temperature for 40 minutes. To the mixture, a tetrahydrofuran (100 ml) solution of 5-phenylpentanoyl chloride (32.4 g) was added, followed by stirring at −78° C. for 5 minutes. An aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively, dried over anhydrous sodium sulfate and concentrated to give the title compound (55.29 g) having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[C:11]([OH:17])[CH:10]=1.I[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:19]([O:17][C:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:14]=[CH:13][C:12]=1[CH:15]=[O:16])[CH3:20]
Reactant: CCI
Reactant: O=Cc1ccc(-c2ccc(F)cc2F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(-c2ccc(F)cc2F)ccc1C=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
A mixture of 2′,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (8.00 g), iodoethane (8.98 g) and potassium carbonate (6.19 g) in acetone (70 mL) was stirred at 60° C. for 3 hours. The mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was separated and concentrated in vacuo. The residue was refluxed for 30 minutes in methanol (30 mL), cooled to room temperature, and further stirred for 1 hour. The solid was collected by filtration, washed with methanol (10 mL) and dried at 70° C. to give the title compound (5.16 g).