Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[CH2:15]([NH:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:16][CH2:17][CH3:18]>O.CO>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCNS(=O)(=O)c1ccc(N)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 6 %

Procedure:
Sodium dithionite (11.4 g, 65 mmol) and sodium carbonate (5.6 g, 53 mmol) were dissolved in water (65 mL) and heated to 70° C. A suspension of the above 4-nitrophenylsulfonamide (2.64 g, 10.2 mmol) in methanol (65 mL) was added and the resulting mixture was stirred at 70° C. for 1.5 hour. The cooled mixture was filtered and the volume of the filtrate was reduced by 50% in vacuo. The aqueous mixture was extracted with ethyl acetate (3×60 mL), and the combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford 0.14 g (6%) of 4-amino-N-butylbenzenesulfonamide as a solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.CN(C(ON1N=NC2[CH:39]=[CH:40][CH:41]=[N:42]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN1C(=O)CCC1>[CH:41]1([NH:42][C:25](=[O:26])[C:21]2[CH:20]=[C:19]([O:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[CH:24]=[CH:23][N:22]=2)[CH2:39][CH2:40]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 5.9 %

Procedure:
To the reaction solution of 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinic acid (5 mg, 39 μmol), HATU (15 mg, 39 μmol) and DIPEA (14 μL, 78 μmol) in 1 ml of NMP was added cyclopropylamine (7 ul mg, 30 μmol). The reaction solution was stirred at room temperature for 12 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give N-cyclopropyl-4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinamide (1 mg, 2.3 μmol) as white powder. ES/MS m/z 425.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[O:24][CH3:25].N1C=CC=CC=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH:21][S:33]([CH3:32])(=[O:35])=[O:34])[NH:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: COc1cc(-c2nc(C(C)(C)CN)[nH]c2-c2ccncc2)ccc1Cl
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nc(C(C)(C)CNS(C)(=O)=O)[nH]c2-c2ccncc2)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A solution of Example 2 (178 mg, 0.5 mmol) in dichloromethane (10 ml) containing pyridine (0.12 ml, 1.5 mmol) at 0° C. was treated with a solution of methanesulfonyl chloride (57.3 mg, 0.5 mmol) in dichloromethane (1 ml). The solution was stirred at 0° C. for 1 hour followed by 30 min at room temperature before being diluted with dichloromethane and saturated sodium hydrogen carbonate solution. The aqueous layer was then separated and extracted with additional dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/0.880 ammonia solution (8:1:0.1) to give the title compound (85 mg, 40%) as a pale yellow solid; MS(ES+) m/e 435/437 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21].ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH3:19])=[C:9]1[S:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:38])=[O:21]
Reactant: COC(=O)C1=C(C)NC(C)=C(S(=O)c2ccc(OC)cc2)C1c1ccccc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)C1=C(C)NC(C)=C(S(=O)(=O)c2ccc(OC)cc2)C1c1ccccc1Cl
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of (-)-4-(2-chlorophenyl)-3-(4-methoxyphenyl)sulfinyl-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine (1.4 g), prepared as in Preparation II above, in dichloromethane (300 ml), cooled to 0° C., was added m-chloroperbenzoic acid (660 mg). After stirring for 24 hours, the reaction mixture was washed with aqueous NaHCO3, dried over MgSO4, and evaporated to dryness. The residue was chromatographed on silica gel (1:1 dichloromethane/ethyl acetate) and recrystallized from dichloromethane/hexane to give (-)-4-(2-chlorophenyl)-3-(4-methoxyphenyl)sulfonyl-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine, m.p. 200°-202° C., [α]D =-126° (C=0.031, methanol) [93% enantiomeric excess (ee)].
Reaction SMILES: ClC1C=C(C=CC=1)C(O[CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:9]1)=O.[O:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1>C(#N)C>[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)[S:9]1
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Reactant: c1ccoc1
Solvent: CC#N
Product: CC1=C(c2ccncc2)SC(c2ccco2)C(=O)N1
Temperature: 50 °C
Reaction time: 35 h
Yield: 38.6 %

Procedure:
Silica gel (Wakogel C-200, 0.03 g) was added as catalyst to a solution of 2-(3-chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one (0.79 g) and furan (0.30 g) in acetonitrile (30 ml) and the mixture was stirred at 50° C. for 35 hours. The mixture was chromatographed on silica gel (Wakogel C-200) column, using acetonitrile as an eluant. The residue was recrystallized from acetonitrile to give the titled compound (0.23 g, yield 37.7%) as pale orange crystals.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][CH2:11][C:12]3=[O:17])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:18]=[C:19]1[NH:28][C:27]2[N:26]=[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH:33]=O)[CH:24]=[CH:23][C:22]=2[CH:21]=[CH:20]1>>[O:17]=[C:12]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:25]4[N:26]=[C:27]5[C:22]([CH:21]=[CH:20][C:19](=[O:18])[NH:28]5)=[CH:23][CH:24]=4)[CH2:5][CH2:6]3)=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: O=C1CCCc2c1cccc2N1CCNCC1
Product: O=C1CCCc2c1cccc2N1CCN(CCCCOc2ccc3ccc(=O)[nH]c3n2)CC1

Procedure:
In a manner similar to that of other examples above, 5-piperazin-1-yl-3,4-dihydro-2H-naphthalen-1-one was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound, mp 158–160° C. MS: APCI: M+1: 447.3 (Exact Mass: 446.23).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([CH2:17][NH:18][C@H:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](O)=[O:21])=[C:11]2[C:10]([C:27]([O:29][CH3:30])=[O:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=N[C:41]2[CH:42]=[CH:43][CH:44]=[N:45][C:40]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CCCC1.CN1CCOCC1>C1COCC1>[CH:40]1([NH:45][C:20](=[O:21])[C@H:19]([NH:18][CH2:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]=[C:10]([C:27]([O:29][CH3:30])=[O:28])[C:11]=23)[C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)O)C(C)(C)C)c12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C(C)(C)C)c12
Temperature: 43 °C
Reaction time: 36 h

Procedure:
To (R)-2-((1-(tert-butoxycarbonyl)-3-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylamino)-3,3-dimethylbutanoic acid was added THF (2 mL), HATU (94 mg, 0.246 mmol), cyclopentanamine (70.0 mg, 0.822 mmol) and 4-methylmorpholine (83 mg, 0.822 mmol). The suspension was stirred at 43° C. for 36 h to afford the title compound, which was used in the next step without further purification. [M+H] calc'd for C26H38N4O5, 487; found, 487.6.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14]/[C:15](/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20]I.[I-]>C1COCC1>[CH3:14]/[C:15](/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCCCI
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a stirred solution of 192 mg (8.01 mmol) of NaH in 20 mL of THF at 0° C. under argon was added 1.21 mL (8.01 mmol) of diethyl malonate dropwise. The mixture was stirred at 0° C. for 0.5 hours at which time was treated with 1.0 g (2.67 mmol) of Example 4, Part A iodide in 2 mL of THF. After 1 hour at 0° C. the reaction was heated to 40° C. for 2 hours, then cooled to room temperature and stirred for 18 hours. The mixture was quenched with NH4Cl and diluted with ether. The organic layer was washed with H2O, brine, dried over MgSO4 and the solvent evaporated to provide 950 mg of a pale yellow oil. Flash chromatography was performed on 50 g of silica gel, packed, loaded and eluted with (95:5) hexane/ether. The pure product fractions were combined and evaporated to provide 580 mg (54%) of title compound as a pale yellow oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]([NH:8][C:9]1[C:10]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:11]=2[S:12][C:13]=1[C:14]([O:16]C)=[O:15])=[O:7])[CH3:4].Cl>C(O)C>[CH2:3]([O:5][C:6]([NH:8][C:9]1[C:10]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:11]=2[S:12][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])[CH3:4]
Reactant: CCOC(=O)Nc1c(C(=O)OC)sc2cc(OC)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Nc1c(C(=O)O)sc2cc(OC)ccc12
Temperature: 60 °C

Procedure:
92 ml of a 10% ethanolic potassium hydroxide solution are added to a solution of 31.4 g (0.101 mol) of methyl 3-[(ethoxycarbonyl)amino]-6-methoxybenzo[b]thiophene-2-carboxylate in 230 ml of ethanol. The mixture is heated at 60° C. for 10 minutes and is then poured onto ice-cold water. The mixture is acidified by addition of a 6N hydrochloric acid solution and the precipitate formed is filtered off, rinsed with water and dried under reduced pressure. The solid is triturated in ethanol. 22.8 g of product are recovered.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13](O)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:25][CH:26]=2)=[S:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(O)=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC[C@H](NS(=O)(=O)c1ccc(Br)cc1)C(=S)Nc1ccc(CC(=O)OCC)cc1
Yield: 41.6 %

Procedure:
The procedure described in Example 180 was repeated, except that (S)-2-(4-bromobenzenesulfonylamino)-4-ethylthiobutanoic acid (199 mg) and ethyl 4-aminophenylacetate (95.7 mg) were condensed in dichloromethane (2 ml) in the presence of N,N'-dicyclohexylcarbodiimide (139.1 mg). The reaction mixture was filtered, and the filtrate was concentrated. The resulting crude product was recrystallized from ethanol to obtain (S)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-4-ethylthiobutanamide (117.3 mg).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[F:44][C:45]1[C:53]([N:54]2[CH2:58][CH2:57][CH2:56][C:55]2=[O:59])=[CH:52][C:51]([N:60]2[CH2:64][CH2:63][CH2:62][C:61]2=[O:65])=[CH:50][C:46]=1[C:47]([OH:49])=O.[CH:66]12[CH2:72][CH:69]([CH2:70][CH2:71]1)[CH2:68][CH:67]2[NH:73][C:74](=[O:89])[C@H:75]([CH3:88])[CH2:76][C@H:77]([OH:87])[C@@H:78]([NH2:86])[CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>>[CH2:79]([C@H:78]([NH:86][C:47](=[O:49])[C:46]1[CH:50]=[C:51]([N:60]2[CH2:64][CH2:63][CH2:62][C:61]2=[O:65])[CH:52]=[C:53]([N:54]2[CH2:58][CH2:57][CH2:56][C:55]2=[O:59])[C:45]=1[F:44])[C@@H:77]([OH:87])[CH2:76][C@H:75]([C:74](=[O:89])[NH:73][CH:67]1[CH2:68][CH:69]2[CH2:72][CH:66]1[CH2:71][CH2:70]2)[CH3:88])[C:80]1[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=1
Reactant: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1F
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1F)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 2-fluoro-3,5-bis-(2-oxopyrrolidin-1-yl)benzoic acid (D40) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: C[C@H](CCl)COc1cccc(Br)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3cccc(Br)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 3-bromophenyl (2S)-3-chloro-2-methylpropyl ether and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 473.0 (M+H)+.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([O-])=[O:6])[CH:3]=1.Cl.[CH3:15][NH:16][CH3:17].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[CH3:15][N:16]([CH3:17])[C:5]([C:4]1[CH:3]=[C:2]([CH:10]=[CH:9][CH:8]=1)[C:1]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: CNC
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a methylene chloride (20 ml) solution of monomethyl isophthalate (317 mg, 1.76 mmol) were added dimethylamine hydrochloride (172 mg, 2.11 mmol), 1-hydroxybenzotriazole (287 mg, 1.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (404 mg, 2.11 mmol) and N-methylmorpholine (0.23 ml, 2.11 mmol) and the resulting mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. The resulting mixture was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column and the fraction obtained from the methanol:methylene chloride (=1:50) eluate was concentrated under reduced pressure, whereby the title compound (290 mg, 80%) was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH2:19]([C:21]1([CH2:25]O)[CH2:24][O:23][CH2:22]1)[CH3:20].ClCCl.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CCCCCCC.C(OCC)(=O)C>[CH2:19]([C:21]1([CH2:25][C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:10]=2[C:4]2[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=2)[CH2:24][O:23][CH2:22]1)[CH3:20]
Reactant: O=C(O)c1ccc(-c2cc(F)c(F)c(F)c2)cc1
Reactant: CCC1(CO)COC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC1(Cc2cc(C(=O)O)ccc2-c2cc(F)c(F)c(F)c2)COC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 107.2 %

Procedure:
In step (c -2), 3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-carboxylic acid (10.0 g, 37.0 mmol), 3-ethyl-3-hydroxymethyloxetane (5.9 g, 37 mmol), 4-dimethylaminopyridine (4.5 g, 37 mmol), and 100 ml of dichloromethane were mixed under nitrogen atmosphere and cooled to 0° C., and then 50 ml of a dichloromethane solution including 8.0 g (39 mmol) of dicyclohexylcarbodiimide was added dropwise thereto at 0° C., and the resulting mixture was stirred at room temperature for 15 hours. The mixture was filtrated by celite to collect a filtrate. The filtrate was condensed under a reduced pressure, followed by column chromatography (volume ratio of ethyl acetate:heptane=1:4) to obtain 13.9 g of (3-ethyloxetane-3-yl)methyl 3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[CH3:9][C:4]1[CH:3]=[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)[S:6][C:5]=1[CH:7]=[O:8]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)sc1C=O
Product: Cc1ccc(-c2cc(C)c(C=O)s2)cc1

Procedure:
5-Bromo-3-methylthiophene-2-carbaldehyde (Spinelli, D. et al., J. Chem. Soc. Perkin Trans. 2, 1972, (12), 1866-9) was reacted with 4-methylphenylboronic acid by method J. The product with the molecular weight of 216.30 (C13H12OS) was obtained in this way; MS (ESI): 217 (M+H+).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH2:16]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][CH:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(O)cn1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCc2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To an N,N-dimethylformamide (50 mL) solution of 3-hydroxy-6-methylpyridine (5.00 g, 45.8 mmol) was added sodium hydride (2.02 g, 50.4 mmol, 60% in oil), which was stirred for 15 minutes at 0° C. Next, benzyl bromide (5.99 mL, 50.4 mmol) was added to this reaction mixture at 0° C., which was stirred for 3.5 hours at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate=2:1) to obtain the title compound (5.99 g, 66%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:25])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:25])=[O:7])#[N:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1cc(C(=O)O)cc(C#N)c1OC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCc1cc(C(=O)Cl)cc(C#N)c1OC
Temperature: 60 °C
Reaction time: 14 h

Procedure:
To 3-cyano-5-ethyl-4-methoxybenzoic acid (347 mg), toluene (3.5 mL), N,N-dimethylformamide (0.01 mL) and thionyl chloride (0.15 mL) were added, and then the mixture was stirred at 60° C. for 14 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (387 mg) as a brown oily substance.
Reaction SMILES: B([O-])([O-])[O-].[Na+].[Na+].[Na+].Cl.[NH2:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:16]([OH:17])=[C:14]([OH:15])[CH:13]=1.[OH-].[Na+].[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O>[C:30]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:16]([OH:17])=[C:14]([OH:15])[CH:13]=1)([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Solvent: O
Product: O=C(NCCc1ccc(O)c(O)c1)OCc1ccccc1
Temperature: 15 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
38.2 g (100 mmol) of sodium borate and 18.9 g (100 mmol) of dopamine hydrochloride were dissolved in 250 ml of water. To the solution thus obtained, was added a 2 N sodium hydroxide solution under a nitrogen gas stream to adjust the pH value to 9. Then 17.1 g (100 mmol) of benzyloxycarbonyl chloride was added dropwise thereto while stirring at 15° C. for 4 hours. Simultaneously, a 2 N sodium hydroxide solution was added to maintain the pH value of the reaction mixture to 9. After continuing the stirring for 2 hours, the mixture was adjusted to pH 1 to 2 with hydrochloric acid and then extracted with diethyl ether. Next, it was dried over anhydrous magnesium sulfate and the solvent was distilled off. After washing the residue with petroleum ether, the crude crystals thus obtained were recrystallized from ethanol/n-hexane (1 : 1 by volume). Thus 27.6 g (yield: 96.5% of the desired compound (m.p.: 134°- 135 ° C.) was obtained in the form of white crystals.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.C[S-].[Na+].Cl>CN1C(=O)CCC1.O>[O:26]1[CH2:27][CH2:28][N:23]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:9]3[N:8]=[CH:7][C:6]4[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=4)[N:10]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:22])[CH2:24][CH2:25]1
Reactant: COc1ccc2cnc(Nc3ccc(S(=O)(=O)N4CCOCC4)cc3)nc2c1
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=S(=O)(c1ccc(Nc2ncc3ccc(O)cc3n2)cc1)N1CCOCC1
Temperature: 80 °C
Yield: 99 %

Procedure:
A mixture of 7-methoxy-N-(4-(morpholinosulfonyl)phenyl)quinazolin-2-amine (1 eq) and sodium thiomethoxide (4 eq) in NMP was heated at 80° C. for 4 h. Reaction mixture was diluted with water and acidified with 1N HCl. Compound was extracted with ethyl acetate. The organic layer was washed with satd. NaHCO3, brine and dried over sodium sulfate. Filtration, evaporation and drying under vacuum provide 2-(4-(morpholinosulfonyl)phenylamino) quinazolin-7-ol as a light yellow viscous liquid in 99% yield. ES/MS m/z 387.0 (MH+).