Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[Cl:34])[C:15]([NH:17][C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([F:30])[CH:19]=1)=[O:16].N1C=CC=CC=1.O>C(OCC)C>[Cl:34][C:33]1[CH:32]=[CH:31][C:14]([C:15]([NH:17][C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[O:16])=[CH:13][C:12]=1[NH:11][C:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: Nc1cc(C(=O)Nc2cc(F)cc(N3CCOCC3)c2)ccc1Cl
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(Nc1cc(F)cc(N2CCOCC2)c1)c1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1
Temperature: 100 °C
Yield: 90.5 %

Procedure:
A mixture of 6-chloropyrid-3-ylcarbonyl chloride (1.96 g), 3-amino-4-chloro-N-(3-fluoro-5-morpholinophenyl)benzamide (3 g) and pyridine (20 ml) was stirred and heated to 100° C. for 4 hours. The mixture was cooled to ambient temperature. Water and diethyl ether were added. The resultant precipitate was washed with a saturated aqueous sodium bicarbonate solution and with methanol. There was thus obtained the title compound (3.8 g); NMR Spectrum: (DMSOd6) 3.1 (t, 4H), 3.75 (t, 4H), 6.52 (d, 1H), 7.1 (s, 1H), 7.2 (d, 1H), 7.6-7.7 (m, 2H), 7.7-7.8 (m, 1H), 8.2 (d, 1H), 8.35-8.4 (m, 1H), 8.97 (d, 1H), 10.2-10. 32 (br S, 1H); Mass Spectrum: M+H+ 489.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([CH2:17][CH:18]2[CH2:20][C:19]2([Cl:22])[Cl:21])=[C:11]([F:23])[C:10]=1[F:24]>CO.Cl>[Cl:22][C:19]1([Cl:21])[CH2:20][CH:18]1[CH2:17][C:12]1[C:11]([F:23])=[C:10]([F:24])[C:9]([CH2:8][OH:7])=[C:14]([F:15])[C:13]=1[F:16]
Reactant: Fc1c(F)c(CC2CC2(Cl)Cl)c(F)c(F)c1COC1CCCCO1
Agent: Cl
Solvent: CO
Product: OCc1c(F)c(F)c(CC2CC2(Cl)Cl)c(F)c1F
Yield: 79.8 %

Procedure:
4-[(2,2-dichlorocyclopropyl)methyl]-2,3,5,6-tetrafluorobenzyl tetrahydropyran-2-yl ether (0.240 g) was heated at the reflux temperature for 3 hours in a mixture of methanol (5 cm3) and 2 M hydrochloric acid (1 cm3). The solvent was evaporated under reduced pressure and water removed azeotropically from the sample by heating with toluene (2×10 cm3). The title product (0.15 g) was obtained as an orange oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:29]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)c3cnc4c(C(=O)O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Product: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Yield: 36.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(1-(tert-butoxycarbonyl)spiro[indoline-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.150 g, 0.258 mmol) obtained in step 2 and methanesulfonamide (0.122 g, 1.29 mmol), the title compound (0.062 g, 25%) was obtained.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].Br[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:30][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: Brc1ncccn1
Reactant: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](Nc2ncccn2)C[C@@H]1C
Temperature: 110 °C
Reaction time: 16 h
Yield: 20.85 %

Procedure:
A flask was charged with 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (for a preparation see intermediate 55) (250 mg, 0.585 mmol), 2-bromopyrimidine (186 mg, 1.169 mmol), sodium tert-butoxide (112 mg, 1.169 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (46.0 mg, 0.117 mmol) and then tris(dibenzylideneacetone)dipalladium(0) (53.5 mg, 0.058 mmol) then filled with 1,4-dioxane (5 mL) and the resulting mixture was stirred at 110° C. for 16 h then cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The layers were separated and the aqueous phase was extracted with EtOAc (25 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuovacuo. Purification of this residue on SP4 using a 50 G silica cartridge (gradient:1 to 5% MeOH in DCM) gave 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-2-methyl-4-(2-pyrimidinylamino)-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (68.5 mg, 0.122 mmol, 20.85% yield) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:11].[C:12](=O)([O-])[O-:13].[K+].[K+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[O:13]=[C:12]1[NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[S:11]1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(C(=O)O)cc1S
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]c(=O)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
4-Amino-3-mercaptobenzoic acid (680 mg) was dissolved in tetrahydrofuran (20 ml), and potassium carbonate (550 mg) was added thereto and stirred for 30 minutes at room temperature. The mixture was cooled to −78° C., and triphosgene (400 mg) was added thereto and stirred for 1 hour. The mixture was warmed to room temperature and concentrated under reduced pressure until the volume of the solvent became ⅓. Water (20 ml) and formic acid were added to the concentrate until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (740 mg, Y.:95%) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[NH2:26][CH2:27][C@@H:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH2:1]([O:3][C:4](=[O:25])[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:26][CH2:27][C@H:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:22][CH2:23]2)=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)C(=Cc1ccc(N2CCC(=O)CC2)cc1)C(=O)OCC
Product: CCOC(=O)C(=Cc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1)C(=O)OCC

Procedure:
2-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidine-1-yl}-benzylidene)-malonic acid diethyl ester was prepared from 2-[4-(4-oxo-piperidin-1-yl)-benzylidene]-malonic acid diethyl ester (which was obtained in Example 153) and N-[5-(-2-amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, J=7.0 Hz, 3 H), 1.23 (t, J=7.0 Hz, 3 H), 1.75–1.95 (m, 2 H), 2.50–3.50 (m, 7 H), 2.90 (s, 3 H), 3.75–3.90 (m, 2 H), 4.16 (q, J=7.0 Hz, 2 H), 4.29 (q, J=7.0 Hz, 2 H), 4.47 (dd, J=8.0, 4.2 Hz, 1 H), 6.84 (d, J=8.2 Hz, 1 H), 6.94 (d, J=9.0 Hz, 2 H), 7.00 (dd, J=8.2, 2.0 Hz, 1 H), 7.17 (d, J=2.0 Hz, 1 H), 7.33 (d, J=9.0 Hz, 2 H), 7.52 (s, 1 H); MS (ES) m/z: 576.0 (MH+); HRMS Calcd. for C28H38N3O8S(MH+): 576.2374. Found: 576.2373.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:11][CH2:10][C:9]2[C:8]([OH:12])=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:3]1.CS(O[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[S:21]1[CH:22]=[CH:23][CH:24]=[C:20]1[CH2:19][CH2:18][N:1]([C@H:2]1[CH2:11][CH2:10][C:9]2[C:8]([OH:12])=[CH:7][CH:6]=[CH:5][C:4]=2[CH2:3]1)[CH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1
Reactant: N[C@H]1CCc2c(O)cccc2C1
Reactant: CS(=O)(=O)OCCc1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Oc1cccc2c1CC[C@H](N(CCc1cccs1)CCc1cccs1)C2
Temperature: 25 °C
Yield: 63.6 %

Procedure:
5.0 g of (S)-5,6,7,8-tetrahydro-6-amino-1-naphthol, 2.2 g of 2-(2-thienyl)ethyl methane-sulfonate, 4.8 g of sodium carbonate and 100 ml of xylene were mixed to form a mixture, and the mixture was refluxed for 48 h to 50 h. The mixture was cooled to room temperature, and washed with an appropriate amount of water. Active carbon was added to decolorize the mixture. The mixture was filtered and left standing. An organic phase was reserved and concentrated under vacuum to obtain a residue. The residue was purified by column chromatography to obtain 1.3 g of (S)-5,6,7,8-tetrahydro-6-[N,N-bis[(2-thienyl)ethyl]]amino-1-naphthol.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:12]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([O:1][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:3]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (11.53 g), benzyl bromide (18 ml), potassium carbonate (21.12 g) and N,N-dimethylformamide (300 ml) was stirred at 80° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dilute hydrochloric acid, then washed successively with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-carboxylate (13.52 g, yield 95%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 71–72° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:40](=[O:41])[N:6]2[C:7]([C:27]([O:29]CC3C=CC([N+]([O-])=O)=CC=3)=[O:28])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].P([O-])([O-])([O-])=O.[Na+:47].[Na+].[Na+].[H][H]>C1COCC1.[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:40](=[O:41])[N:6]2[C:7]([C:27]([O-:29])=[O:28])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+:47]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (128.5 mg) was dissolved in 6.7 ml of THF and 6.7 ml of 1/15 M sodium phosphate buffer (pH 6.6) to prepare a solution, and 130 mg of 10% Pd-C was added to the solution. The air in the reaction vessel was replaced by hydrogen, and the contents of the reaction vessel were stirred at room temperature for 2 hr. The catalyst was removed by filtration through Celite, followed by washing with water. The filtrate was washed with ethyl acetate and was then concentrated under the reduced pressure to a volume of about 2 ml. The concentrate was purified by column chromatography on Cosmosil 40C18-PREP (5% aqueous methanol solution) to give 40.9 mg of the title compound.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[I:17])=[N:6][O:7][C:8]=1[CH3:9])([OH:3])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C>ClCCl.C1COCC1.CN(C=O)C>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([NH:34][C:32](=[O:33])[CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([NH:24][C:1]([C:4]3[C:5]([C:10]4[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=4[I:17])=[N:6][O:7][C:8]=3[CH3:9])=[O:3])[CH:26]=2)[CH:36]=[C:37]([O:45][CH3:46])[C:38]=1[O:43][CH3:44]
Reactant: Cc1onc(-c2c(F)cccc2I)c1C(=O)O
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(NC(=O)Cc2cccc(NC(=O)c3c(-c4c(F)cccc4I)noc3C)c2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
To a solution of 4-carboxy-5-methyl-3-(2-iodo-6-fluoro-phenyl)isoxazole (1.75 g, 5 mmol) in dichloromethane (30 ml) and THF (1 ml) was added oxalyl chloride (0.88 ml, 10 mmol, 2 eq.) under N2, then DMF (3 drops) to initiate the reaction. The reaction was stirred for 2 h, concentrated, and re-dissolved in dichloromethane (50 ml) under N2. A solution of 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (1.59, 5 mmol) in THF (14 ml) was added, cooled to 0° C., and then added triethylamine (0.7 ml, 5 mmol), and stirred for 17 h. Crude reaction was partitioned between ethyl acetate and 1N HCl. The organic layer was washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude material was titrated with diethyl ether (3×) and purified by flash chromatography (silica gel) using 1-10% acetone in dichloromethane to give the title compound (1.67 g, 51%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][N:15]=[C:14](F)[CH:13]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[OH-:19].[Na+]>Cl>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:19])[CH:13]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: [OH-]
Reactant: Nc1nc(-c2ccco2)c(-c2ccnc(F)c2)s1
Agent: Cl
Agent: [Na+]
Product: Nc1nc(-c2ccco2)c(-c2cc[nH]c(=O)c2)s1
Yield: 51 %

Procedure:
2-Amino-5-(2-fluoropyridin-4-yl)-4-(2-furyl)thiazole (2.00 g, 7.65 mmol) obtained in Step 1 was suspended in 6 mol/L hydrochloric acid (20 mL), followed by stirring under heating and reflux for 1 hour. The reaction mixture was neutralized with aqueous 10 mol/L sodium hydroxide solution added thereto, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=17:3) to afford the entitled Compound p (1.01 g, 51%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:16](S(C)(=O)=O)[S:17]([CH3:20])(=[O:19])=[O:18])[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CN(C)CCN>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)cc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: CN(C)CCN
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ncc(Br)cc1NS(C)(=O)=O
Yield: 100 %

Procedure:
A solution of tert-butyl 5-bromo-3-(N-(methylsulfonyl)methylsulfonamido)pyridin-2-ylcarbamate (68 mg, 0.15 mmol) and N,N-dimethylethylenediamine (169 uL, 1.5 mmol) in dioxane (1 mL) was stirred at rt for 70 min. After diluting with ethyl acetate, the mixture was washed with aqueous citric acid (10%) followed by water. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was then diluted with dichloromethane which was then washed with 1 N HCl. After partitioning, the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide tert-butyl 5-bromo-3-(methylsulfonamido)pyridin-2-ylcarbamate (57 mg, 0.15 mmol, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, 1H), 8.07 (d, 1H), 2.98 (s, 3H), 1.54 (s, 9H); MS (EI) for C10H16BrN3O4S: 310, 312 (Br isotopes, MH+-t-butyl).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:5]([C:14]#[C:15][C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:35])[C@@H:24]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[CH:19]=[CH:20][CH:21]=2)=[CH:4][N:3]=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:34][N:26]([C@@H:24]([CH3:25])[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]#[C:14][C:5]2[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:7][C:2]([NH:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[N:3][CH:4]=2)[CH:17]=1)=[O:35])[C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32]
Reactant: C[C@@H](C(=O)Nc1cccc(C#Cc2cnc(Cl)nc2N2CCOCC2)c1)N(C)C(=O)OC(C)(C)C
Reactant: NCCc1ccncc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H](C(=O)Nc1cccc(C#Cc2cnc(NCCc3ccncc3)nc2N2CCOCC2)c1)N(C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 12 h
Yield: 20.3 %

Procedure:
To (S)-tert-butyl (1-((3-((2-chloro-4-morpholinopyrimidin-5-yl)ethynyl)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (L5, 437 mg), 4-(2-aminoethyl)pyridine (214 mg), tris(dibenzylideneacetone)dipalladium(0) (80 mg), 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene (101 mg) and cesium carbonate (856 mg), 1,4-dioxane (10 mL) was added at room temperature, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was cooled to room temperature, then the insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 95% ethyl acetate/5% methanol) to obtain (S)-tert-butyl methyl(1-((3-((4-morpholino-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidin-5-yl)ethynyl)phenyl)amino)-1-oxopropan-2-yl)carbamate (L6, 104 mg).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:32][CH2:31][CH2:30][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:29])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)=[O:11])=O)(C)(C)C.[CH2:33]([N:40]=C=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:6]([N:8]1[CH2:32][CH2:31][CH2:30][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17](=[O:29])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)=[O:11])=[O:5])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccc2c(c1)OCO2
Reactant: O=C=NCc1ccccc1
Product: O=C(COc1ccc2c(c1)OCO2)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1

Procedure:
By the same procedure as in Example 21-C), while using (2S)1-[N-(tert-butoxycarbonyl)-L-prolyl]-2-{1-hydroxy-2-[(3,4-methylenedioxy)phenoxy]ethyl} pyrrolidine (2.07 g) and benzyl isocyanate (0.63 ml), there was obtained 2.06 g of the title compound.
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24]([C:26](=O)[C:27]([OH:29])=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]1([CH:37]([O:44][C:45](=[O:64])[C:46]([C:50]2[CH:55]=[CH:54][C:53]([O:56][C:57](=[O:59])[CH3:58])=[C:52]([O:60][C:61](=[O:63])[CH3:62])[CH:51]=2)([O:48][NH2:49])[CH3:47])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO>[C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:49]/[O:48][C:46]([C:45]([O:44][CH:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:64])([C:50]3[CH:55]=[CH:54][C:53]([O:56][C:57](=[O:59])[CH3:58])=[C:52]([O:60][C:61](=[O:63])[CH3:62])[CH:51]=3)[CH3:47])/[C:27]([OH:29])=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)Oc1ccc(C(C)(ON)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Solvent: CO
Product: CC(=O)Oc1ccc(C(C)(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C(=O)OC(c2ccccc2)c2ccccc2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
To a solution of (2-triphenylmethylamino-4-thiazolyl)glyoxylic acid (0.49 g) in methanol (25 ml) was added dropwise a solution of the product obtained in Step 3 (0.61 g) in methanol (10 ml). The mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, giving 0.8 g of the objective compound.
Reaction SMILES: FC1C=CC=CC=1NC(=S)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1.[CH3:35][CH:36]([CH3:69])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][C:64]([CH3:67])=[CH:63][CH:62]=4)=[S:59])=[CH:53][CH:52]=3)=[CH:47][CH:48]=2)[C:43]1=[O:68])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:69])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:62]=[CH:63][C:64]([CH3:67])=[CH:65][CH:66]=4)=[S:59])=[CH:53][CH:52]=3)=[CH:47][CH:48]=2)[C:43]1=[O:68])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(C)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Product: Cc1ccc(NC(=S)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)cc1
Yield: 83 %

Procedure:
The compound of example 54 was prepared analogous to compound of example 52 by hydrolysis of compound of example 53.