Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]([NH:8][C:9]1[NH:10][C:11]2[C:16]([C:17]=1[C:18]([NH2:20])=[O:19])=[CH:15][CH:14]=[C:13]([O:21][C:22]1[CH:27]=[CH:26][C:25](N)=[CH:24][CH:23]=1)[CH:12]=2)=[O:7].[Cl:29]CCl>O.Cl.CO.[Cu]Cl>[NH2:5][C:6]([NH:8][C:9]1[NH:10][C:11]2[C:16]([C:17]=1[C:18]([NH2:20])=[O:19])=[CH:15][CH:14]=[C:13]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=1)[CH:12]=2)=[O:7]
Reactant: NC(=O)Nc1[nH]c2cc(Oc3ccc(N)cc3)ccc2c1C(N)=O
Reactant: ClCCl
Agent: Cl[Cu]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CO
Product: NC(=O)Nc1[nH]c2cc(Oc3ccc(Cl)cc3)ccc2c1C(N)=O
Reaction time: 2 h
Yield: 8 %

Procedure:
Under ice-cooling, a solution of sodium nitrite (42 mg, 0.61 mmol) in water (400 μL) was added to a suspension of 2-aminocarbonylamino-6-(4-aminophenyloxy) indole-3-carboxamide (Compound No.5-1, 99 mg, 0.30 mmol) in anhydrous dichloromethane (2 mL) and 6N hydrochloric acid (4 mL) and the mixture was stirred for 2 hours. Moreover a solution of copper(I) chloride (162 mg, 1.6 mmol) in concentrated hydrochloric acid (500 μL) was added thereto and the mixture was stirred 30 minutes. The whole was stirred overnight at room temperature. The reaction solution was diluted with water (30 mL) and methanol (20 mL), extracted with ethyl acetate (100 mL). The organic layer was washed with brine (100 mL) and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (9 mg) as a brown solid (8%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N:12]1([CH2:11][CH2:10][O:8][C:4]2[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][CH:5]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Oc1cccc(I)c1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1cccc(OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirred solution of 3-iodophenol (2.2 g, 10 mmol), N-(2-hydroxyethyl)morpholine (2 eq. 2.4 mL) and Ph3P (2 eq. 5.24 g) in THF (90 mL)at 0° C. was added dropwise a solution of diisopropylazodicarboxylate (2 eq. 3.96 g) in THF (20 mL). The resulting solution was stirred at room temperature overnight and was then quenched with NaHCO3. The product was extracted with EtOAc and the EtOAc layer was washed with NaCl (sat.), dried over sodium sulfate. The crude mixture was then purified on a silica gel column with 25% acetone in hexane to give 3-(2-morpholin-4-ylethyloxy)iodobenzene (2.8 g, 84% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([OH:7])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]([CH2:27][CH2:28]O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[O:20]([CH2:27][CH2:28][O:7][C:4]1[CH:3]=[C:2]([NH2:1])[NH:6][N:5]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cc(O)n[nH]1
Reactant: OCCOc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: Nc1cc(OCCOc2ccccc2)n[nH]1
Temperature: 130 °C
Reaction time: 5 h
Yield: 32.8 %

Procedure:
There was suspended, in 2-phenoxy ethanol (25 g, 180 mM), 5-amino-1H-pyrazol-3-ol (4.00 g, 41.4 mM), then p-toluenesulfonic acid monohydrate (15.4 g, 80.8 mM) was added to the suspension and the mixture was stirred at 130° C. for 5 hours under reduced pressure. This reaction liquid was diluted with acetonitrile, the solid precipitated out of the liquid was filtered off and washed with acetonitrile. The resulting solid was suspended in a 6% aqueous sodium bicarbonate solution (250 mL), the suspension was stirred at room temperature and the solid was then filtered off. The resulting solid was dissolved in ethyl acetate, dried over anhydrous sodium sulfate and then the solvent was distilled off to thus give the title compound (2.90 g, yield: 33%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:25]2=[O:28])=[CH:20][C:19]=1F>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][C:18]=2[Br:17])[C:25](=[O:28])[N:24]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[CH:23]=[CH:22]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1ccc(Cn2ccc3cc(F)c(Br)cc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)c(Br)cc3c2=O)cc1

Procedure:
126 mg (0.625 mmol) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester were dissolved in 2.5 mL of dimethylacteamide and 30 mg (0.75 mmol) of NaH (60% purity) were added at room temperature. After 15 minutes 181 mg (0.5 mmol) of 7-bromo-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (313) were added and stirring was continued at room temperature. After 5.5 h the solvent was removed i. vac. After adding saturated sodium bicarbonatesodium bicarbonate solution, the mixture was extracted twice with dichloromethane. The organic layers were dried with MgSO4 and evaporated. After final purification by preparative HPLC, 182 mg of the product could be isolated. Rt=1.93 min (Method C). Detected mass: 543.5/545.5 (M+H+).
Reaction SMILES: C1OC(C(O)CO)[C@@H](O)C1O.[CH2:12]([OH:23])[C@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]>>[OH:22][CH2:21][C@@H:19]([C@H:17]([C@@H:15]([C@@H:13]([CH2:12][OH:23])[OH:14])[OH:16])[OH:18])[OH:20]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OCC(O)C1OCC(O)[C@@H]1O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
sorbitan; mannitol; and mannitan
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(O[C:12](=O)[NH:13][CH2:14][CH:15]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16]1)(C)(C)C>C1COCC1>[CH2:20]([N:17]1[CH2:18][CH2:19][CH:15]([CH2:14][NH:13][CH3:12])[CH2:16]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCC1CCN(Cc2ccccc2)C1
Temperature: -5 °C
Yield: 90 %

Procedure:
To a cooled (−5° C.) and stirred solution of LAH (1 M, 7.6 ml) in dry THF (75 ml) was added a solution of (1-benzyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester (1.47 g, 5.06 mmol) in THF (22 ml) over 20 minutes. The mixture was then heated at reflux for 2.5 hrs and cooled to room temperature and quenched by successive addition of ethyl acetate (50 ml). The organic layer was then washed with water (2×), 10% NaOH and brine, dried and evaporated to give the desired product in 90% yield.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[CH2:8][N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:18]([N:7]1[CH2:8][C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[C@@H:5]([CH2:3][OH:2])[CH2:6]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3R,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (28.5 g, 0.078 mol) were dissolved in THF (800 mL). At 0° C. LiAlH4 (3.12 g, 0.082 mol) was added portion wise. After stirring at 0° C. for 4 h water (20 mL), then 5N NaOH (20 mL) and additional water (30 mL) was added. After stirring at ambient temperature for 30 min the mixture was extracted with ethyl acetate (3×10 mL), the combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude title product was obtained as a white solid (25.0 g, 95%) and directly used in the next step. ES-MS m/e: 337.8 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21]CC)=[O:20].Cl>CN(C)C=O.[OH-].[Na+].O.C(O)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:18][C:19]([OH:21])=[O:20])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CC(C)c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1OCC(=O)O
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of o-isopropylphenol (39.5 g), potassium carbonate (40 g) and ethyl α-bromoacetate (40 ml) in dimethylformamide (300 ml) is heated with stirring at 80° C. for 8 hours. To the mixture is added water, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure to remove the solvent. The residue thus obtained is dissolved in a solution of sodium hydroxide (20 g) in water (300 ml) and ethanol (200 ml), and the mixture is refluxed for 1.5 hour. After cooling, the mixture is acidified with conc. hydrochloric acid, and the precipitated crystals are collected by filtration to give α-(2-isopropylphenoxy)acetic acid (37 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[NH:18][C:19]([CH:21]=O)=[CH:20][C:12]2=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34](=[O:40])[NH:35]2>N1CCCCC1.C(O)C>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1/[C:33](=[CH:21]/[C:19]1[NH:18][C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][N:11]([C:9](=[O:10])[CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:12]=3[CH:20]=1)/[C:34](=[O:40])[NH:35]2
Reactant: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Reactant: O=Cc1cc2c([nH]1)CCCCN2C(=O)CCN1CCCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(-c3c(F)cccc3F)c2/C1=C/c1cc2c([nH]1)CCCCN2C(=O)CCN1CCCCC1
Yield: 60.3 %

Procedure:
4-(3-Piperidin-1-yl-propionyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine-2-carbaldehyde (80 mg, 0.26 mmol) was condensed with 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one (61 mg, 0.25 mmol) and piperidine (1 drop) in ethanol (3 mL) at rt for over the weekend. The precipitate was filtered, washed with ethanol and dried to give 80 mg of the titled compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](O)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[N:19]([CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1ccccc1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(O)cc2OCc2ccccc2)S1(=O)=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(OCCc3ccccc3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
A solution of 5-(2-benzyloxy-4-hydroxyphenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (90 mg, 0.21 mmol), phenethyl alcohol (37.9 mg, 0.31 mmol), DIAD (0.0612 mL, 0.31 mmol), and triphenylphosphine (81.5 mg, 0.31 mmol) in (THF 5 mL) is stirred at RT for 18 h. The solvent is removed under reduced pressure and the residue chromatographed on a Biotage 40S column using a gradient of 80:20 to 60:40 hexane/EtOAc as eluent to afford the title compound: 1H NMR (CDCl3δ7.30 (m, 11H), 6.62 (d, J=2.8 Hz, 1H), 6.43 (dd, J=8.6, 2.8 Hz, 1H), 5.00 (s, 2H), 4.25 (s, 2H), 4.11 (t, J=7.1 Hz, 2H), 3.51 (m, 2H), 3.03 (t, J=7.1 Hz, 2H), 0.99 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([OH:19])=O.CN(C)C=O.S(Cl)([Cl:27])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([Cl:27])=[O:19]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
To a solution of 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (40.0 g) described in Reference Example 8 in toluene (147 ml) were added N,N-dimethylformamide (catalyst quantity) and thionyl chloride (52.6 g) at room temperature, and stirred at 80° C. for 4.5 hours. After completion of the reaction, the solvent and excessive thionyl chloride were evaporated, azeotropy was performed with toluene twice, and then dried in vacuo to give the titled compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[C:23]([CH3:24])=[N:22][S:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17](=[O:25])[C:18]2[C:23]([CH3:24])=[N:22][S:21][C:19]=2[N:20]=1)[CH2:13][CH3:14])[C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([Cl:34])=[CH:36][CH:37]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.7 %

Procedure:
A reaction mixture of 33 (350 mg, 0.74 mmol), 4-chlorobenzoyl chloride (390 mg, 2.29 mmol) and Et3N (412 μl, 2.96 mmol) in CH2Cl2 was stirred at room temperature for 14 h. The mixture was purified by silica gel column directly to give 34 (301 mg, 67%). 34 had an analytical HPLC retention time=4.41 min. (Column: YMC S5 Combiscreen 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=1)=O.N(O)=O.C([O:20][C:21]([CH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH2:33])=[NH:32])[CH:27]=[CH:28][CH:29]=1)=[O:22])C.[OH-].[Li+]>CC(O)CC>[C:21]([CH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]2[N:32]=[C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[CH:8]=3)[CH:4]=[CH:3][N:33]=2)[CH:27]=[CH:28][CH:29]=1)([OH:20])=[O:22]
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Reactant: CCOC(=O)Cc1cccc(NC(=N)N)c1
Agent: O=NO
Agent: [Li+]
Agent: [OH-]
Solvent: CCC(C)O
Product: O=C(O)Cc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one (1.05 g, 5.0 mmol), 3-ethoxycarbonylmethyl-phenyl-guanidine nitrite (1.42 g, 5.0 mmol), lithium hydroxide (0.12 g, 5.0 mmol) in 2-butanol (15 mL) is heated to reflux for 24 hours. After cooling to room temperature, the solvent is evaporated under reduced pressure. Water (40 mL) is added and extracted with ethyl acetate (2×50 mL). The combined organic layers are dried over sodium sulfate, filtrated and concentrated. The residue is dissolved in ethanol (30 mL) and treated with lithium hydroxide (0.48 g, 20 mmol). The reaction mixture is heated to reflux for 1 hour. After cooling to room temperature, the mixture is concentrated. The residue is dissolved in water and acidified with 10% hydrochloric acid. The solid is collected by filtration and washed with water, methanol and dried to give N-[3-carboxymethyl-phenyl]-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (1.34 g); ESI-MS (m/z): 341.0 (M++H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]([CH2:13][CH2:14][CH:15]=O)[CH:12]=2)[S:5][CH:6]=1.C(O)(=O)C.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[CH:29][C:28]([C@:31]23[CH2:36][C@H:35]2[CH2:34][NH:33][CH2:32]3)=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(#N)C>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]([CH2:13][CH2:14][CH2:15][N:33]3[CH2:34][C@H:35]4[C@:31]([C:28]5[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:38])[F:37])=[CH:30][CH:29]=5)([CH2:36]4)[CH2:32]3)[CH:12]=2)[S:5][CH:6]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: Cc1csc(-c2cn(CCC=O)c(=O)[nH]c2=O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1csc(-c2cn(CCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)[nH]c2=O)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13.1 %

Procedure:
3-[5-(4-methyl-1,3-thiazol-2-yl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]propanal (Prep.45, 0.109 mmol) was suspended in 1,2-Dichloroethane (DCE) (1 ml) and Acetonitrile (1 ml). Acetic acid (9.36 μl, 0.164 mmol) followed by (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (P4 24.77 mg, 0.109 mmol) were added and the mixture was stirred at rt for 20 minutes. Then the resulting solution was cooled to 0° C. and SODIUM TRIACETOXYBOROHYDRIDE (25.4 mg, 0.120 mmol) was added. The mixture was allowed to reach r.t. under stirring and left at rt overnight. The mixture was treated with NaHCO3 aqueous saturated solution (5 mL) and extracted with EtOAc (3×5 mL). The organic was dried (Na2SO4 and rotary) to afford a yellow solid that was submitted to LC preparative purification. Fractions were collected, dried under vacuum to afford the title compound as a white solid (6.8 mg, 12%).
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:6]=[C:7]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4])[NH2:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:26])=[C:21]([C:23](=O)[CH3:24])[CH:22]=1>CO.C(O)(=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([OH:26])=[C:21](/[C:23](=[N:2]/[NH:1][C:3]([C:5]2[CH:6]=[C:7]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)=[O:4])/[CH3:24])[CH:22]=1
Reactant: CNS(=O)(=O)c1cccc(C(=O)NN)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: CNS(=O)(=O)c1cccc(C(=O)N/N=C(\C)c2cc(Cl)ccc2O)c1
Temperature: 120 °C
Yield: 36.7 %

Procedure:
3-(hydrazinecarbonyl)-N-methylbenzenesulfonamide (120 mg, 0.523 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (89 mg, 0.523 mmol) was dissolved in Methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-3-(2-(1-(5-chloro-2-hydroxyphenyl)ethylidene)hydrazinecarbonyl)-N-methylbenzenesulfonamide (75 mg, 0.192 mmol, 36.8% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.21 (m, 1H), 8.06 (m, 1H), 7.95 (d, 1H, J=7.6 Hz), 7.59 (t, 1H, J=8.0 Hz), 7.39 (d, 1H, J=2.4 Hz), 7.18 (m, 1H), 6.90 (d, 1H, J=8.0 Hz), 2.56 (s, 3H), 2.36 (5, 3H). Mass [M+H]+: 382.1
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH2:13]O.CN(C=O)C>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[CH2:13][Cl:3]
Reactant: OCc1cc(I)ccc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cc(I)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (13 mL) is added to a suspension of 4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture is stirred at ambient temperature for 3 h. Then, the solvent and the excess reagent is removed under reduced pressure. The residue is triturated with methanol and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccc(CNS(=O)(=O)c2ccc(Cl)cn2)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
5-Chloro-N-(4-methoxybenzyl)pyridine-2-sulfonamide (983 mg, 3.14 mmol) synthesized in Example (120a) was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (132 mg, 3.30 mmol) was added. After ice cooling, p-methoxybenzyl chloride (1.02 mL, 3.37 mmol) was added, and the temperature was raised to room temperature, followed by stirring for 2 hours. Water (20 mL) was added to the reaction solution, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-100%) to afford the desired compound (1.14 g, yield 84%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][O:17][CH2:18][O:19][CH3:20])[O:11][C:10]=1[C:21]([OH:23])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:40]=[CH:41][C:42]=1[Cl:43])[CH2:28][NH:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][O:17][CH2:18][O:19][CH3:20])[O:11][C:10]=1[C:21]([N:29]([CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:28][C:27]1[CH:40]=[CH:41][C:42]([Cl:43])=[C:25]([Cl:24])[CH:26]=1)=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCOCc1cc(=O)c(OCc2ccccc2)c(C(=O)N(CCNC(=O)OC(C)(C)C)Cc2ccc(Cl)c(Cl)c2)o1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
3-Benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-carboxylic acid (658 mg) obtained in Step 4 was dissolved in dimethylformamide (5 ml), and tert-butyl [2-(3,4-dichlorobenzylamino)ethyl]carbamate (596 mg) obtained in Step 1, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (429 mg) and 1-hydroxybenzotriazole (343 mg) were added at room temperature, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the obtained reaction mixture and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=15:1) to give crude tert-butyl {2-[N-(3-benzyloxy-6-methoxymethoxymethyl-4-oxo-4H-pyran-2-carbonyl)-N-(3,4-dichlorobenzyl)amino]ethyl}carbamate (1.12 g).