Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: O
Solvent: CCO
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(N4CCOCC4)ncnc32)[C@]1(C)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 30 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.3 g, 0.64 mmol) in ethanol (about 5 ml) was added morpholine (about 0.56 ml, 6.49 mmol) and stirred at room temperature for about 15 hours. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compounds Isomer A and B (0.1 g) as a colorless gummy mass. Yield: 30%.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH:16]([C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:32][CH3:33])=[C:26]([C:29](=O)[CH3:30])[CH:27]=2)[O:22][C:21]([CH3:35])([CH3:34])[CH:20]=1)([CH3:18])[CH3:17]>>[F:7]/[C:6](=[C:29](/[C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:32][CH3:33])[O:22][C:21]([CH3:35])([CH3:34])[CH:20]=[C:19]2[CH:16]([CH3:17])[CH3:18])\[CH3:30])/[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: COc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.44 mL, 2.18 mmol) and 1-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-ethanone (Compound 54, 199 mg, 0.73 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[C:19]([N+:33]([O-])=O)[CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]>CO.[Ni]>[CH3:1][O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:24]=2[O:31][CH3:32])=[C:19]([NH2:33])[CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)c([N+](=O)[O-])c1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Ni]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)c(N)c1)NC(=O)c1c(Cl)cccc1Cl
Yield: 83.7 %

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-3-nitro-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (1.07 g) in MeOH (15 mL) was added Raney-Ni (100 mg) and H2 gas was bubbled through the mixture for 15 min. The mixture was filtered through Celite and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 1:1) to give N-(2,6-dichlorobenzoyl)-3-amino-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (845 mg). ESMS: m/z 503 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([S:18](Cl)(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([S:18]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 1.7 g. (0.02 mole) of piperidine and 5.8 g. (0.02 mole) of 2,4-dichloro-5-chlorosulfonylbenzoic acid (Sturm, et al., Ber., 99, 328 (1966) in 70 ml. of water and cooled to 15° C. is treated dropwise with 50 ml. of 1N sodium hydroxide. When the addition is complete, the mixture is allowed to warm to room temperature and remain for 1 hr. The hazy suspension is filtered and the clear filtrate acidifiedwith 12N hydrochloric acid. The precipitated solids are filtered and dried,7.7 g., m.p. 200°-205° C. A sample is recrystallized from acetonitrile, m.p. 205°-206° C.
Reaction SMILES: [C:1]([CH:3]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])#[CH:2].[CH2:19]([SnH:23]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])/[CH:2]=[CH:1]/[CH:3]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(CCCCCCCC)OC1CCCCO1
Product: CCCCCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)OC1CCCCO1
Temperature: 110 °C

Procedure:
To 0.05 g (0.19 mmol) of the titled product of Example 8 is added 0.6 ml (0.22mmol) of tri-n-butyltin hydride, and 20 mg of azoisobutyronitrile (AIBN). The reaction mixture was heated at 110° C. for 3 hours, whereupon thin layer chromatography indicated that the reaction was complete, producing the titled product. The product was used without further purification.
Reaction SMILES: N1C=CC=C(CN)C=1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][NH2:16].FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59](O)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59]([NH:16][CH2:15][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=4)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)O
Reactant: NCc1ccccn1
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)NCc1ccccn1

Procedure:
Following the procedure as described in EXAMPLE 2, making variations as required to replace pyridin-3-ylmethanamine with pyridin-2-ylmethanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (S)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid (72%): mp 112-113° C. (diethyl ether/hexane); 1H NMR (300 MHz, DMSO-d6) δ 8.50-8.46 (m, 2H), 7.75-7.70 (m, 1H), 7.34-7.14 (m, 6H), 4.56-4.51 (m, 1H), 4.46-4.39 (m, 4H), 3.56-3.50 (m, 1H), 3.01 (dd, J=9.1, 3.4 Hz, 1H), 2.46 (s, 3H), 1.36 (d, J=6.2 Hz, 3H); MS (ES+) m/z 439.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: OCc1ccccn1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCc2ccccn2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl amine, 2-(hydroxymethyl)pyridine and DBU in dioxane. 349 (M{81Br}+H+, 98), 347 (M{79Br}+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35].O>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(O)cc1Cl)OCc1ccccc1
Reactant: C[Si](C)(C)CCOCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCOc1ccc(NC(=O)OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl (2-chloro-4-hydroxyphenyl)carbamate (9.26 g) in dichloromethane (100 mL) were added tetra-n-butylammonium iodide (12.3 g), diisopropyl ethylamine (11.4 mL), and [2-(chloromethoxy)ethyl](trimethyl)silane (11.8 mL) under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)carbamate (10.3 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](OC)(OC)[O:4][CH3:5].[NH2:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13]C=1O>C(O)C>[Br:17][C:15]1[CH:14]=[CH:13][C:5]2[O:4][C:3]([CH2:2][Cl:1])=[N:10][C:11]=2[CH:16]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: COC(CCl)(OC)OC
Solvent: CCO
Product: ClCc1nc2cc(Br)ccc2o1
Reaction time: 48 h

Procedure:
1.79 mL (13.3 mmol) 2-chloro-1,1,1-trimethoxy-ethane are added dropwise at RT to a solution of 2.5 g (13.29 mmol) 2-amino-4-bromophenol in 20 mL ethanol and stirred for 48 h. Then 0.4 mL 2-chloro-1,1,1-trimethoxy-ethane are added and stirred for 20 h. The reaction mixture is evaporated down. The purification is carried out by column chromatography on silica gel (DCM/ethanol 80:1).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20](O)[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].P(Cl)(Cl)([Cl:30])=O>>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([Cl:30])[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCOc1ccc(-c2ncc(C(=O)OCC)c(O)n2)cc1
Product: CCCCCCCCOc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Yield: 91 %

Procedure:
Then, 5 g (0.013 mole) of the obtained ethyl 2-(p-octyloxyphenyl)-4-hydroxypyrimidine-5-carboxylate was dissolved in 25 ml of phosphorus oxychloride, and the mixture was refluxed with heating for 3 hours. The excess phosphorus oxychloride was distilled under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent: CHCl3) to give 4.9 g of ethyl 2-(p-octyloxyphenyl)-4-chloropyrimidine-5-carboxylate (yield: 91%).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][C:10]([O:12]C(C)(C)C)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[C:1]1([CH2:7][CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C=CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C=CCc1ccccc1
Yield: 99.8 %

Procedure:
A solution of 6.3 g (28.86 mmol) of t-butyl 4-phenylbut-2-enoate in 100 mL of CH2Cl2 and 30 mL of trifluoroacetic acid is stirred at 25° C. for 18 hours. The reaction is concentrated in vacuo to afford 4.67 g (99.85%) of 4-phenylbut-2-enoic acid as a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1.[B-](F)(F)(F)[F:23].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[C:10]([F:23])=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1
Reactant: C[C@H](CO)Nc1cc(O)nc(SCc2cccc(Cl)c2)n1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2)nc(O)c1F
Reaction time: 20 h

Procedure:
The product of Example 3 (0.1 g) was dissolved in methanol (10 ml), Selectfluor™ (0.12 g) added and stirred for 20 h. The mixture was evaporated and purified by silica gel chromatography (5% methanol/DCM) to yield the title product as a white solid. Yield 19 mg.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1.[H-].[Na+].CO>CN(C=O)C>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc2c(ccn2Cc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a solution of methyl 1H-indole-5-carboxylate (1.09 g, 6.2 mmol, 1 equiv) and 1-(bromomethyl)-4-bromobenzene (1.70 g, 6.82 mmol, 1.1 equiv) in anhydrous DMF (30 mL) under argon atmosphere was added sodium hydride (500 mg, 12.4 mmol, 2 equiv) in small portions. The mixture was stirred 2 h at room temperature. The reaction mixture was then neutralized by addition of methanol and concentrated in vacuo. The residue was dissolved in AcOEt, washed with brine and dried over MgSO4. The crude was purified by flash chromatography (Hexane/AcOEt 7.5/2.5) to afford the title compound as a white powder (1.09 g, 3.2 mmol, 52%). ESI-MS (m/z): 344/346 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[Li]CCCC.CN([CH:17]=[O:18])C.Cl>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:17]=[O:18])=[CH:4][N:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccc(Br)nc1
Temperature: -80 °C

Procedure:
To a suspension of 2,5-dibromopyridine (2.00 g, 8.44 mmol) in dry diethyl ether (25 mL) was added n-BuLi (3.55 mL, 8.87 mmol, 2.5 M solution in hexane) at −80° C. under a nitrogen atmosphere. After stirring for 1 h at −80° C. dry DMF (0.68 mg, 9.28 mmol) was added. After stirring for an additional hour at −80° C. the reaction mixture was allowed to warm to 0° C. and HCl (18.0 mL, 1 M) was added. After stirring for 15 minutes the phases were separated and aqueous layer was extracted twice with diethyl ether. The combined organic layers were washed with water (50 mL), brine (50 mL) and dried over MgSO4. The organic phase was concentrated under reduced pressure and the crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (8:1) as eluent. White solid. Yield: 1.03 g, 66%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=7.67-7.71 ppm (m, 1H), 8.02 (dd, J=8.2, 2.5 Hz, 1H), 8.84 (dd, J=2.5, 0.6 Hz, 1H), 10.10 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=129.0, 130.6, 137.5, 148.3, 152.5, 189.4; MS (ESI): m/z=187.19 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][NH2:17])=[N:4][C:5]([CH3:15])=[N:6][C:7]=1[NH:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.[CH:18]1([CH2:23][C@H:24]([CH2:28][N:29]([CH:37]=[O:38])[O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[C:25](O)=[O:26])[CH2:22][CH2:21][CH2:20][CH2:19]1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH:18]1([CH2:23][C@@H:24]([C:25]([NH:17][NH:16][C:3]2[C:2]([F:1])=[C:7]([NH:8][CH2:9][C:10]3[S:11][CH:12]=[CH:13][N:14]=3)[N:6]=[C:5]([CH3:15])[N:4]=2)=[O:26])[CH2:28][N:29]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH:37]=[O:38])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1nc(NN)c(F)c(NCc2nccs2)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1nc(NCc2nccs2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
5-Fluoro-4-hydrazino-2-methyl-6-[(1,3-thiazol-2-ylmethyl)amino]pyrimidine (80 mg, 0.33 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (Hunigs base salt, 140 mg, 0.33 mmol), and HOAt (45 mg, 0.33 mmol) were dissolved in 3 mL of DMF. NMM (0.1 mL, 0.9 mmol) was added, followed by EDC (65 mg, 0.33 mmol). After stirring overnight at room temperature, the reaction mixture was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(1,3-thiazol-2-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (72 mg, 45%). LCMS: (M+H)+: 536.2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1)#[CH:2].CCN([CH:25]([CH3:27])[CH3:26])C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:16][CH2:15][C@@H:11]1[CH2:10][C@H:27]1[C:25]#[C:26][C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: C#Cc1ccc(-c2ccnc(C(=O)OC)c2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(C#CC#C[C@@H]3C[C@H]3CO)cc2)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45.9 %

Procedure:
To a stirring solution of compound 2.6 (1.77 g, 7.5 mmol), Pd(PPh3)2Cl2 (262 mg, 0.37 mmol), CuI (143 mg, 0.75 mmol), and DIPEA (2.9 g, 22.5 mmol) in THF (50 mL) was added compound 2.8 (1.84 g, 10.5 mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 5 hr. The solvent was removed under reduced pressure, and the resulting residue was diluted with water (100 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were dried and concentrated under reduced pressure to give a red oil, which was purified by flash chromatography (silica gel/PE:EA 5:1˜3:1) to yield methyl 4-(4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)phenyl)picolinate (2.9, 570 mg, 23%): MS: m/z calcd for C21H17NO3 331.12. found [M+H]+ 332; 1H-NMR (DMSO-d6, 400 MHz) δ 8.77 (d, J=5.6 Hz, 1H), 8.30 (s, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 4.72 (t, J=5.6 Hz, 1H), 3.91 (s, 3H), 3.44 (m, 1H), 3.24 (m, 1H), 1.45 (m, 2H), 0.88 (m, 2H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35](O)=[O:36]>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35]([C:27]4[NH:26][C:34]5[C:29]([CH:28]=4)=[CH:30][CH:31]=[CH:32][CH:33]=5)=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc5ccccc5[nH]4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1H-indole-2-carboxylic acid as starting compounds. The crude product is treated with DMF, the solids are removed by filtration, and the solvent is removed under reduces pressure. The resulting solid is purified by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[NH2:10][C:11]1[C:16](Br)=[N:15][C:14]([Br:18])=[CH:13][N:12]=1>CS(C)=O>[Br:18][C:14]1[N:15]=[C:16]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: OCC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ncc(Br)nc1OCC1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
To a solution of 4.24 g (0.042 mol) cyclopentanmethanol in 40 mL DMSO was added 1.74 g sodium hydride 55% in oil and the mixture was stirred at room temperature for 45 min. To the resulting solution was added 5.06 g (0.020 mol) 2-amino-3,5-dibromopyrazine and the mixture was stirred at room temperature for 20 h. To the resulting solution was added 1.0 g (0.011 mol) cyclopentanemethanol and the mixture was stirred at room temperature for 20 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase washed with water (3×) and brine, dried over magnesium sulfate, evaporated and the residue was purified by chromatography on silica gel with heptane:ethyl acetate=9:1 to 3:1 to yield 3.845 g of the title compound as yellow orange crystals melting at 78-79° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:24]=[C:23]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:22]=[CH:21][C:20]=3[N+:31]([O-])=O)[CH:14]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:24]=[C:23]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH:22]=[CH:21][C:20]=3[NH2:31])[CH:14]=2)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(-c2cn(Cc3ccccc3)nn2)ccn1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCCCC2)cc1-c1cc(-c2cn(Cc3ccccc3)nn2)ccn1
Reaction time: 1 h
Yield: 107.3 %

Procedure:
A solution of 22 mg of 4-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridine 24c in 1 mL of methanol was treated with 10 mg of Pd/C and stirred under a hydrogen atmosphere for 1 h. The mixture was filtered through celite and the solvent was evaporated to give 22 mg of product.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1([C:21]2[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:21]2[N:26]=[CH:25][C:24]([NH:27][C:12]([C:9]3[S:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)=[O:14])=[CH:23][CH:22]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)cs1
Product: O=C(Nc1ccc(N2CCOCC2)nc1)c1nc(-c2ccccc2)cs1

Procedure:
With a procedure similar to example 1 above, 4-phenyl-thiazole-2-carboxylic acid (6-morpholin-4-yl-pyridin-3-yl)-amide was prepared from 4-phenyl-thiazole-2-carboxylic acid and 6-morpholin-4-yl-pyridin-3-ylamine. LCMS calcd for C19H18N4O2S (m/e) 366, obsd 367 (M+H).