Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]2[S:31][C:32]([C:35]([NH:37][NH2:38])=[O:36])=[CH:33][CH:34]=2)=[O:29])=[CH:20][CH:19]=1.O>CN(C)C=O>[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]2[S:31][C:32]([C:35]([NH:37][N:38]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:36])=[CH:33][CH:34]=2)=[O:29])=[CH:20][CH:19]=1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: NNC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reaction time: 16 h
Yield: 95 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (42 mg, 0.14 mmol) and 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-(pyridin-4-yl)propylamide (40 mg, 0.13 mmol) prepared in Reference Synthetic Example 26 were dissolved in N,N-dimethylformamide (1.0 mL) and left at 70° C. for 16 hours and then at room temperature for 24 hours. Water (0.36 mL) was added with stirring, and the precipitated solid was recovered by filtration to give the desired product, 5-{1-[5-(3,4-dichlorophenyl)-4-hydroxythiophen-3-yl]ethylidenehydrazinocarbonyl}thiophene-2-carboxylic acid 3-(pyridin-4-yl)propylamide (yield 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[N:10]=2)[CH:7]=1.[OH:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl.C(#N)C>[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([C:27]3[CH:28]=[C:23]([CH2:22][OH:21])[CH:24]=[CH:25][CH:26]=3)=[CH:7][N:6]2[CH:8]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Brc1ccc2nc(-c3ccc4ccccc4c3)cn2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: OCc1cccc(-c2ccc3nc(-c4ccc5ccccc5c4)cn3c2)c1
Yield: 406 %

Procedure:
Under a stream of nitrogen, 500 mg of 6-bromo-2-(naphthalen-2-yl)imidazo[1,2-a]pyridine, 235 mg of 3-(hydroxymethyl)phenylboronic acid and 90 mg of tetrakis(triphenylphosphine)palladium are placed in a microwave tube containing 5 ml of toluene degassed beforehand under a stream of nitrogen, 5 ml of acetonitrile and 6 ml of a 0.5M solution of sodium carbonate. The tube is placed in a microwave apparatus and irradiated at 150° C. for 15 min. The organic phase is separated and dried and the filtrate is concentrated under reduced pressure. The residue obtained is taken up with 5 ml of dichloromethane. A precipitate forms and is recovered by filtration, washed with dichloromethane and then with diisopropyl ether and dried under reduced pressure. The experiment is repeated several times (6) and the solids are combined. 2.2 g of compound are obtained and are recrystallized from a 1/1 n-propanol/water mixture. The precipitate is filter-dried, washed with diisopropyl ether and dried under reduced pressure. 1.96 g of compound are obtained. Mp=161-163° C. 1H NMR (DMSO-d6, δ in ppm): 4.58 (d, J=5.5 Hz, 2H); 5.24 (t, J=5.7 Hz, 1H); from 7.29 to 7.73 (m, 8H); from 7.86 to 8.13 (m, 4H); 8.52 (m, 2H); 8.84 (m, 1H). M+H=351.
Reaction SMILES: [CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:4])[OH:3].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH3:1][P:2]([CH:5]([O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])[CH3:6])(=[O:3])[O:4][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CBr
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])P(C)(=O)O
Product: CCOC(=O)COP(C)(=O)C(C)Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
In the same way, P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinic acid and ethyl bromoacetate are reacted together to give ethoxycarbonylmethyl P-methyl-α-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]ethylphosphinate.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)=[O:3].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>[Cu].[Cu](I)I>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[CH2:14][CH2:13]1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CN1CCNCC1
Agent: I[Cu]I
Agent: [Cu]
Agent: O=C([O-])[O-]
Product: CC(=O)c1ccc(N2CCN(C)CC2)cc1
Yield: 82 %

Procedure:
In a procedure identical to Example 53, 4-bromoacetophenone was reacted with N-methylpiperazine in the presence of potassium carbonate, copper and copper iodide to furnish the desired product in 82% yield.
Reaction SMILES: [S:1]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:14](C(O)C([O-])=O)C>>[S:1]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([C:4]([F:6])([F:7])[F:5])(=[O:3])=[O:2]
Reactant: CCC(O)C(=O)[O-]
Reactant: COC(=O)COS(=O)(=O)C(F)(F)F
Product: CCOC(=O)COS(=O)(=O)C(F)(F)F

Procedure:
Prepared in the same way as described for TfO-CH2COOMe starting with ethylglycolate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)(Cl)=O.[CH3:14]O>>[OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([O:9][CH3:14])=[O:8])[CH2:3]1
Reactant: CO
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1C[C@@H](O)CN1
Temperature: 0 °C

Procedure:
7.1 30 g of (2R,4R)-4-hydroxy pyrrolidine-2-carboxylic acid are suspended in 200 ml of methanol and cooled to 0° C. Thionyl chloride (18.1 ml) is subsequently added dropwise at the same temperature distributed over an hour. The reaction mixture (RM) is warmed to room temperature (RT) over 12 h, during which a clear solution forms. The solvent is removed in vacuo, and the residue obtained is recrystallised from ether, giving 50 g of methyl (2R,4R)-4-hydroxypyrrolidine-2-carboxylate; Rt.: 0.386 min; [M+H]+146.2.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:2]#[C:1][C:3]2([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: C#CC1(O)CCOCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC3(O)CCOCC3)c21

Procedure:
Using Method C above, 4-ethynyl-tetrahydro-pyran-4-ol (41.1 mg, 0.33 mmol) (Example 85A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg) and CuI (2.5 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 85° C. for 7 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[(4-hydroxy-tetrahydro-pyran-4-yl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 36 mg, 75%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].[CH3:13][S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:31]=[C:30]([O:32][CH:33]3CCNC[CH2:34]3)[N:29]=[CH:28][N:27]=1)[CH2:21][CH2:20]2)(=[O:16])=[O:15]>C1COCC1>[N:8]1([C:1]([N:3]2[CH2:4][CH2:34][CH:33]([O:32][C:30]3[N:29]=[CH:28][N:27]=[C:26]([N:22]4[C:23]5[C:19](=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:25][CH:24]=5)[CH2:20][CH2:21]4)[CH:31]=3)[CH2:6][CH2:7]2)=[O:2])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)n3ccnc3)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
1,1′-carbonyldiimidazole (67.0 mg, 0.413 mmol) was added to a THF (2.06 mL) solution of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline (103 mg, 0.275 mmol) produced in Reference Example 28, and the mixture was stirred at room temperature for 1 hour. From the reaction solution, the solvent was distilled off under reduced pressure. To the residue, water was added, and the mixture was stirred. The deposit was collected by filtration and washed with water to obtain the title compound as white powder (105 mg, yield: 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Ni].CCO>[N:13]1([CH2:12][CH2:11][NH:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(NCCN2CCCC2)cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(NCCN2CCCC2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A 25 mL round bottom flask was charged with (4-Nitro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine (0.352 g, 1.50 mmol mmol) and EtOH (5 mL). Hydrazine Hydrate (0.326 mL, 10.5 mmol) was then added to the solution. Excess RaNi was then added in dropwise until gas evolution ceased. The suspension was then allowed to stir for an additional 1 h at 65° C. The suspension was cooled to room temperature and then was filtered over celite. The celite was washed with MeOH (˜20 mL) and the combined organic solutions were then concentrated in vacuo affording pure N-(2-Pyrrolidin-1-yl-ethyl)-benzene-1,4-diamine as a light purple oil (0.219 g, 1.07 mmol, 71% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH:16]4[CH:27]=3)=[CH:10][CH:11]=2)[N:6]([CH3:28])[C:5]1=[O:29].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:27]=3)=[CH:10][CH:11]=2)[N:6]([CH3:28])[C:5]1=[O:29]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CN(C(=O)OC(C)(C)C)CC4C3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reaction time: 18 h

Procedure:
tert-Butyl 5-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo-[4,5-b]pyridin-5-yl]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (8-3, 1 g, 2.3 mmol) was added to a mixture of dichloromethane (18.7 mL) and trifluoroacetic acid (4.6 mL) at room temperature. After stirring for 18 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (100 mL) and washed sequentially with saturated sodium bicarbonate (2×50 mL), water (1×50 mL) and brine (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8-4) as a white solid. This material was carried on without further purification.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18]CC(O)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[Cl:4][C:2](=[O:3])[CH2:1][CH2:18][CH2:17][CH2:16][C:15]([O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:23]
Reactant: O=C(O)CCCCC(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)CCCCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Next, oxalyl chloride (52.2 g; 0.41 mol) was dissolved in CHCl3 (1000 ml), and cooled to 0° C. To this was slowly added a solution of 6(benzyloxy)-6-oxohexanoic acid, (81.0 g; 0.34 mol) in CHCl3 (250 ml), and stirring was continued for 18 hr at room temperature. The reaction mixture was concentrated, coevaporated with CHCl3 (2 times 250 ml), and dried in vacuo, to yield benzyl 6-chloro-6-oxohexanoate as a colourless liquid (87 g; 100%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[NH2:29]>C(O)(=O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH2:22][CH2:23][C:24](=[O:26])[N:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:29]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: NNc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)CCC(=O)O)cc2)CC1
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(OC3CCNCC3)cc2)=NN1c1ccccn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 4-[4-(3-carboxy-propionyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (1.34 g, 3.55 mmol) in acetic acid (20 mL) was added 2-hydrazinopyridine (1.94 g, 17.8 mmol). After overnight stirring at 120° C., the reaction was concentrated under vacuum and the product was purified using a Single Step column (9:1 dichloromethane:methanol) to obtain 295 mg; MS m/z 351 (M+H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:43]([CH3:45])[CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[Cl:42])[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>O1CCCC1.CCCCCC>[OH:8][CH2:9][CH2:10][N:11]([CH:43]([CH3:45])[CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[Cl:42])[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (206) (250 mg, 0.37 mmol) in tetrahydrofuran (3.3 mL) was added 1N HCl (1.9 mL, 1.86 mmol) at room temperature and the mixture was stirred for 2 h at room temperature. Silica thin layer chromatography was performed (50% ethyl acetate in hexane, Rf=0.2). After completion of the reaction, the mixture was basified (pH ˜8) with a saturated solution of NaHCO3, extracted with ethyl acetate, dried over sodium sulfate and concentrated to get a crude product which was purified by a CombiFlash column (eluted at 30% ethyl acetate in hexane) to get 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (207) (200 mg, 96.26%) as a white foam-like solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=2)[CH2:3]1.[C:14]([O:18][C:19]([NH:21][C:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=S)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:28]([O:27][C:25]([NH:24][C:22]([NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[N:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][N:8]=2)[CH2:3]1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: Cc1ccnc(N2CCC(N)C2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(N2CCC(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C2)c1
Reaction time: 16 h
Yield: 69.2 %

Procedure:
To a suspension of 3-amino-1-(4-methylpyridin-2-yl)pyrrolidine (177 mg) and N,N′-bis(tert-butoxycarbonyl)thiourea (331 mg) and diisopropylethylamine (0.4 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (332 mg), and the mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate=4:1) and crystallized from diisopropyl ether to give N,N′-bis(tert-butoxycarbonyl)-N″-(1-(4-methylpyridin-2-yl)pyrrolidin-3-yl)guanidine (290 mg).
Reaction SMILES: Br[CH:2]1[CH:10]([F:11])[C:9]([C:12]([NH2:14])=[O:13])=[C:8]2[C:4]([C:5]([CH:15]3[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]3)=[CH:6][NH:7]2)=[CH:3]1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:21]=[S:18]1(=[O:22])[CH2:19][CH2:20][CH:15]([C:5]2[C:4]3[C:8](=[C:9]([C:12]([NH2:14])=[O:13])[C:10]([F:11])=[C:2]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:16][CH2:17]1
Reactant: OB(O)c1ccccc1
Reactant: NC(=O)C1=c2[nH]cc(C3CCS(=O)(=O)CC3)c2=CC(Br)C1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1c(F)c(-c2ccccc2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 100 °C
Reaction time: 0.3 h
Yield: 42.1 %

Procedure:
A mixture of 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6-fluoro-5,6-dihydro-1H-indole-7-carboxamide (9.2 mg, 0.024 mmol), phenylboronic acid (5.73 mg, 0.047 mmol), and K2CO3 (9.75 mg, 0.071 mmol) was taken up in 1,4-dioxane (0.3 mL) and water (0.150 mL). The mixture was degassed with argon for 10 min, and PdCl2(dppf) (1.721 mg, 2.351 μmol) was added. The vial was sealed, and the reaction was heated in a Biotage microwave for 5 min at 100° C. on high absorption. The aqueous layer was removed via pipette, and the reaction mixture was filtered through a Stratosphere PL-Thio MP SPE cartridge (0.5 g), eluting with 1:1 DCM/MeOH (10 mL). The eluent was concentrated under a stream of nitrogen at 50° C., and the crude product was dissolved in DMSO (1.2 mL) and purified on a Gilson HPLC (XBridge C18 5 μm OBD 19×100 mm preparatory column), eluting at 15 mL/min with a linear gradient running from 20% CH3CN/H2O (0.1% NH4OH) to 70% CH3CN/H2O (0.1% NH4OH) over 18 min. The desired fractions were concentrated under a stream of nitrogen at 50° C. and dried under high vacuum, giving 3.9 mg (43%) of the title compound.
Reaction SMILES: COC(C1OC(C2[Se]C=CC=2[C:15]([C:17]2[CH:21]=[CH:20][Se:19][C:18]=2[C:22]2[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:26]=2)=O)=CC=1)=O.[CH2:31]([NH:38][NH2:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1>C(O)(=O)C>[CH2:31]([N:38]1[C:15]2[Se:19][CH:20]=[CH:21][C:17]=2[C:18]([C:22]2[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:26]=2)=[N:39]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NNCc1ccccc1
Reactant: COC(=O)c1ccc(-c2[se]ccc2C(=O)c2cc[se]c2-c2ccc(C(=O)OC)o2)o1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3[se]ccc23)o1

Procedure:
Compound 73 (5.6 g, 0.02 mole), benzylhydrazine 50 (4.88 g, 0.04 mole) and glacial acetic acid (1.5 ml) were allowed to react as in the preparation of compound 55 to afford compound 79. Yield: 0.82 g (10.6%); white crystals;
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=O.Cl.N[C:10]1[NH:14][CH:13]=[N:12][C:11]=1[C:15]([NH2:17])=[O:16]>CO>[F:1][C:2]([F:7])([F:6])[C:3]1[NH:17][C:15](=[O:16])[C:11]2[N:12]=[CH:13][NH:14][C:10]=2[N:5]=1
Reactant: NC(=O)c1nc[nH]c1N
Reactant: NC(=O)C(F)(F)F
Agent: Cl
Solvent: CO
Product: O=c1[nH]c(C(F)(F)F)nc2[nH]cnc12
Temperature: 110 °C
Yield: 65.3 %

Procedure:
A 1 L round-bottom flask (three neck) containing 340 g of trifluoroacetamide was heated in an oil bath at 110° C. After the trifluoroacetamide melted, 50 g of 5-aminoimidazole-4-carboxamide-HCl was added. The mixture was warmed to reflux (bath temp 160 to 165° C.) for 4 hours, cooled to room temperature, and the rocky solid was triturated with 1 L of ether. The ether was decanted off and the remaining solid was warmed until melted and 200 mL of ether was introduced by a dropping-funnel through a water-cooled condenser. The mixture was cooled to room temperature and an additional 200 mL of ether was added with stirring. The solid was removed by filtration, triturated with 3×500 mL of ether, washed with 200 mL of H2O, and filtered to provide 89 g of crude product. The product was treated with 3 L of MeOH and 9 g of activated carbon, warmed to reflux for 20 minutes, filtered through a pad of celite, and concentrated to a volume of 2.5 L. The material was warmed to dissolve all the precipitate that formed and then cooled slowly to room temperature. The crystalline material was isolated by filtration and dried in vacuo to provide 41 g of the desired hypoxanthine as a white solid. 1H NMR (DMSO-d6) δ 8.34 (s, 1H), 7.18 (bs, 2H). MS (ES+), 205.0 (100%, M+H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[CH2:27]([NH2:30])[C:28]#[CH:29]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:30][CH2:27][C:28]#[CH:29])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: C#CCN
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: ClCCl
Product: C#CCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of (2S,3R,4R,5R,6R)-6-(acetoxymethyl)-3-isothiocyanatotetrahydro-2H-pyran-2,4,5-triyl triacetate (1.4 g, 3.6 mmol) in DCM (15 mL) at 0° C., was added propargyl amine (0.345 mL, 5.4 mmol) dropwise. After the addition, reaction mixture was stirred at RT for 1 h. DCM layer was washed with satd. NaHCO3, dried over anhydrous Na2SO4 and concentrated. The crude product (2S,3R,4R,5R,6R)-6-(acetoxymethyl)-3-(3-(prop-2-yn-1-yl)thioureido)tetrahydro-2H-pyran-2,4,5-triyl triacetate (1.59 g, 98%) thus obtained was carried forward without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[N:5]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cc(Cl)cc(N=Cc2ccccc2)c1

Procedure:
To a reaction flask, equipped with a Dean-Stark trap, is added 3,5-dichloroaniline (16.2 g., 0.10 mole), benzaldehyde (10.6 g., 0.10 mole), p-toluenesulfonic acid monohydrate (0.2 g.), and toluene (100 ml.). The reaction mixture is then warmed to reflux and the water (1.65 ml.) collected by azeotroping. The cooled reaction mixture is treated with charcoal and the filtrate reduced in vacuo to give an amber oil, that crystallizes on standing to give 24.6 g. of product, which is recrystallized from pentane to give 18.5 g. of yellow solid, m.p. 52°-53° C.