Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([CH3:25])[N:16]=1.C([O-])([O-])=O.[K+].[K+].COCCOC>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.CCOC(C)=O.C(O)C.O>[CH3:25][C:17]1[N:16]=[C:15]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1cc(C(F)(F)F)cc(-c2ccc(C(F)(F)F)nc2)n1
Temperature: 120 °C
Yield: 303.9 %

Procedure:
A 20 mL microwave vial was charged with 6-(trifluoromethyl)pyridin-3-ylboronic acid (644 mg, 3.37 mmol), 2-chloro-6-methyl-4-(trifluoromethyl)pyridine (600 mg, 3.07 mmol), bis(triphenylphosphine)palladium(II) chloride (108 mg, 0.153 mmol), and K2CO3 (848 mg, 6.14 mmol), followed by the addition of DME (9.0 mL), water (3.86 mL) and ethanol (2.57 mL). The mixture was heated in the microwave at 120° C. for 10 minutes. The combined reaction mixtures were added 200 mL EtOAc, and filtered through a celite pad. The filtrate was washed with 200 mL water and 200 mL brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 80 g column, eluted with 0-40% EtOAc in Hexanes (35 mL/min) to provide the title compound (2.858 g, 9.33 mmol, 101% yield) as a yellow solid. MS (ESI+) m/z 307.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 9.51 (d, J=2.1, 1H), 8.82 (ddd, J=8.4, 2.2, 0.5, 1H), 8.36 (s, 1H), 8.06 (dd, J=8.4, 0.5, 1H), 7.78 (s, 1H), 2.70 (s, 3H).
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:49]([O:51][C:52](=[O:73])[C@H:53]([O:55][C:56]1[CH:61]=[C:60](Cl)[N:59]=[C:58]([S:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[C:66]=2[F:72])[N:57]=1)[CH3:54])[CH3:50]>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>[CH2:49]([O:51][C:52](=[O:73])[C@H:53]([O:55][C:56]1[CH:61]=[C:60]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[N:59]=[C:58]([S:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[C:66]=2[F:72])[N:57]=1)[CH3:54])[CH3:50]
Reactant: NS(=O)(=O)N1CCC1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.61 g), tris(dibenzylideneacetone)dipalladium (0) (0.15 g), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (105 mg), cesium carbonate (0.77 g), 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 11, step i) (0.61 g) and dioxane (15 mL). Purification was by column chromatography on silica gel using MeOH/DCM (5:95) as eluent, followed by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) to give the title compound as a white solid. Yield: 46 mg
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[Na+].[SH:31][CH2:32][CH2:33][S:34]([O-:37])(=[O:36])=[O:35].COC1C=C(C=CC=1OC)C(Cl)=O>C(Cl)Cl>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][S:31][CH2:32][CH2:33][S:34]([OH:37])(=[O:36])=[O:35])[CH:15]=1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(CCl)c1
Reactant: O=S(=O)([O-])CCS
Agent: COc1ccc(C(=O)Cl)cc1OC
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(CSCCS(=O)(=O)O)c1
Temperature: 40 °C
Reaction time: 96 h
Yield: 46.1 %

Procedure:
Subsequently, methyl 5-chloro-2-[3-(chloromethyl)benzoyl]aminobenzoate (1.8 g) was dissolved in anhydrous methylene chloride. Triethylamine (1.5 ml) and 2-mercaptoethanesulfonic acid sodium salt (compound B′) (1.3 g) were added to the solution at room temperature, and the mixture was stirred at 40° C. for 4 days. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, was dried over sodium sulfate, and was then concentrated. The residue was purified by column chromatography on silica gel to give 5-chloro-2-[3-(2-sulfo-ethylsulfanylmethyl)-benzoylamino]-benzoic acid methyl ester (1.08 go yield 46.1%) as a useful intermediate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:35][CH2:34]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1.C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[CH2:56][CH:57]([F:59])[F:58])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:56][CH:57]([F:59])[F:58])[CH2:10][CH2:9]2)=[CH:6][C:5]([C:14]#[N:15])=[CH:4][C:3]=1[NH:16][C:17]1[N:22]=[C:21]([N:23]([CH:33]2[CH2:34][CH2:35]2)[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:20]2=[N:36][CH:37]=[C:38]([C:39]#[N:40])[N:19]2[N:18]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(CC(F)F)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To the stirred solution of 2-((2-chloro-5-cyano-3-(piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 11) (0.100 g, 0.180 mmol) in DMF (2.0 mL) and N,N-diisopropylethylamine, (63 μL, 0.361 mmol) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.046 g, 0.216 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. On completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated and aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum to give off-white solid, which was purified by flash chromatography on silica gel using an automated ISCO system (12 g Redisep column, eluting with 0-5% methanol/chloroform) to get 2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (100 mg) as an off-white solid.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[CH2:11][N:10]2[CH2:12][CH2:13][N:14]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[CH3:29])[C:19]([N:30]([C:32](=[O:50])[C:33]([C:36]4[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=4)([CH3:35])[CH3:34])[CH3:31])=[CH:18][N:17]=3)[CH2:15][CH:9]2[CH2:8][N:7]1[C:51](=[O:53])[CH3:52])(=O)C.[OH-].[Na+]>C1COCC1.O>[C:51]([N:7]1[C@@H:6]([CH2:5][OH:4])[CH2:11][N:10]2[CH2:12][CH2:13][N:14]([C:16]3[N:17]=[CH:18][C:19]([N:30]([CH3:31])[C:32](=[O:50])[C:33]([C:36]4[CH:37]=[C:38]([C:46]([F:47])([F:48])[F:49])[CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=4)([CH3:34])[CH3:35])=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[CH3:29])[CH:21]=3)[CH2:15][CH:9]2[CH2:8]1)(=[O:53])[CH3:52]
Reactant: CC(=O)OC[C@H]1CN2CCN(c3cc(-c4ccc(F)cc4C)c(N(C)C(=O)C(C)(C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cn3)CC2CN1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CC2CN(c3cc(-c4ccc(F)cc4C)c(N(C)C(=O)C(C)(C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cn3)CCN2C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {(3R)-2-acetyl-8-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]octahydro-2H-pyrazino[1,2-a]pyrazin-3-yl}methyl acetate (D97, 27 mg, 0.0472 mmol) in 2 mL of THF and 0.5 mL of water was added 1M NaOH (1 mL) and the resulting solution was stirred at room temperature for 30 min. It was checked by UPLC/MS, which showed a peak for the expected product at 0.76 min. (m/z=710 (M+1), 355 (M+2)/2). The target compound was isolated by SCX, obtaining 21 mg of the title compound.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[I-:18].[K+].II.N(OC(C)(C)C)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.[Cu](I)I>[I:18][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(-c2ccccc2)c2c1C(=O)NC2
Reactant: [I-]
Agent: I[Cu]I
Agent: CC(C)(C)ON=O
Agent: II
Solvent: CC#N
Product: O=C1NCc2c(-c3ccccc3)ccc(I)c21
Temperature: 25 °C
Yield: 60.7 %

Procedure:
7-Amino-4-phenylisoindolinone (80.0 mg, 0.357 mmol) was dissolved in acetonitrile (4.8 mL), and the solution was added with potassium iodide (71.0 mg, 0.428 mmol), copper iodide (82.0 mg, 0.428 mmol), iodine (109 mg, 0.428 mmol) and tert-butyl nitrite (0.068 mL, 0.57 mmol), followed by stirring under ice-cooling for 1.5 hours. Then, the reaction mixture was warmed to room temperature and further added with tert-butyl nitrite (0.068 mL, 0.57 mmol), followed by stirring at 50° C. for 1.5 hours. The reaction mixture was added with 10% aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/acetonitrile=6/1) to obtain 7-iodo-4-phenylisoindolinone (72.6 mg, yield 61%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([B-](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C(C)=CC=CC=1>[C:2]1([N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 91.8 %

Procedure:
A 100-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 5.403 g (48 mmol) of chlorobenzene, 6.769 g (40 mmol) of diphenylamine, 4.613 g (48 mmol) of sodium-tert-butoxide, 0.002 g (0.01 mmol) of palladium (II) acetate and 5 ml of xylene were weighed in the flask, followed by stirring. Further, 0.021 g (0.04 mmol) of tri-tert-butylphosphonium tetraphenylborate obtained in Example A-1 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 100-120° C. for 10 hours. After the completion of the reaction, 45 ml of xylene and 50 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 9.008 g of triphenylamine (yield: 92 mol % based on diphenylamine). The melting point was 125-126° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[N:24]4[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]4=[N:22][CH:21]=3)[C:17]([C:30]#[N:31])=[CH:16][N:15]=2)[CH3:12])=[CH:7][CH:6]=1)=[O:4].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:29][C:28]1[C:23]2[N:24]([C:20]([C:18]3[C:17]([C:30]#[N:31])=[CH:16][N:15]=[C:14]([NH:13][C@H:11]([C:8]4[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:6][CH:7]=4)[CH3:12])[N:19]=3)=[CH:21][N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccn2c(-c3nc(N[C@@H](C)c4ccc(C(=O)CBr)cc4)ncc3C#N)cnc12
Reactant: C1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccn2c(-c3nc(N[C@@H](C)c4ccc(C(=O)CN5CCCC5)cc4)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 mg of the compound [3-2] was dissolved in 0.4 mL of N,N-dimethylformamide, and 7 μL of pyrrolidine was added thereto. The reaction mixture was stirred for 30 minutes at room temperature, and then thereto was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The resulting organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin-layer chromatography, to obtain 3 mg of 4-(8-methylimidazo[1,2-a]pyridin-3-yl)-2-({(1S)-1-[4-(pyrrolidin-1-ylacetyl) phenyl]ethyl}amino)pyrimidine-5-carbonitrile [3-3] (hereinafter, referred to as the compound [3-3]) as a colorless oily product.
Reaction SMILES: [Si:1]([O:18][C@@H:19]([CH3:23])[C:20]([OH:22])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:57]([CH2:60][CH2:61][CH2:62][C:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[NH:67][N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]>C(#N)C>[N:57]([CH2:60][CH2:61][CH2:62][C@:63]1([C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[N:67]([C:20](=[O:22])[C@@H:19]([O:18][Si:1]([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:23])[N:66]=[C:65]([C:68]2[CH:73]=[C:72]([F:74])[CH:71]=[CH:70][C:69]=2[F:75])[S:64]1)=[N+:58]=[N-:59]
Reactant: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.1 %

Procedure:
To a solution of (S)-2-(t-butyldiphenylsilyloxy)propanoic acid (339 mg, 1.09 mmol) in acetonitrile (6 mL) was added HATU (550 mg, 1.45 mmol) followed by DIEA (0.378 mL, 2.17 mmol). After stirring at room temperature for 15 minutes, a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (260 mg, 0.72 mmol) in acetonitrile (4 mL) was added. After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure and partitioned between saturated NaHCO3 (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The brown oil was chromatographed (9:1 hexanes/ethyl acetate) to provide the less polar diastereomer, (S)-1-((S)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (121 mg) and the more polar diastereomer, (S)-1-((R)-2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-(t-butyldiphenylsilyloxy)propan-1-one (175 mg) as pale yellow oils. Absolute stereochemistry was assigned by examination of a protein:inhibitor co-crystal structure of Eg5 and (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15](C(OC)=O)[C:16]([O:18]C)=[O:17])=[C:11]([N+:24]([O-:26])=[O:25])[CH:10]=2)=[CH:5][CH:4]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([N+:24]([O-:26])=[O:25])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(-c2ccc(OC)cc2)cc1[N+](=O)[O-]
Agent: Cl
Product: COc1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1

Procedure:
Crude dimethyl 4'-methoxy-3-nitro-biphenyl-4-malonate was heated at 100° C. in 60 mL of 6N hydrochloric acid for 15 hours and cooled. The precipitate was collected by filtration, washed with water and hexane, and dried to give 7.2 g of crude 4'-methoxy-3-nitrobiphenyl-4-acetic acid as a light tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH2:18][CH3:19])=[N:16][N:15]=[C:14]1[CH2:20][NH:21][C:22]([C:24]1[N:25]([CH2:33][C:34]([O:36]CC)=[O:35])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:5].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:42]=[CH:41][CH:40]=[CH:39][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH2:18][CH3:19])=[N:16][N:15]=[C:14]1[CH2:20][NH:21][C:22]([C:24]1[N:25]([CH2:33][C:34]([OH:36])=[O:35])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[O:5]
Reactant: CCOC(=O)Cn1c(C(=O)NCc2nnc(CC)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(CC)nnc2CNC(=O)c2cc3ccccc3n2CC(=O)O)s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-ethyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetate (1.0 g) and a solution of sodium hydroxide (0.13 g) in ethanol were added to ethanol (20 ml), and the mixture was stirred at 50° C. for 1 hour. The solvent was evaporated, and the residue was dissolved in water. Toluene was added to the solution for washing. The aqueous layer was taken out, and 2M hydrochloric acid was added to adjust the solution to pH 2. The solution was extracted with chloroform, and the extract was dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 0.34 g of 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-ethyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetic acid.
Reaction SMILES: [NH2:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5].O.C(=O)(O)[O-].[C:15](O)(=[O:26])[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.Cl>COCCOC.CN(C)C=O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:15]([NH:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5])=[O:26]
Reactant: NC(=O)[C@@H](N)CC(=O)O
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: COCCOC
Solvent: CN(C)C=O
Product: NC(=O)[C@H](CC(=O)O)NC(=O)c1ccc2ccccc2n1
Yield: 69.1 %

Procedure:
To a solution of 0.50 g (3.78 mmol) of L-isoasparagine in 5.0 mL H2O containing ˜45 mg (1.5 eq) of solid bicarbonate. To this was added a suspension of 1.02 g (3.78 mmol) quinaldic acid, N-hydroxysuccinamide ester in ethylene glycol dimethylether, and the suspension was solubilized by the addition of 10 mL of dimethylformamide. After 3 hours the solution was acidified by the addition of 5% HCl (aqueous) and the product was filtered and washed with water, dried under vacuum to yield 750 mg (70% yield) of N-(2-quinolinylcarbonyl)-L-isoasparagine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:30]=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=[O:33].C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:33])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:30]=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[Se]=O
Reactant: COc1cccc(Cc2ncc(C=O)c3cc(OCc4ccccc4)c(OC)cc23)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COc1cccc(C(=O)c2ncc(C=O)c3cc(OCc4ccccc4)c(OC)cc23)c1
Temperature: 120 °C
Yield: 53.2 %

Procedure:
To a stirred solution of 6-benzyloxy-7-methoxy-1-(3-methoxy-benzyl)-isoquinoline-4-carbaldehyde (90 mg, 0.22 mmol) in acetic acid (3 mL) was added selenium dioxide (120 mg, 1.08 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 6-benzyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde as a yellow solid (50 mg, 57% yield).
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][NH:22][CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[CH3:45][N:46]([CH3:51])[CH2:47][C:48](O)=[O:49].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH3:45][N:46]([CH3:51])[CH2:47][C:48]([N:22]1[CH2:23][C@@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C@H:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:21]1)=[O:49]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CNC[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN(C)CC(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(C(=O)CN(C)C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
Compound 1 (100 mg, 0.167 mmol) obtained in Example 1 was dissolved in chloroform (2 mL), and stirred at room temperature for 1.5 hours after adding N,N-dimethylglycine hydrochloride (Tokyo Chemical Industry Co.; 46.5 mg, 0.333 mmol), diisopropylethylamine (0.146 mL, 0.833 mmol), and (benzotriazol-1-yloxy)tripyrrolizinophosphonium hexafluorophosphate (Watanabe Chemical Industries, Ltd.; 217 mg, 0.417 mmol). The aqueous layer was extracted with chloroform after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to give compound 25 (98.9 mg, 86.8%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[NH:7][C:8]2[N:9]([N:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=2)[C:10](=O)[CH:11]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:22])=O>>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([Cl:22])[N:9]2[N:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:8]2[N:7]=1)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1nc2[nH]c(COC(C)=O)cc(=O)n2n1
Product: COC(=O)c1nc2nc(COC(C)=O)cc(Cl)n2n1

Procedure:
A suspension of 100 mg (0.38 mmol) of methyl 5-(acetoxymethyl)-4,7-dihydro-7-oxo-s-triazolo[1,5-a]pyrimidine-2-carboxylate in 7 ml of phosphorus oxychloride is held under reflux for 6 hours and subsequently concentrated in a vacuum. The residue is dissolved in dichloromethane. The solution is washed with ice/water, dried over sodium sulphate and concentrated. After crystallization from methanol/diethyl ether there are obtained 70 mg of methyl 5-(acetoxymethyl)-7-chloro-s-triazolo[1,5-a]pyrimidine-2-carboxylate as brown crystals of melting point 120° C.