Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29]([C:32]3[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=3)[C:35]([O:37]C)=[O:36])(=[O:31])=[O:30])[CH:25]=2)[O:20]1)[CH2:9][C@H:10]([OH:17])[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[OH:17][C@H:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][CH2:18][C@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([S:29]([C:32]3[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=3)[C:35]([OH:37])=[O:36])(=[O:31])=[O:30])[CH:25]=2)[O:20]1
Reactant: COC(=O)c1cccc(S(=O)(=O)c2ccc3c(c2)CC[C@H](CN(C[C@H](O)c2cccnc2)C(=O)OC(C)(C)C)O3)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(S(=O)(=O)c2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)c1
Temperature: 45 °C
Reaction time: 2 h
Yield: 12.6 %

Procedure:
To a solution of 66.3 mg (0.11 mmol) methyl 3-{[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]sulfonyl}benzoate (Example 176) diluted in 5 mL 1,4-dioxane, was slowly added 0.05 mL of 6N hydrochloric acid. The resulting mixture was then stirred at 45° C. for 2 hours. The crude mixture was concentrated in vacuo, then purified by preparative HPLC. The purified intermediate product was then treated with 0.8 mL of 2N sodium hydroxide and allowed to stir for 36 hours and then concentrated in vacuo. The crude product was then purified by preparative HPLC (0-70% Acetonitrile/0.1% aq TFA) to obtain 6.5 mg of product as the bis-TFA salt. MH+ 469.3 (free base)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([O:30][CH3:31])[CH:21]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([NH:18][CH2:17][CH2:16][CH2:15][N:12]2[CH2:13][CH2:14][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11]2)=[O:25])=[C:22]([O:30][CH3:31])[CH:21]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCCN1CCC(CNC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.9 %

Procedure:
3-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)propylamine (5 g) was dissolved in dimethylformamide (50 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (3.9 g) and 1-hydroxybenzotriazole (3.2 g) were added. The mixture was stirred at 0° C. for 15 min and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (4.5 g) was added, followed by stirring at room temperature for 10 hr. The reaction mixture was concentrated under reduced pressure, and aqueous potassium carbonate solution was added to the residue. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 3.4 g of 4-amino-N-(3-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)propyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: FC(F)(F)c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
To a solution of 6-(trifluoromethyl)-1H-indole (250 mg, 1.350 mmol) in dry DMF (3 ml), sodium hydride (60% w/w dispersion in mineral oil, 64.8 mg, 1.620 mmol) was added at room temperature. After 10 minutes, methyl 2-bromoacetate (150 μl, 1.620 mmol) was added and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude was purified by flash chromatography on silica gel column (hexane/ethyl acetate 90/10) to afford methyl 2-(6-(trifluoromethyl)-1H-indol-1-yl)acetate (120 mg, 0.467 mmol, 34.6% yield). MS/ESI+ 258.1 [MH]+.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH:5]=[CH2:6])[CH3:3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[S:19])[S-:18])=[N:14][CH:15]=1.C([NH+](CC)CC)C>C(#N)C.C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[S:18])[S:19][CH2:6][CH2:5][C:4](=[O:7])[C:2]([CH3:8])([CH3:3])[CH3:1])=[N:14][CH:15]=1
Reactant: S=C([S-])Nc1ccc(Cl)cn1
Reactant: C=CC(=O)C(C)(C)C
Agent: CC[NH+](CC)CC
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)C(=O)CCSC(=S)Nc1ccc(Cl)cn1
Reaction time: 3 h
Yield: 82.6 %

Procedure:
A solution of 2,2-dimethylpent-4-en-3-one (30.0 g) in anhydrous acetonitrile (60 cc) is added, at a maximum temperature of 5° C., to a suspension of triethylammonium 5-chloropyrid-2-yldithiocarbamate (82.0 g) in anhydrous acetonitrile (400 cc). The reaction is allowed to proceed for 3 hours at between 5° and 20° C. The crystals which appear are filtered off; the filtrate is evaporated under reduced pressure (20 mmHg) at 45° C. The residue obtained and the crystals separated off beforehand are dissolved in methylene chloride (750 cc). The organic solution is washed four times with distilled water (total 600 cc), dried over sodium sulphate and evaporated. The product obtained (98.0 g) is dissolved in chloroform (400 cc). The solution is chromatographed on a column of diameter 6.8 cm, containing silica (0.063-0.2 mm; 800 g). Elution is carried out with chloroform (2.6 liters), this eluate being discarded, and then with chloroform (7.2 liters), this eluate being collected and evaporated to dryness. The product obtained (85.0 g) is purified by recrystallisation from acetonitrile (350 cc). 4,4-Dimethyl-3-oxopentyl 5-chloropyrid-2-yldithiocarbamate (70.0 g) (structure determined by IR spectroscopy in petroleum jelly), which melts at 111° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].N#N.[CH:11]1([NH:17][C:18](=[O:51])[C@H:19]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[NH:20]C([C@]2(NC(=O)C3C=CC=CC=3)CCC3C(=C(OC)C=CC=3)C2)=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CO>[F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[CH:11]1([NH:17][C:18](=[O:51])[C@H:19]([CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH2:20])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc2c1C[C@](NC(=O)c1ccccc1)(C(=O)N[C@@H](Cc1ccccc1)C(=O)NC1CCCCC1)CC2
Agent: N#N
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CO
Product: N[C@@H](Cc1ccccc1)C(=O)NC1CCCCC1
Reaction time: 4 h
Yield: 83.5 %

Procedure:
7.1 ml (80.74 mmol) of trifluoromethanesulphonic acid were added dropwise under argon and while cooling with ice to a suspension of 7.5 g (13.54 mmol) of N2 -[(S)-2-benzamido-8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carbonyl]-L-phenylalanine cyclohexylamide in 35 ml of methanol. The mixture was stirred at 80° in a bomb tube for 4 hours, then cooled and subsequently concentrated to a volume of ~20 ml. 50 ml of dichloromethane were added while stirring, the suspension was filtered and the filter residue was washed with dichloromethane and dried, 4.48 g (83%) of L-phenylalanine cyclohexylamide trifluoromethanesulphonate being isolated. The filtrate was washed with water, dried over MgSO4 and concentrated. The residue was chromatographed on 350 g of silica gel with ethyl acetate/hexane (2:3), whereupon 4.0 g (87%) of methyl (S)-2-benzamido-8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylate were obtained. [α]D =+144.0° (CHCl3, c=0.2). IR(KBr): 3366w(br.), 3062w, 2998w, 2948w, 1739s, 1647s, 1586m, 1527s, 1468s, 1437m, 1292m, 1259s, 1099m, 1047m, 774w, 713m. (D. Obrecht, Helv. Chim. Acta 1992, 75, 1666).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]([CH3:37])[CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]3[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:23]1>>[CH3:20][N:21]([CH3:37])[CH:22]1[CH2:26][CH2:25][N:24]([C:27]2[S:28][C:29]3[CH:35]=[C:34]([NH:36][C:10]([C:8]4[O:9][C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=5[CH:7]=4)=[O:12])[CH:33]=[CH:32][C:30]=3[N:31]=2)[CH2:23]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)c4cc5cc(Cl)ccc5o4)cc3s2)C1
Yield: 43.5 %

Procedure:
Prepare according to Method C (Example 9), using 5-chlorobenzofuran-2-carboxylic acid (109 mg, 0.554 mmol), oxalyl chloride (300 μL, 3.43 mmol), and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (100 mg, 0.381 mmol) to afford the title compound (73 mg, 43%). mass spectrum (m/e): 441.0 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.26 (d, 1H, J=1.8 Hz), 7.93 (d, 1H, J=2.2 Hz), 7.76 (d, 1H, J=8.6 Hz), 7.73 (d, 1H, J=0.9 Hz), 7.60 (dd, 1H, J=8.8, 2.2 Hz), 7.52 (dd, 1H, J=8.8, 2.2 Hz), 7.45 (d, 1H, J=8.4 Hz), 3.72 (dd, 1H, J=9.5, 7.3 Hz), 3.63 (m, 1H), 3.48 (m, 1H), 3.27 (m, 1H), 2.89 (m, 1H), 2.22-2.15 (m, 7H), 1.91 (m, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[P:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](=[O:38])[CH:5]1[CH:39]([OH:41])[CH3:40])[CH:2]=[CH2:3].[C:42](OC(=O)C)(=[O:44])[CH3:43]>ClCCl>[CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])=[P:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:38])[CH:5]1[CH:39]([O:41][C:42](=[O:44])[CH3:43])[CH3:40])[CH:2]=[CH2:3]
Reactant: C=CCC1C(C(C)O)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C=CCC1C(C(C)OC(C)=O)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of one cis and two trans-isomers of 4-allyl-3-(1-hydroxyethyl)-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one (5.0 g) in dry dichloromethane (150 cm3) was treated with 4-N,N-dimethylaminopyridine (1.22 g) followed by acetic anhydride (2.27 g) and the solution was stirred overnight at room temperature. The solution was evaporated under reduced pressure and the residue was chromatographed using high performance liquid chromatography, eluting with a 6:4 ethyl acetate/60°-80° petroleum ether mixture. This gave one cis and two trans-isomers of 4-allyl-3-(1-acetoxyethyl)-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one. The yields were the cis isomer (1.10 g, 21%) one trans isomer (0.28 g, 5%) and the other trans isomer (1.23 g, 23%). The cis-isomer crystallised (m.p. 156°-160° decomp). The infra-red spectra of all three isomers were identical; νmax (CHCl3) 3000, 1730, 1635 and 1610 cm-1.
Reaction SMILES: [CH2:1]([C:5]1([CH2:34][CH2:35][CH2:36][CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33])[CH2:2][CH2:3][CH3:4].[OH-].[Na+:39]>C(#N)C>[CH2:1]([C:5]1([CH2:34][CH2:35][CH2:36][CH3:37])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33])[CH2:2][CH2:3][CH3:4].[Na+:39]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A suspension of the compound of Example 12B (45 mg, 0.082 mmol) in acetonitrile (2 mL) was treated with 1.0 N NaOH solution (82 μL, 0.082 mmol) followed by stirring at 25° C. for 30 min. The solution was lyophilized to afford the title compound (46 mg, 98%). 1H NMR (300 MHz, DMSO-d6): δ 15.61 (s, 1 H), 9.87 (s, 1 H), 8.05 (d, J=7.72 Hz, 1 H), 7.38 (m, 6 H), 2.98 (s, 3 H), 2.11 (m, 2 H), 1.69 (m, 2 H), 1.02 (m, 4 H), 0.87 (m, 2 H), 0.65 (t, J=7.35 Hz, 6 H), 0.52 (d, J=5.52 Hz, 2 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:2].N>Cl>[CH2:20]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:21]
Reactant: CCN(CC)CCOc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: N
Product: CCN(CC)CCOc1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 1.85 g (6.26 mmol) of N-[4-(2-diethylaminoethoxy)-3-nitrophenyl]acetamide in semiconcentrated aqueous hydrochloric acid is stirred for 2 hours at 100° C., cooled to ambient temperature, made basic with ice, and concentrated aqueous ammonia and the aqueous phase is exhaustively extracted with ethyl acetate. The combined organic phases are washed with water and dried over sodium sulfate. Yield: 1.38 g (87% of theory); C12H19N3O3 (M=253.30); calc.: molecular ion peak (M+H)+: 254; found: molecular ion peak (M+H)+: 254; Rf value: 0.68 (Alox, dichloromethane/methanol (39:1)).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1.N1C=CC=CC=1.CS([Cl:21])(=O)=O.O>CN(C)C=O>[Cl:21][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCC1C=CCC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: ClCCCCC1C=CCC1
Temperature: 70 °C

Procedure:
3-(4-Hydroxybut-1-yl)cyclopentene {2-cyclopentene-1-butanol}(51 g, 0.37 moles) is diluted in dimethylformamide (100 ml) and added to pyridine (38 g, 0.40 moles). The solution is stirred and methane sulfonyl chloride (46 g, 0.40 moles) is added dropwise in the course of 10 minutes. The reaction is then heated in a 70° C. water bath for 30 minutes. Then the mixture is cooled and water (1 liter) is added over 20 minutes. The reaction is partitioned between hexane (500 ml) and the organic phase separated. The aqueous layer is extracted with hexane (2×500 ml) and the extracts combined with the organic layer. The solvent volume is reduced under vacuum and the residue dried over anhydrous magnesium sulfate. The solid is filtered off and the remaining solvent removed leaving a clear yellow oil. The crude product is fractionally distilled under reduced presure leaving a clear, colorless oil (43 g, 0.27 moles), BP 40° C./0.2 mm.
Reaction SMILES: 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.[Cl:34][C:35]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:36]=1[C:37]([OH:39])=O.[S:45]1[C:49]([C:50]2[N:54]3[CH2:55][CH2:56][NH:57][CH2:58][C:53]3=[N:52][N:51]=2)=[N:48][CH:47]=[N:46]1>CN(C)C=O.C(OCC)C>[Cl:34][C:35]1[CH:43]=[C:42]([Cl:44])[CH:41]=[CH:40][C:36]=1[C:37]([N:57]1[CH2:56][CH2:55][N:54]2[C:50]([C:49]3[S:45][N:46]=[CH:47][N:48]=3)=[N:51][N:52]=[C:53]2[CH2:58]1)=[O:39]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: c1nsc(-c2nnc3n2CCNC3)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Cl)cc1Cl)N1CCn2c(nnc2-c2ncns2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
HATU (274 mg, 0.720 mmol) and DIPEA (0.252 ml, 1.441 mmol) were added to a colourless solution of 2,4-dichlorobenzoic acid (I38 mg, 0.720 mmol, commercially available) in N,N-dimethylformamide (DMF) (4.718 ml). The mixture was stirred at RT for 15 minutes. 3-(1,2,4-thiadiazol-5-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (I115) (100 mg, 0.480 mmol) was added and the reaction mixture was stirred at RT for 18 h. The mixture was diluted in diethyl ether (100 mL) and washed with water (25 mL). The aqueous layer was extracted with diethyl ether (2×50 mL) and DCM (2×50 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product (brown liquid, 329.0 mg) was purified by flash chromatography (10 g SNAP, 0-100% ethyl acetate in hexane, 12 CV). The obtained oil residue was triturated with hexane. The product was diluted in DCM (100 mL) and washed with brine (3×25 mL). The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained product was dried at 50° C. under vacuum 3 days to afford the desired product in 62.05 mg as a white foam.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[C:20](I)[CH:19]=[CH:18][N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].ClCCl.Br[C:50]1[N:51]=[C:52]([C:71]#[C:72][Si](C)(C)C)[C:53]([N:56]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[N:54][CH:55]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:3]([C:16]2[CH:21]=[C:20]([C:50]3[CH:55]=[N:54][C:53]([N:56]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C:57]([O:58][C:59]([CH3:60])([CH3:61])[CH3:62])=[O:63])=[C:52]([C:71]#[CH:72])[N:51]=3)[CH:19]=[CH:18][N:17]=2)([C:1]#[N:2])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cc(I)ccn2)CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1C#C[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#Cc1nc(-c2ccnc(C3(C#N)CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 50.7 %

Procedure:
tert-butyl 4-cyano-4-(4-iodo-2-pyridyl)piperidine-1-carboxylate (1.01 g, 2.444 mmol) was dissolved in dioxane (15 mL) and bis(pinacolato)diboron (934.0 mg, 3.678 mmol) followed by potassium acetate (721.9 mg, 7.356 mmol) were added. The reaction mixture was degassed with 5× vacuum/nitrogen cycles. [PdCl2(dppf)].dichloromethane (199.6 mg, 0.2444 mmol) was then added and the reaction heated to 90° C. for 15 hours. The reaction mixture was cooled to ambient temperature and tert-butyl N-[5-bromo-3-(2-trimethylsilylethynyl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (1.150 g, 2.444 mmol) and a 2 M aqueous solution of sodium carbonate (3.666 mL of 2 M, 7.332 mmol) were added. The reaction mixture was degassed with 3× vacuum/nitrogen cycles then Pd(PPh3)4 (283.2 mg, 0.2451 mmol) was added. The reaction mixture was degassed with 5× vacuum/nitrogen cycles and then heated to 90° C. for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate/water. The aqueous layer was extracted with ethyl acetate (×1) and the combined organic extracts washed with brine (×2), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 120 g column), loaded in dichloromethane eluted with 0 to 50% ethyl acetate/petroleum ether. Product fractions were combined and concentrated in vacuo to give the sub-title product as a beige solid (749 mg, 51% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.33 (s, 18H), 1.38 (s, 9H), 2.07 (dt, 2H), 2.21 (d, 2H), 3.01 (br s, 2H), 4.10 (br d, 2H), 4.99 (s, 1H), 8.11 (dd, 1H), 8.25 (s, 1H), 8.78 (d, 1H) and 9.40 (s, 1H) ppm; LC/MS m/z 605.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].C([Li])(C)(C)C.CN([CH:23]=[O:24])C>C1COCC1.CCCCC>[OH:12][C:3]1[N:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[CH:23]=[O:24]
Reactant: Oc1ncc(C(F)(F)F)cc1Br
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: O=Cc1cc(C(F)(F)F)cnc1O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 122.9 %

Procedure:
3-Bromo-5-(trifluoromethyl)pyridin-2-ol (8.20 g, 31.2 mmol) was added in small portions to a suspension of sodium hydride (0.8575 g, 33.94 mmol) in anhydrous THF (76 mL) at room temperature. After complete addition, the reaction mixture was cooled to −78° C. and treated with a 1.7 M solution of tert-butyllithium in pentane (40.0 mL) which was added dropwise via a syringe over a period of 15 min. After stirring for 5 min, anhydrous DMF (8.16 mL, 105 mmol) was added slowly while maintaining the temperature below −50° C. The reaction mixture was then stirred overnight allowing it to warm to room temperature. The resulting light brown mixture was quenched by addition of a saturated NH4Cl solution. The pH of the solution was adjusted to 9-10 by addition of aqueous NaHCO3. The resulting solution was extracted with EtOAc four times. The combined extracts were dried (MgSO4), filtered and concentrated to provide a brown solid crude product (7.33 g, >100% crude yield). MS calculated for C7H4F3NO2 (M+H)+192; found 192.1.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[S:6][CH:7]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[CH2:24][N:25]=[C:26]=[O:27]>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[N:4]=[C:5]([N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:26]([NH:25][CH2:24][C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([F:20])[CH:22]=2)=[O:27])[S:6][CH:7]=1
Reactant: COc1ccc(CNc2nc(CCl)cs2)c(OC)c1
Reactant: O=C=NCc1cccc(F)c1
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)NCc2cccc(F)c2)c2nc(CCl)cs2)c(OC)c1
Reaction time: 8 h

Procedure:
The 4-(chloromethyl)-N-(2,4-dimethoxybenzyl)thiazol-2-amine was dissolved in DCM (50 ml) and 3-fluorobenzylisocyanate (1.2 eq.) was added and stirred overnight. The mixture was concentrated and the residue was purified on a column using 0-100% gradient of EtOAc and hexanes to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:26])=[C:6]([NH:8][C:9]2[S:10][C:11](=[CH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[C:12](=[O:14])[N:13]=2)[CH:7]=1.Cl.[C:28](=[NH:31])(S)[CH3:29].CO>CN(C=O)C>[ClH:26].[Cl:26][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28](=[NH:31])[CH3:29])=[CH:7][C:6]=1[NH:8][C:9]1[S:10][C:11](=[CH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][CH:20]=[CH:19]3)[C:12](=[O:14])[N:13]=1
Reactant: CC(=N)S
Reactant: Nc1ccc(Cl)c(NC2=NC(=O)C(=Cc3ccc4ncccc4c3)S2)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=N)Nc1ccc(Cl)c(NC2=NC(=O)C(=Cc3ccc4ncccc4c3)S2)c1
Temperature: 25 °C

Procedure:
To a stirred, cooled (0 deg.) solution of 2-(5-amino-2-chloro-phenylamino)-5-quinolin-6-ylmethylene-thiazol-4-one (39.7 mg, 0.1 mmol) in DMF (1 ml) was added thioacetimidate hydrochloride 9 (28 mg, 0.11 mmol). The mixture was warmed to room temperature and stirred for over night. DMF was removed by nitrogen gas blowing and resulting oil was dissolved with methanol. Insoluble solid was collected by filtration and washed with methanol, followed by desiccation in vacuo to afford the title (14 mg, 0.031 mmol).