Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:25][CH2:24][CH2:23][C:10]3([C:14](=[O:15])[N:13]([C@H:16]4[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28].C(N(CC)CC)C.C(Cl)Cl>>[OH:22][C@H:19]1[CH2:18][CH2:17][C@H:16]([N:13]2[CH2:12][CH2:11][C:10]3([CH2:23][CH2:24][CH2:25][N:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:27](=[O:28])[O:29][CH:30]([CH3:32])[CH3:31])=[CH:3][CH:4]=4)[CH2:9]3)[C:14]2=[O:15])[CH2:21][CH2:20]1
Reactant: Nc1ccc(N2CCCC3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)cc1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1ccc(N2CCCC3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(4-aminophenyl)-2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00006 mol), isopropyl chloroformate (11 mg, 0.000087 mol), and triethylamine (20 μL, 0.0002 mol) in methylene chloride (300 μL, 0.005 mol) was stirred at rt for 2 h. The crude reaction mixture was purified by prep.-HPLC to afford 17.4 mg of the desired product. LC-MS: 430.3 (M+H)+.
Reaction SMILES: FC1C(O[C:9](=[O:28])[C:10]2[CH:15]=[C:14]([Cl:16])[C:13]([F:17])=[C:12]([F:18])[C:11]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[Cl:27])=C(F)C(F)=C(F)C=1F.[CH3:33][C:34]1([CH3:42])[O:38][CH:37]([CH2:39][O:40][NH2:41])[CH2:36][O:35]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:16][C:14]1[C:13]([F:17])=[C:12]([F:18])[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[Cl:27])=[C:10]([CH:15]=1)[C:9]([NH:41][O:40][CH2:39][CH:37]1[CH2:36][O:35][C:34]([CH3:42])([CH3:33])[O:38]1)=[O:28]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl
Reactant: CC1(C)OCC(CON)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OCC(CONC(=O)c2cc(Cl)c(F)c(F)c2Nc2ccc(I)cc2Cl)O1
Reaction time: 20 h
Yield: 67.9 %

Procedure:
To a stirring solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid pentafluorophenyl ester (5.80 g, 9.51 mmol) is freshly distilled tetrahydrofuran (40 mL) was added O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (1.54 g, 10.5 mmol) and diisopropylethylamine (1.8 mL, 10.5 mmol). After 20 hours, the mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water and twice with saturated brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by crystallization in ethyl acetate/hexanes affording 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide as a white solid (3.7 g, 67.9%): 1H NMR (400 MHz; CDCl3) δ 9.82 (bs, 1H), 8.10 (bs, 1H), 7.68 (s, 1H), 7.47 (bs, 1H), 7.40-7.43 (m, 1H), 6.44-6.47 (m, 1H), 4.40 (bs, 1H), 3.97-4.20 (m, 3H), 3.77 (t, 1H, J=8.0), 1.44 (s, 3H), 1.37 (s, 3H); MS (APCI+)=573.0/575.0.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([N:5]([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8])=[O:4].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[CH3:21][S:22]([O:11][CH2:10][CH2:9][N:5]([C:3](=[O:4])[C:2]([F:12])([F:13])[F:1])[CH2:6][CH2:7][O:8][S:22]([CH3:21])(=[O:24])=[O:23])(=[O:24])=[O:23]
Reactant: O=C(N(CCO)CCO)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)C(=O)C(F)(F)F
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
Trifluoro-N,N-bis-(2-hydroxy-ethyl)-acetamide (2.01 g, 10 mmol) of in THF (12 mL) was cooled to ice bath temperature. Triethylamine (20.1 mol, 2.3 g=1.56 mol) was added between 5-10° C. Methanesulphonyl chloride was then added to the reaction mixture at a temperature between 5-10° C. The reaction mixture was stirred for 1 h at 5-10° C. and then allowed to warm to ambient temperature overnight. The resulting precipitated solids were filtered off and the reaction flask was rinsed with THF (2×10 mL portions), then filtered. The filtrate was concentrated to yield the title compound as a clear thick oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:16](=[O:29])[C:15]=1[Cl:30].CN1CCOCC1.[C:43]1([N:49]=[C:50]=[O:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CC(N(C)C)=O>[Cl:30][C:15]1[C:16](=[O:29])[N:17]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[CH2:9][NH:8][C:50]([NH:49][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:51]
Reactant: Cc1cc(OCc2ccc(F)cc2CN)c(Cl)c(=O)n1-c1c(F)cccc1F
Reactant: O=C=Nc1ccccc1
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCc2ccc(F)cc2CNC(=O)Nc2ccccc2)c(Cl)c(=O)n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one trifluoroacetate (0.25 g, 0.48 mmol) in DMA (2.0 mL) was added 4-methylmorpholine (0.06 mL, 0.53 mmol) and phenyl isocyanate (0.06 mL, 0.53 mmol). The reaction was stirred at RT for 1.5 h. Solvent distilled and crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (30 mL) and extracted in DCM (3×25 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to a white solid, dried in vacuo (0.18 g, 71%). 1H NMR (CD3OD/400 MHz) δ7.60 (m, 1H), 7.54 (m, 1H), 7.33 (d, 2H, J=7.6 Hz), 7.22 (m, 5H), 7.06 (m, 1H), 6.95 (t, 1H, J=7.2 Hz), 6.73 (s, 1H), 5.44 (s, 2H), 4.53 (s, 2H), 2.07 (s, 3H). ESHRMS m/z 528.1304 (M+H calculated for C27H22ClF3N3O3 requires 528.1296).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[CH3:15].[H-].[Na+].Cl[C:19]1[N:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=1>C1COCC1.O>[CH3:15][C@H:3]1[C@H:2]([O:1][C:19]2[N:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@H]1[C@H](O)CCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1[C@H](Oc2ncc(C(F)(F)F)cn2)CCCN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 72.3 %

Procedure:
To (2S,3R)-tert-butyl 3-hydroxy-2-methylpiperidine-1-carboxylate (670 mg, prepared according to J. Org. Chem. 2008, 73, 2898) in THF (15 mL) at 0° C. was added NaH (60 wt %, 188 mg). After 15 min, 2-chloro-5-(trifluoromethyl)pyrimidine (570 mg) was added and the reaction allowed to proceed at rt overnight. The reaction was diluted with H2O and extracted with DCM. The organic layers were dried (MgSO4). Purification via silica gel chromatography (0-40% EtOAc in heptane) gave the title compound (813 mg, 72%).
Reaction SMILES: Cl.[C:2]1([C:8]2[S:9][CH:10]=[C:11]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=3)=[O:14])[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>C1COCC1>[N:35]1([C:41]([N:25]2[CH2:24][CH:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:13]([C:11]3[N:12]=[C:8]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[S:9][CH:10]=3)=[O:14])[CH2:27][CH2:26]2)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: O=C(Nc1ccccc1C1=CCNCC1)c1csc(-c2ccccc2)n1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1C1=CCN(C(=O)N2CCOCC2)CC1)c1csc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 170 mg of 2-phenyl-N-[2-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-1,3-thiazole-4-carboxamide hydrochloride in 7 ml of THF was added 0.30 ml of triethylamine, and 60 μl of 4-morpholinecarbonylchloride was added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction liquid was added 100 ml of water, followed by extraction with EtOAc, and the organic layer was washed with saturated brine, dried over sodium sulfate, and then filtered. A solvent was evaporated under reduced pressure, and the residue was recrystallized from 5 ml of ethanol to obtain 165 mg of N-{2-[1-(4-morpholinylcarbonyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl}-2-phenyl-1,3-thiazole-4-carboxamide.
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH:2]([CH3:4])[CH3:3].[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([NH:52][C@H:53]([C:58]([OH:60])=O)[CH2:54][C:55]([OH:57])=[O:56])(=[O:51])=[O:50])=[CH:45][CH:44]=1>>[CH3:42][C:43]1[CH:44]=[CH:45][C:46]([S:49]([NH:52][C@H:53]([C:58]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]([N:5]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:1][CH:2]([CH3:4])[CH3:3])[C:29]([OH:31])=[O:30])=[O:60])[CH2:54][C:55]([OH:57])=[O:56])(=[O:50])=[O:51])=[CH:47][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](CC(=O)O)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N[C@@H](CC(=O)O)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-(4-methylbenzenesulfonyl)-L-aspartic acid (340 mg, 1.2 mmol) prepared in step A of this example. The final product was purified by preparative HPLC to yield 20 mg (26%) of the desired material.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[O:6][Si](C(C)(C)C)(C)C)=[N+]=[N-].CC1CC=CCC=1.[ClH:40].O1CCOCC1>C(O)C.[Pd]>[ClH:40].[NH2:1][CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:32])[NH:19]2)[OH:6]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Agent: CC1=CCC=CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: NC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of (R)-5-(2-azido-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one (4.50 g, 10.0 mmol) in ethanol (50 mL) was added 10% palladium on charcoal (4.50 g) followed by 1-methyl-1,4-cyclohexadiene (11.0 mL, 97.9 mmol). The reaction was warmed to 60° C. (CARE—POSSIBLE EXOTHERM) and then stirred at 60° C. for 2 hours. The reaction mixture was allowed to cool and filtered through a pad of celite. The filter cake was washed with further ethanol and the filtrate was evaporated at reduced pressure. The residue was evaporated from iso-propanol (×2) and dissolved in iso-propanol (30 mL). HCl-dioxane (4 M, 50 mL, 200 mmol) was added and the reaction mixture stirred at RT for 18 hours. The resultant suspension was filtered, the filter cake washed with ether and the solid dried under vacuum in the presence of P2O5 to afford the title compound (1.65 g, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:13]([CH2:24][C:25]([OH:27])=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C@@H:13]1[CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C[C@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
To a solution of the compound of step 1 (2.52 g, 6.66 mmol) in 45 ml of acetone were added potassium carbonate (5.522 g, 39.96 mmol) and iodomethane (1.24 ml, 19.98 mmol) and the solution was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated to dryness. The residue was dissolved in EA, washed twice with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 85:15) to give 2.334 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O[CH2:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cc2c(Cl)ncnc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(Cl)ncnc2n1C[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To the solution of 4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 5.97 mmol, 1.0 eq) and (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.32 g, 6.57 mmol, 1.1 eq) and PPh3 (3.03 g, 11.94 mmol, 2.0 eq) in THF (50 mL), DIEA (2.08 g, 11.94 mmol, 2.0 eq) was added at 0° C. The resulted mixture was stirred and warmed to RT for 12 h. Solvent was removed and purified by column chromatography (eluting with 10% EtOAc in PE) to afford (S)-tert-butyl 2-[(4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl)pyrrolidine-1-carboxylate as a white solid (2.08 g, 100% in yield).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=O>COCCOC>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][C:16]([CH:14]=[CH:3][C:1]#[N:2])=[CH:17][CH:18]=1)=[O:21]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(C=CC#N)cc1

Procedure:
To a stirred solution of diethyl cyanomethylphosphonate (96 ml) in 1,2-dimethoxyethane (375 ml) was added sodium hydride (60%: 22g) portionwise below 5° C. and the stirring was continued at 0° C. for half an hour and then at ambient temperature for half an hour. The reaction mixture was recooled to 0° C. and a solution of methyl p-formylbenzoate (75 g) in 1,2-dimethoxyethane (375 ml) was added to the reaction mixture below 6° C. The reaction mixture was quenched with saturated aqueous sodium bicarbonate and diluted with ethyl acetate. The organic layer was washed with water and aqueous saturated sodium bicarbonate and dried over magnesium sulfate and filtered. The solvent was removed in vacuo and the solid product was recrystallized from ethanol to give 4-methoxycarbonylcinnamonitrile (52.12 g) as a white needle.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[C:9](OCC=C)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:19]1[CH:24]=CC=C[C:20]=1Cl>>[CH:20]([C:9]1[CH:8]=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:12]=[CH:11][C:10]=1[OH:13])=[CH:19][CH3:24]
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1cc(C2CCCCC2)ccc1O
Product: CC=Cc1cc(C2CCCCC2)ccc1O
Temperature: 25 °C

Procedure:
A solution of 4-cyclohexyl allyloxyphenol (12.3 g) in ortho-dichlorobenzene (50 mL) was kept at reflux for 36 h. The mixture was cooled to room temperature and chromatographed over silica gel to afford 2-propenyl-4-cyclohexylphenol (11.0 g). This material was dissolved in methanol (150 mL) and hydrogenated over Pd/C (1.2 g) at 50 psi. The reaction was filtered through Celite and concentrated in vacuo to afford the title compound (11.0 g).
Reaction SMILES: [N:1]1([C:5]([C:7]2[O:11][C:10]([S:12]([NH:15][C:16]3[CH:21]=[C:20]([O:22][C@H:23]([CH3:45])[CH2:24][O:25]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:19]=[C:18]([S:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:49]=4[F:55])[N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(OC)C=CC=CC=1.O>CO>[N:1]1([C:5]([C:7]2[O:11][C:10]([S:12]([NH:15][C:16]3[CH:21]=[C:20]([O:22][C@H:23]([CH3:45])[CH2:24][OH:25])[N:19]=[C:18]([S:46][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:49]=4[F:55])[N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(C(=O)N3CCC3)o2)nc(SCc2cccc(F)c2F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: COc1ccccc1
Product: C[C@H](CO)Oc1cc(NS(=O)(=O)c2ccc(C(=O)N3CCC3)o2)nc(SCc2cccc(F)c2F)n1

Procedure:
To a solution of 5-(azetidin-1-ylcarbonyl)-N-{2-[(2,3-difluorobenzyl)thio]-6-[(1R)-1-methyl-2-(triphenylmethyloxy)ethoxy]pyrimidin-4-yl}furan-2-sulfonamide (the product of step iv) (0.24 g) in methanol (5 mL) was added para-toluenesulfonic acid hydrate (58 mg) and anisole (0.34 mL). After stirring at room temperature for 2d, H2O (5 mL) was added and the mixture extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered and evaporated to dryness in vacuo. The resulting crude solid was purified by reverse phase HPLC (50% to 5% gradient of 0.1% aqueous ammonium acetate in acetonitrile as eluent) to give the title compound as a white solid. Yield: 10 mg.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Cl)nc2c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Yield: 41.3 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, with methyl 3-chloro-2-phenylquinoxaline-6-carboxylate (50 mg, 0.17 mmol, 1.00 equiv) and 4-methoxyphenylboronic acid (38 mg, 0.25 mmol, 1.50 equiv) as reactants. Purification via Prep-TLC (silica gel) yielded 25 mg (42%) of 3-(4-methoxyphenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.[Br-].[Li+].N1CCNCC1>CN(C)C=O>[Br:10][C:6]1[CH:5]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:27][CH:28]=4)=[CH:22][C:14]2=3)=[O:12])[CH:3]=[C:2]([Br:1])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccc(OC(F)(F)F)cc4)cc32)cc1Br
Agent: C1CNCCN1
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3ccc(OC(F)(F)F)cc3)cc21

Procedure:
By the same method as in the step d) of Example 45, (3,5-dibromo-4-methoxy-phenyl)-[7-(4-trifluoromethoxy-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone (110 mg, 0.19 mmol), lithium bromide (65 mg, 0.75 mmol) and piperazine (25 mg, 0.29 mmol) were dissolved in N,N-dimethyl formamide (3 ml) and reacted at 100□ to obtain the target compound 66, i.e., (3,5-dibromo-4-hydroxy-phenyl)-[7-(4-trifluoromethoxy-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone, as white solid (54 mg, 48%).
Reaction SMILES: C(N1CCP(C2C=CC(N)=C(OC)C=2)(=O)CC1)C.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:29]1[N:34]=[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([P:42]3(=[O:50])[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]3)=[CH:38][C:37]=2[O:51][CH3:52])[C:32]([Cl:53])=[CH:31][N:30]=1.[CH:54]1([C:57]2[O:61][C:60]([NH2:62])=[N:59][CH:58]=2)[CH2:56][CH2:55]1>>[Cl:53][C:32]1[C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([P:42]3(=[O:50])[CH2:47][CH2:46][N:45]([CH2:48][CH3:49])[CH2:44][CH2:43]3)=[CH:38][C:37]=2[O:51][CH3:52])=[N:34][C:29]([NH:62][C:60]2[O:61][C:57]([CH:54]3[CH2:56][CH2:55]3)=[CH:58][N:59]=2)=[N:30][CH:31]=1
Reactant: CCN1CCP(=O)(c2ccc(Nc3nc(Cl)ncc3Cl)c(OC)c2)CC1
Reactant: Nc1ncc(C2CC2)o1
Agent: CCN1CCP(=O)(c2ccc(N)c(OC)c2)CC1
Agent: Clc1ncc(Cl)c(Cl)n1
Product: CCN1CCP(=O)(c2ccc(Nc3nc(Nc4ncc(C5CC5)o4)ncc3Cl)c(OC)c2)CC1

Procedure:
This compound can be prepared as in Example 32 by reacting 4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyaniline with 2,4,5-trichloropyrimidine to generate 2,5-dichloro-N-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidin-4-amine. 2,5-dichloro-N-[4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]pyrimidin-4-amine is then reacted with 5-cyclopropyl-1,3-oxazol-2-amine according to the procedure described in Example 32.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].[CH3:10][O:11][N:12]=[C:13]([C:17](=O)[CH:18](Br)Br)[C:14]([OH:16])=[O:15]>O1CCCC1.O>[NH2:1][C:2]1[S:3][CH:18]=[C:17]([C:13](=[N:12][O:11][CH3:10])[C:14]([OH:16])=[O:15])[N:4]=1
Reactant: CON=C(C(=O)O)C(=O)C(Br)Br
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)O)c1csc(N)n1
Temperature: 30 °C
Reaction time: 4 h
Yield: 40.6 %

Procedure:
Thiourea (377 mg) and sodium acetate (406 mg) were added to a solution of 2-methoxyimino-3-oxo-4,4-dibromobutyric acid (syn isomer, 500 mg) in tetrahydrofuran (5 ml) and water (5 ml), and the solution was stirred at 30° C. for 4 hours. The solution was adjusted to pH 3.5, concentrated under reduced pressure and allowed to stand at 0° C. overnight. The precipitates were collected by filtration, washed with water and dried to give 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 135 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=O)[NH:6]2.Cl.[OH-].[Na+].O>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2
Reactant: O=C1Cc2c(Br)cccc2N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Brc1cccc2c1CCN2
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A mixture of 4-bromooxindole (2.77 g, 0.01 mol) and a solution of BH3 in THF (2 M, 40 mL) was stirred at room temperature overnight. The mixture was cooled to 0° C. and diluted with 30 mL of methanol, followed by addition of 12 N HCl (7.5 mL). The resulting mixture was stirred at room temperature for 1 hour, adjusted to pH 8-9 with 10% aqueous NaOH. Water was added to the mixture and extracted with ethyl acetate (3×100 mL). The organic layer was dried and concentrated to get the crude product which was washed through a silica gel column (ethyl acetate in petroleum ether (10%). The crude product was dissolved in 10% HCl (3×10 mL). The aqueous layer was adjusted to pH7 with NaHCO3, extracted with ethyl acetate (3×20 mL). The organic layer was dried and concentrated to get 4-bromoindoline (1.16 g, 45%) as an oil. LCMS: 200 [M+1]+. 1H-NMR (400 MHz. DMSO-d6) δ 2.90 (t, J=8.8 Hz, 2H), 3.46 (t, J=8.8 Hz, 2H), 5.86 (s, 1H), 6.43 (m, 1H), 6.64 (m, 1H), 6.83 (t, J=8.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][C:13](I)=[N:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1.[NH2:32][CH2:33][CH2:34][OH:35]>CC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][C:13]([NH:32][CH2:33][CH2:34][OH:35])=[N:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([S:18][CH2:19][C:20]2[N:21]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[S:23][CH:24]=2)[N:3]=1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cnc(I)s1
Reactant: NCCO
Solvent: CC(C)=O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cnc(NCCO)s1

Procedure:
94 mg (0.159 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(2-iodo-1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile were initially charged in 2.5 ml of acetone, 0.479 ml (7.927 mmol) of 2-aminoethanol was added