Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccnc4)cc3)cc2)CC1
Temperature: 110 °C

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.200 g, 0.552 mmol) and 3-bromo-pyridine (0.087 g, 0.552 mmol) were dissolved in toluene along with Pd(dba)2 (0.032 g, 0.055 mmol), BINAP (0.069 g, 0.11 mmol) and cesium carbonate (0.270 g, 0.828 mmol). The reaction was heated to 110° C. overnight then allowed to cool. The reaction mixture was filtered through Celite then purified via preparatory HPLC to afford the title
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C:2]([C:5]([NH:7][C@H:8]([C:16]([NH:18][C@H:19]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])([CH3:4])[CH3:3].[ClH:35]>C(OCC)(=O)C>[NH2:1][C:2]([C:5]([NH:7][C@H:8]([C:16]([NH:18][C@H:19]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])([CH3:3])[CH3:4].[ClH:35]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)C(C)(C)N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Boc-Aib-Phe-Leu-OMe (14.38 g.) was dissolved in ethyl acetate (25 ml.). A solution of 3M-hydrogen chloride in ethyl acetate (33 ml.) was added and the mixture was stirred at ambient temperature for 1 hr., during which time a white crystalline solid separated out. The solid was collected by filtration, washed with ethyl acetate (3×15 ml.) and then dried in vacuo at ambient temperature to give H-Aib-Phe-Leu-OMe hydrochloride, RfKNH3 0.89, RfRNH3 0.74.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25]O)[CH2:20][CH2:19]2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[CH3:32][C:33]1([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:42][CH:41]=2)[NH:37][C:36](=[O:38])[NH:35][C:34]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.Cl>CN(C)C=O.O>[F:30][C:2]([F:1])([F:31])[C:3]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:37]3[C:33]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH:47]([CH3:49])[CH3:48])=[CH:42][CH:41]=4)([CH3:32])[C:34](=[O:39])[NH:35][C:36]3=[O:38])[CH2:20][CH2:19]2)=[C:14]([CH2:27][CH2:28][CH3:29])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(CCO)CC1
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)NC2=O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(CCN2C(=O)NC(=O)C2(C)c2ccc(OC(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
2-(4-{4-[1,1,1,3,3,3-Hexafluoro-2-(methoxymethoxy)propan-2-yl]-2-propylphenyl}piperazin-1-yl)ethanol (7.8 mg, 0.0170 mmol), 5-methyl-5-(4-(1-methylethoxy)phenyl)imidazolidine-2,4-dione (A11)(15.6 mg, 0.0631 mmol) and triphenylphosphine (15.8 mg, 0.0601 mmol) were dried with a vacuum pump, dissolved in N,N-dimethylformamide (284 μL), added DEAD (23 μL, 0.0167 mmol) under ice-cold conditions, and the mixture was stirred at room temperature for 1 hour. Under ice-cold conditions, the reaction solution was added water (1.0 mL) and 2N aqueous solution of hydrochloric acid (1.0 mL), and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (3.1 mg (yield 26%)) was obtained as a yellow oil.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:17])=[C:3](\[C:9](=[S:16])[NH:10][C:11](OCC)=[O:12])/[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)(=O)C>C(N(CC)CC)C>[OH:12][C:11]1[N:10]=[C:9]([SH:16])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:17])[N:1]=1
Reactant: CCOC(=O)NC(=S)/C(C(=O)OCC)=C(/C)N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc(O)nc1S
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(Z)-ethyl 3-amino-2-(ethoxycarbonylcarbamothioyl)but-2-enoate was dissolved in 30% aqueous triethyl amine and the reaction mixture stirred at 70° C. After 2 hours, the reaction mixture was cooled and neutralized with glacial acetic acid and the aqueous mixture extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under vacuum to give the desired product. 1H NMR (400 MHz, DMSO-d6): δ 12.54 (s, 1H), 11.85 (s, 1H), 4.21 (q, J=7.6 Hz, 2H), 2.03 (s, 3H), 1.24 (t. J=7.6 Hz, 3H); MS m/z 213.1 (M−1).
Reaction SMILES: C1(SC2C=CC=CC=2)C=CC=CC=1.C[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([O:23]C)[CH:22]=1)N.[I:25]I.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:15][C:16]1[CH:17]=[C:18]([I:25])[CH:20]=[C:21]([OH:23])[CH:22]=1
Reactant: II
Reactant: COc1cc(N)cc(OC)c1
Agent: CN(C)c1ccncc1
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Oc1cc(O)cc(I)c1
Reaction time: 16 h

Procedure:
Preparation of substituted iodobenzene 39, conversion of 38 to the corresponding thiol, and formation of diphenylsulfide 40: 3,5-Dihydroxyiodobenzene was prepared from 3,5-dimethoxyaniline (Aldrich) by diazotization and iodine introduction followed by demethylation of the methoxy groups all under standard conditions. This material (3.78 g 16.0 mmol) was dissolved in CH2Cl2 (30 mL). Triethylamine (11.15 mL, 80 mmol), acetic anhydride (4.55 mL, 48 mmol) and DMAP (390 mg, 3.2 mmol) were added and the reaction stirred for 16 h. The reaction was evaporated to dryness, and passed through a plug of silica gel eluting with 4:1 hexane:ethyl acetate to afford the desired product. This material (12.8 mmol) was dissolved in a mix of ethanol (32 mL) and benzene (16 mL). Potassium hydroxide (0.72 g, 12.8 mmol) was dissolved in 8 mL ethanol and added over 30 min. After 30 min the reaction was diluted with ether and washed with 0.5N H2SO4, sat NaHCO3, sat NaCl, dried over Na2SO4, and evaporated. The product was recrystallized from toluene to afford 86% yield of the monoacetate which was dissolved in CH2Cl2 (50 mL) and triethylamine (3.45 mL, 24.8 mmol), DMAP (0.3 g, 2.5 mmol) and benzoyl chloride (1.8 mL, 15.5 mmol) was added. The reaction was complete in 10 min then diluted with CH2Cl2 and washed with sat NH4Cl, sat NaHCO3, and sat NaCl. The solution was dried (Na2SO4) and evaporated. Purification was accomplished via silica chromatography 19:1 hexane:ethyl acetate to afford 4.4 g (95% yield) of desired product 39.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([CH3:21])([CH3:20])[CH2:11][C:12]([C:16]([F:19])([F:18])[F:17])([OH:15])CO)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1>CO>[O:1]1[C:5]2[C:6]([C:10]([CH3:21])([CH3:20])[CH2:11][C:12](=[O:15])[C:16]([F:18])([F:19])[F:17])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(C)(CC(O)(CO)C(F)(F)F)c1cccc2c1OCC2
Solvent: CO
Product: CC(C)(CC(=O)C(F)(F)F)c1cccc2c1OCC2
Yield: 99.6 %

Procedure:
A solution of 4-(2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentane-1,2-diol (24.0 g, 78.9 mmol) and NaIO4 (84.3 g, 394 mmol) in 360 mL of methanol was stirred at room temperature overnight. The resulting mixture was filtered through pad of CELITE® filter aid and the filter cake was washed with three 100 mL portions of methanol. The filtrate was concentrated in vacuo, taken up in hexanes, filtered again, and concentrated in vacuo to give 21.4 g of 4-(2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-one as colorless oil (100%), which was used without purification.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]=[CH2:3].[C:15](#[N:18])C=C>C1(C)C=CC=CC=1>[C:15](/[CH:3]=[CH:2]\[CH2:1][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:18]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: C=CC#N
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C/C=C\C#N)C(=O)OCC
Reaction time: 40 h
Yield: 60.2 %

Procedure:
A solution of 100.0 mg (0.48 mmol) diethyl allylmalonate, 77.4 mg (1.45 mmol) acrylonitrile and 35.0 mg (0.05 mmol) [RuCl2(ImH2Mes)((4-chloro-2-trifluoromethyl-8-quinolinyl)methylene)] in 5 ml toluene was stirred at 110° C. To monitor the conversion and selectivity, 0.05-ml samples were taken were taken after 3 h and 40 h. Each sample was filtered over a silica gel pad, the filtrate was evaporated to dryness and analyzed by GC (column: HP-5, 5% phenyl methyl siloxan (Agilent 19091-413); injector: 250° C.; detector: 250° C.; oven: 100 to 150° C./5° C. per min, 5 min at 150° C., 150 to 200° C./5° C. per min and 200 to 300° C./20° C. per min; carrier gas: He (0.46 bar); retention times: 9.2 min diethyl allylmalonate, 17.5 min (Z)-diethyl 2-[3-cyano-2-propenyl]malonate and 18.8 min (E)-diethyl 2-[3-cyano-2-propenyl]malonate). After 3 h (66% conversion), 57% of the title compound and after 40 h (94% conversion) 83% of the title compound as an (E):(Z) mixture of 1:2 was formed. After evaporation of the solvent under reduced pressure, the crude product was purified by silica gel chromatography (cyclohexane/ethyl acetate 8:2) to yield 65.1 mg (60%) of the title compound as a (E):(Z) mixture of 1:2. MS: 226.3 (M+). 1H-NMR of diethyl 2-[3-cyano-2-propenyl]malonate (300 MHz, C6D6): (Z)-isomer: 1.29 (t, J=7.1 Hz, 6H); 2.99 (td, J=7.1, 1.5 Hz, 2H); 3.51 (t, J=7.0 Hz, 1H); 4.20-4.24 (m, 4H); 5.40-5.42 (m, 1H); 6.54 (m, 1H). (E)-isomer: 1.28 (t, J=7.1 Hz, 6H); 2.79 (td, J=7.1, 1.5 Hz, 2H); 3.46 (t, J=7.1 Hz, 1H); 4.20-4.24 (m, 4H); 5.40-5.42 (m, 1H); 6.68 (m, 1H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14]>ClCCl>[CH2:16]([O:15][C:13](=[O:14])[NH:6][N:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH3:17]
Reactant: Nn1cccc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1cccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 15 g of sodium bicarbonate and 9.2 g of (N-amino)pyrrole in 50 ml of dichloromethane was treated over a period of fifteen minutes with 11.4 ml of ethyl chloroformate. The reaction mixture was then stirred at ambient temperature for four hours and filtered. The filtrate was washed with water followed by a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered. Concentration afforded 17 g of N-(1H-pyrrol-1-yl)carbamic acid ethyl ester, m.p. 60°-61° C.; MS(EI)M+ @ 154(100%); IR(CHCl3)-NH @ 3430 cm-1, C=O @ 1755 cm-1.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=O)[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(CCCN=C=NCC)C>C(Cl)Cl>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Reactant: Nc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)Nc2cccnc2)NC1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.100 g, 0.35 mmol), 3-aminopyridine (0.036 g, 0.38 mmol), 1-hydroxybenzotriazole (0.047 g, 0.35 mmol), and 4-methylmorpholine (0.077 mL, 0.70 mmol) are dissolved in methylene chloride (2.5 mL), and the reaction is cooled to 0° C. To this solution is added N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.134 g, 0.70 mmol), and the reaction is allowed to warm up to room temperature and then stirred overnight. The reaction is partitioned between methylene chloride and water, the organic layer is dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (70% ethyl acetate/hexane) to give 3-(N-[[trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecan-10-yl]-carbonyl]-amino)-pyridine, MS: M+1=364.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.S(OC)(O[CH3:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:14][C:3]1[C:2]([O:1][CH3:19])=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C1CCCCc2cc(O)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc2c(cc1O)C(=O)CCCC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 2,3-dihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (1.0 g), dimethyl sulfate (0.65 g), anhydrous potassium carbonate (0.86 g) and acetone (20 ml) is stirred at 50° C. for two hours. After cooling, the reaction mixture is subjected to filtration, and the filtrate is concentrated under reduced pressure. To the concentrate is added water, which is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to afford 3-hydroxy-2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (0.67 g), which is recrystallized from ethyl acetate-hexane to give colorless needles, m.p. 115°-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:10])([CH3:9])[C:4](=[N:7][OH:8])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:22][CH:23]=1.CC(C)=O.CN(C)C=O>C1CCCCC1.C(OC)(C)(C)C>[CH3:1][O:2][C:3]([CH3:10])([CH3:9])[C:4](=[N:7][O:8][CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:22][CH:23]=1)[C:5]#[N:6]
Reactant: COC(C)(C)C(C#N)=NO
Reactant: Fc1ccc(-c2nc(CCl)co2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Solvent: COC(C)(C)C
Product: COC(C)(C)C(C#N)=NOCc1coc(-c2ccc(F)cc2)n1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
2.55 g (18 mmol) of 3-methoxy-3-methyl-2-oximinobutyronitrile, 3.72 g of potassium carbonate and 3.8 g (18 mmol) of 4-chloromethyl-2-(4-fluorophenyl)-oxazole in 36 ml of dry 2:1 acetone/dimethylformamide are stirred for 1 hour at 45° C. and then for 12 hours at room temperature. Working up by a method similar to that stated in Example 1 and chromatographing of the crude product over silica gel using 5:1 cyclohexane/methyl tert-butyl ether give 5.4 g (95% of theory) of the title compound as a crystalline solid.
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([C:12]2[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH3:22])[N:20]=2)[C:15]([NH2:17])=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[CH:7]1([C:12]2[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH3:22])[N:20]=2)[C:15]#[N:17])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COc1cc(C(N)=O)cc(C2CCCC2)n1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C#N)cc(C2CCCC2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Pyridine (8.86 g, 91.3 mmol) is added to a solution of 2-cyclopentyl-6-methoxy-isonicotinamide (3.35 g, 15.2 mmol) in DCM (100 mL). The mixture is cooled to 0° C. before trifluoroacetic acid anhydride (9.58 g, 45.6 mmol) is added portionwise. The mixture is stirred at 0° C. for 1 h before it is diluted with DCM (100 mL) and washed with sat. aq. NaHCO3 solution (100 mL) and brine (100 mL). The separated org. phase is dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2-cyclopentyl-6-methoxy-isonicotinonitrile (2.09 g) as a pale yellow oil; LC-MS**: tR=0.80 min, [M+1]+=not detectable; 1H NMR (D6-DMSO): δ 1.61-1.82 (m, 6H), 1.94-2.03 (m, 2H), 3.16 (quint, J=7.8 Hz, 1H), 3.89 (s, 3H), 7.15 (s, 1H), 7.28 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:65]([O:69][C:70]([NH:72][C:73]1[S:77][C:76]([C:78]2[C:83]([F:84])=[CH:82][CH:81]=[CH:80][C:79]=2[F:85])=[N:75][C:74]=1[C:86](O)=[O:87])=[O:71])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[F:85][C:79]1[CH:80]=[CH:81][CH:82]=[C:83]([F:84])[C:78]=1[C:76]1[S:77][C:73]([NH:72][C:70](=[O:71])[O:69][C:65]([CH3:67])([CH3:66])[CH3:68])=[C:74]([C:86](=[O:87])[NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:22])[C:6]=2[N:7]2[CH2:8][CH2:9][CH:10]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH:11]([OH:14])[CH2:12][CH2:13]2)[N:75]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(O)C(NC(=O)C(F)(F)F)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(O)C(NC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.2 %

Procedure:
To a solution of N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-hydroxyazepan-4-yl)-2,2,2-trifluoroacetamide (504 mg, 1.57 mmol) in DCM (20 mL) was added DIPEA (1.65 mL, 9.42 mmol), PyBOP (1.17 mg, 2.20 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (559 mg, 1.57 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (100 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0 to 100% EtOAc/heptane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-hydroxy-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (240 mg, 23%). This solid (240 mg, 0.36 mmol) was stirred with HCl in 1,4-dioxane (4 M, 6 mL, 24 mmol) in MeOH (5 mL) at room temperature for 18 h. The solvent was removed under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 333. LCMS (ES+) m/z 464 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([S:13][C:14]3[NH:18][C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[N:15]=3)[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([S:13]([C:14]3[NH:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[O:31])[CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc2c(Sc3nc4ccccc4[nH]3)cccc12
Solvent: CCOC(C)=O
Product: COc1ccnc2c(S(=O)c3nc4ccccc4[nH]3)cccc12

Procedure:
The product of step (b) above (390 mg) in ethyl acetate (20 ml) was cooled to -5° and treated with m-chloroperbenzoic acid (273 mg of 85% pure material). The temperature was allowed to rinse to ambient. The reaction mixture was then diluted with ethyl acetate and methylene chloride, and then washed with sodium bisulphite solution, sodium bicarbonate solution and brine. The solution was dried and evaporated. Column chromatography (SiO2 /ethyl acetate) gave the title compound 140 mg, mp 178°-9° (d).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1.[C:13](=[O:20])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[NH2:14].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[N:8]1([C:4]2[CH:3]=[C:2]([NH:14][C:13](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:6][N:5]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: CC(C)(C)OC(N)=O
Reactant: Brc1ccnc(-n2cccn2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccnc(-n2cccn2)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Commercial 4-bromo-2-(1H-pyrazol-1-yl)pyridine (500 mg, 2.23 mmol) was dissolved in 30 mL dioxane. To it were added t-butyl carbamate (392 g, 3.35 mmol), cesium carbonate (1.46 g, 4.46 mmol), Pd2(dba)3 (101 mg, 0.11 mmol) and XantPhos (192 mg, 0.33 mmol). The mixture was degassed with Ar stream and stirred under Ar in 85° C. bath for overnight. The mixture was concentrated, taken into 200 mL EtOAc and 100 mL water. The organic phase was separated, dried, concentrated and subjected to flash column (0-20% EtOAc in DCM) to obtain tert-butyl 2-(1H-pyrazol-1-yl)pyridin-4-ylcarbamate. This compound was treated with 2:1 DCM/TFA mixture at RT for 2 h. The mixture was pumped to dryness to afford 2-(1H-pyrazol-1-yl)pyridin-4-amine di-TFA salt.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1
Reactant: COc1ccc(Cl)c(N)c1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Product: COCc1cc(Nc2cc(OC)ccc2Cl)nc(-c2cccc(C)c2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (50 mg, 0.201 mmol) and 2-chloro-5-methoxyaniline (39 mg, 0.201 mmol) similar to Example 13 and isolated as a white solid (18 mg, 24%). 1H NMR (CDCl3): 8.27-8.25 (m, 3H), 7.40 (t, J=7.7 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 6.83 (s, 1H), 6.66 (dd, J=3.0, 9.0 Hz, 1H), 4.59 (s, 2H), 3.93 (s, 3H), 3.58 (s, 3H), 2.47 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[NH:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[NH:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]c(Br)nc1C
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CCOC(=O)c1[nH]c(-n2ccc(OCc3ccccc3)cc2=O)nc1C
Yield: 26 %

Procedure:
Following the procedure as described in Example 12, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-phenylpyridin-2-ol to react with ethyl 2-bromo-4-methyl-1H-imidazole-5-carboxylate in place of ethyl 2-bromo-4-methylthiazole-5-carboxylate at 130° C. for 64 hours, the title compound was obtained as a colorless solid in 26% yield: mp 135-136° C.; 1H NMR (300 MHz, CDCl3) δ 12.01 (s, 1H), 8.60-8.50 (m, 1H), 7.44-7.36 (m, 5H), 6.21 (dd, J=8.0, 2.6 Hz, 1H), 6.04 (d, J=2.6 Hz, 1H), 5.06 (s, 2H), 4.44-4.29 (m, 2H), 2.59-2.51 (m, 3H), 1.44-1.34 (m, 3H); MS (ES+) m/z 354.2 (M+1).