Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23]C(=O)OC(C)(C)C)=[N:21][CH:22]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([CH2:16][NH:15][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[N:14]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cn1
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of tert-butyl 5-((3-(3,5-dichlorophenylamino)-1H-1,2,4-triazol-5-ylamino)methyl)pyridin-2-ylcarbamate Compound 6 (50 mg, 111 μmol) in DCM (1 ml) was added TFA (1 ml) and the reaction was stirred for 1 hour. The reaction mixture was concentrated in vacuo and was partitioned between DCM (5 ml) and sat. NaHCO3 (3 ml). The layers were separated and the aqueous layer was extracted with DCM (3×5 ml). The combined organic solution was washed with brine (5 ml), dried over Na2SO4, filtered and concentrated to give a white solid as desired product (10.2 mg, 26% yield). MS +m/z: 350 (M+H)+
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[F:18][C:19]([F:29])([F:28])[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[NH2:21].CO>CCCCCCC>[F:29][C:19]([F:18])([F:28])[CH:20]([NH:21][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: NC(c1ccccn1)C(F)(F)F
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CCCCCCC
Solvent: CO
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-(trifluoromethyl)-2-pyridinemethanamine (CAN 503173-14-6) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (S)-(−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 392.1950 (M+H)+; αD20 (MeOH)=−91.1°.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3](Cl)=[O:4].[C:9]1([S:15][CH3:16])[CH:14]=[CH:13][CH:12]=CC=1>>[CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([C:9]1[S:15][CH:16]=[C:13]([CH3:12])[CH:14]=1)=[O:4]
Reactant: CCCC(C)C(=O)Cl
Reactant: CSc1ccccc1
Product: CCCC(C)C(=O)c1cc(C)cs1

Procedure:
Following the procedure described for Example 1, Step 1, the title compound was prepared from 2-methyvaleryl chloride and thioanisole.
Reaction SMILES: C(O)(C(F)(F)F)=O.CC([N:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[C:19]([O:25][C:26]2[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[C:28]([Cl:34])[CH:27]=2)[C:18]=1[F:35])C(=O)[O-])(C)C>C(Cl)Cl>[NH2:12][CH2:16][C:17]1[C:18]([F:35])=[C:19]([O:25][C:26]2[CH:31]=[C:30]([CH:29]=[C:28]([Cl:34])[CH:27]=2)[C:32]#[N:33])[C:20]([CH2:23][CH3:24])=[CH:21][CH:22]=1
Reactant: CCc1ccc(CN(C(=O)[O-])C(C)(C)C)c(F)c1Oc1cc(Cl)cc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(CN)c(F)c1Oc1cc(Cl)cc(C#N)c1
Reaction time: 16 h
Yield: 101 %

Procedure:
TFA (1.903 ml, 24.70 mmol) was added to a solution of 1,1-dimethylethyl({3-[(3-chloro-5-cyanophenyl)oxy]-4-ethyl-2-fluorophenyl}methyl)carbamate (0.5 g, 1.235 mmol) in DCM (30 mL) at RT under an atmosphere of nitrogen. After 16 h, the solution was concentrated under vacuum. Saturated NaHCO3 solution (100 mL) and ethyl acetate (100 mL) were added and the mixture was stirred for 1 h. The organic layer was separated, washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated to give the title compound (0.38 g, >99%) as a brown oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29-7.33 (m, 1H), 7.21-7.27 (m, 1H), 7.13 (t, 1H), 7.09 (d, 1H), 6.98 (s, 1H), 3.92 (s, 2H), 2.54 (d, 2H), 1.54 (d, 2H), 1.13-1.19 (m, 3H).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16]Br)[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH2:16][S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1nc(CBr)cs1)N(C1CCCCC1)C1CCCCC1
Reactant: Sc1ccccn1
Product: O=C(Nc1nc(CSc2ccccn2)cs1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (L) from 1,1-dicyclohexyl-3-(4-bromomethyl-thiazol-2-yl) urea and 2-mercaptopyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1c(O)c2ccc(-c3ccc(OC)cc3)cc2sc1=O
Yield: 71.2 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) (180 mg, 0.57 mmol) in dimethoxyethane (DME) (2.5 mL) was added 4-methoxyphenylboronic acid (104 mg, 0.69 mmol), Pd(PPh3)4 solid (66 mg, 0.06 mmol) and then 2M aqueous Na2CO3 solution (0.7 mL). The resulting mixture was purged with nitrogen gas for 1 min and heated to reflux for 2 h. After cooling the reaction mixture was diluted with water (50 mL) and acidified using 1 N HCl to pH 3-4. The precipitate was collected by filtration, rinsed with water and dissolved in CH2Cl2. The organic solution was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was triturated with MeOH (5 mL) and the solid collected, rinsed with MeOH (2 mL) and dried in vacuo to provide 4-hydroxy-7-(4-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (139 mg). MS ESI(+) m/e: 343.11 (M+1).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:20](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>ClCCl.CN(C=O)C>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[C:10]([CH2:14][C:18]#[N:20])[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(CO)c1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of [3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanol (10.52 g, 41.67 mmol) in dichloromethane (80 ml) at 0° C. (ice bath), was added triethylamine (8.78 ml, 62.5 mmol) followed by methanesulfonyl chloride (3.87 ml, 50 mmol). After stirring for 2 hr, the reaction mixture was washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow oil. The crude product was then dissolved in anhydrous DMF (80 ml) and sodium cyanide (6.28 g, 128 mmol) was added into the mixture. The mixture was stirred in an oil bath (60° C.) for 2 hr. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 1:20 to 1:10)) to afford 8.2 g (75%) of a pale yellow oil. 1H NMR (200 MHz, CDCl3) δ 0.11 (6H, s), 0.95 (9H, s), 3.75 (2H, s), 4.75 (2H, s), 7.27-7.35 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][NH:29]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][N:29]1[C:25]([C:10]1[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:24])[CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:9]=1)=[O:27]
Reactant: c1ccc2c(c1)CNC2
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
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: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3Cc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (50 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) were added isoindoline (40 mg, 0.34 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (120 μL, 0.69 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction solution was purified by preparative HPLC to afford the final product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[NH2:21][C@H:22]([C:25]([OH:27])=[O:26])[CH2:23][SH:24]>>[NH2:21][C@@H:22]([CH2:23][S:24][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1)[C:25]([OH:27])=[O:26]
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Reactant: N[C@@H](CS)C(=O)O
Product: CC1(c2ccccc2)OC(CC(SC[C@H](N)C(=O)O)c2ccsc2)=CC1=O

Procedure:
Following the procedure of Method C, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with L-cysteine to provide (2R)-2-amino-3-{[2-(5-methyl-4-oxo-5-phenyl-4,5-dihydrofuran-2yl)-1-thien-3-ylethyl]thio}propanoic acid: 1H NMR (DMSO-d6) δ1.50-1.60 (overlapping singlets, 3H), 2.70-3.10 (m, ˜2H), 4.00-4.25 (m, 1H), 4.64 (m, 1H), 5.50-5.57 (overlapping singlets, 1H), 7.12-7.38 (m, 6H), 7.52-7.63 (m, 2H), 8.35 (br s, ˜2H); MS (LR-ESI) m/z 402 (M-H calcd. for C20H20NO4S2 402)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NC1C=CC(CN2CCOCC2)=CC=1.BrC1C=C2C(=CC=1)[C:36](=[O:40])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:40][CH3:36]
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/Nc1ccc(CN2CCOCC2)cc1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, 5.11 g (81.9% yield) of yellow solid is obtained from 4.0 g (14.18 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 3.24 g (17.0 mmol) of 4-[(2-methylpyrrolidin-1-yl)methyl]phenyl}amine: mp 183-184° C.; MS (ESI) m/z 440.0 (M+H)+1
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]([O:20][CH3:21])=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1)#[CH:23]>CC#N.CCN(CC)CC.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>[CH3:9][O:8][C:7]1[C:2]([C:23]#[C:22][C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[N:3][CH:4]=[C:5]([O:20][CH3:21])[C:6]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(COc2c(OC)cnc(I)c2OC)cc1
Reactant: C#Cc1cnn(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(COc2c(OC)cnc(C#Cc3cnn(C)c3)c2OC)cc1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a stirred solution of 2-iodo-3,5-dimethoxy-4-(4-methoxy-benzyloxy)-pyridine (95 mg, 0.237 mmol) and 4-ethynyl-1-methyl-1H-pyrazole (30 mg, 0.283 mmol) in dry MeCN (1.5 ml) and NEt3 (0.5 ml) was added Pd(Ph3P)2Cl2 (12 mg, 7 mol %) and the reaction vessel was evacuated and backfilled with nitrogen three times. Copper (I) iodide (5 mg, 11 mol %) was added and the reaction mixture immediately became dark. Stirring was continued for 0.5 hours then the crude mixture was concentrated directly onto silica-gel under reduced pressure and the solid residue was purified by flash chromatography (silica-gel, eluted sequentially with EtOAc:hexanes, 2:1, 3:1, 1:0) to give the product as a white solid (85 mg, 95%). 1H—NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 6.86 (d, J=2H), 5.13 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][C:18]([CH3:26])([C:20]1[N:24]=[C:23]([CH3:25])[O:22][N:21]=1)[NH2:19]>>[CH3:17][C:18]([NH:19][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1)=[O:16])([C:20]1[N:24]=[C:23]([CH3:25])[O:22][N:21]=1)[CH3:26]
Reactant: O=C(O)c1cccc(-c2ccc(Cl)cc2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2cccc(-c3ccc(Cl)cc3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-chlorophenyl)-2-pyridinecarboxylic acid (CAN 135432-77-8) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (LC/MS): 357.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]2=[N:5][N:4]=1.ClCCl>[Pd].C(O)C>[F:12][C:2]([F:1])([F:13])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C:6]2=[N:5][N:4]=1
Reactant: FC(F)(F)c1nnc2cnccn12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: FC(F)(F)c1nnc2n1CCNC2

Procedure:
3-(Trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine (540 mg, 2.87 mmol, from Step A) was hydrogenated under atmospheric hydrogen with 10% Pd/C (200 mg) as a catalyst in ethanol (10 mL) at ambient temperature for 18 h. Filtration through Celite followed by concentration gave a dark colored oil. Dichloromethane was added to the above oil and the insoluble black precipitate was filtered off. Concentration of the filtrate gave the title compound as an oil.
Reaction SMILES: [NH:1]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@@H:23]1[C:24]([O:26]CC1C=CC=CC=1)=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1>CO.[Pd]>[NH:1]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Boc-D-Tyr(Me)-L-Ile-D-Pro-OBzl (1.44 g, 2.42 mmol) was dissolved in methanol (12 mL), and Pd—C (150 mg) was added. The mixture was stirred under hydrogen atmosphere at room temperature for 5 hours. Pd—C was filtered off, methanol was removed by evaporation, and the desired product was obtained as a foam. Yield: 1.21 g (2.4 mmol, 99%).
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[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[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[S:18][C:19]([C:23]([NH:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[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: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1cccnc1
Yield: 47 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 2-bromo-4-methyl-N-(pyridin-3-ylmethyl)thiazole-5-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 47% yield: mp 208-209° C.; 1H-NMR (300 MHz, DMSO-d6) δ 8.86 (br s, 1H), 8.68-8.60 (m, 1H), 7.81-7.72 (m, 1H), 7.51-7.33 (m, 7H), 6.35-6.48 (m, 1H), 6.27 (s, 1H), 5.19 (s, 2H), 4.47 (s, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.0, 161.5, 161.1, 153.5, 150.1, 135.2, 131.6, 128.5, 128.3, 128.0, 122.9, 103.9, 97.0, 70.3, 17.0; MS (ES+) m/z: 433.3 (M+1).
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[F:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[O:26])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: CC(C)(CN)CO
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NCC(C)(C)CO)cn1
Yield: 48 %

Procedure:
As described for example 125f, 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 3-amino-2,2-dimethyl-1-propanol instead of 2,2,2-trifluoroethylamine, to the title compound (120 mg, 48%) which was obtained as a colourless oil. MS: m/e=432.2 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2.C(N(CC)CC)C>ClCCl>[C:1]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: OCCCCCCn1c2ccccc2c2ccccc21
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 30 mmol of methacryloyl chloride in 10 ml of dichloromethane was added dropwise to a solution of 25 mmol of N-(6-hydroxyhexyl)-carbazole and 30 mmol of triethylamine in 100 ml of dry dichloromethane. Thereafter, the reaction mixture was stirred for 3 hours at room temperature and then worked up by washing it with 2 N sodium hydroxide solution and water. After the reaction mixture had been evaporated down, the 6-(N-carbazolyl)-hexyl methacrylate formed was isolated by column chromatography over silica gel (eluent: dichloromethane). The 6-(N-carbazolyl)-hexyl methacrylate thus obtained in 70% yield was in the form of a colorless oil and had the following characteristic data:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8].[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl>[OH-].[Na+]>[CH:13]1([C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH2:9])=[O:8])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NCCC[C@H](NC(=O)C1CCCCC1)C(=O)O
Temperature: 25 °C
Yield: 77.5 %

Procedure:
L-Citrulline (35.2 g., 0.2 mole) was dissolved in 200 mL of 2N sodium hydroxide. Cyclohexanoyl chloride (29 mL, 0.2 mole) was added dropwise to the mixture. The reaction mixture was maintained at about 25° C. for 1 hour. The mixture was then acidified to pH 2.6 with aqueous (4:1) hydrochloric acid. The precipitate which formed was separated by decantation. The solids were dissolved in 2N sodium hydroxide to pH 6.5 and dried by lyophilization to furnish 44.2 g of N-cyclohexanoyl-(L)-citrulline. The product was a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:11])[N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:6]=2[CH:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Temperature: 90 °C
Yield: 15.6 %

Procedure:
(S)-1-[6-Fluoro-1-(3-fluorophenyl)-1H-benzoimidazol-2-yl]ethylamine (0.45 g, 1.64 mmol) was dissolved in n-butanol (10 mL) and 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.39 g, 1.64 mmol) and DIPEA (1.45 mL, 8.24 mmol) were added. The reaction mixture was heated at 90° C. overnight. The resultant mixture was allowed to cool to RT and was concentrated in vacuo. The residue was passed down an Isolute® SCX-2 cartridge, eluting with DCM, MeOH and 2M NH3 in MeOH to afford crude product. This material was purified by column chromatography (silica gel, gradient 0-7.5% MeOH in DCM) to afford 185 as an off-white solid (100 mg, 20%). LCMS (Method K): RT 3.52 min [M+H]+ 392.0 1H NMR (DMSO-d6, 400 MHz): δ 8.09 (1H, s), 8.05 (1H, s), 7.91 (1H, s), 7.68 (1H, dd, J=8.80, 4.85 Hz), 7.58-7.47 (2H, m), 7.42 (1H, d, J=7.91 Hz), 7.32-7.23 (1H, m), 7.09 (1H, td, J=9.32, 2.48 Hz), 6.92 (1H, dd, J=8.93, 2.50 Hz), 5.63-5.47 (1H, m), 1.58 (3H, d, J=6.82 Hz)
Reaction SMILES: Br[C:2]1[C:3]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:16]([N:19]1[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]1)[C:17]#[CH:18].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:10]1[C:3]2[N:4]=[C:5]([C:8]#[N:9])[N:6]=[CH:7][C:2]=2[CH:18]=[C:17]1[CH2:16][N:19]1[CH2:20][CH2:21][S:22](=[O:25])(=[O:26])[CH2:23][CH2:24]1
Reactant: C#CCN1CCS(=O)(=O)CC1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Cn1c(CN2CCS(=O)(=O)CC2)cc2cnc(C#N)nc21
Temperature: 80 °C
Reaction time: 31 h
Yield: 1.4 %

Procedure:
To a solution of 0.54 g (2 mmoles) of 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile and 0.75 g (4.3 mmoles) of 4-propargylthiomorpholine-1,1-dioxide in 5 ml of DMF are added 0.841 ml (6 mmoles) of triethylamine, 0.38 g (2 mmoles) of copper(I) iodide and 0.14 g (0.2 mmoles) of Pd(PPh3)2Cl2under nitrogen atmosphere. The mixture is stirred for 31 hours at 80° C. The mixture is filtered through celite, diluted with AcOEt, washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by HPLC(H2O—0.1% TFA/CH3CN—0.1% TFA). Fractions are collected, basified with 5% aqueous NaHCO3, extracted with AcOEt, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue is then purified by HPLC (n-Hexane/AcOEt) to give 0.01 g of desired 7-(2,2-dimethyl-propyl)-6-(1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 1.4% yield.