Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Br[CH:27]1[CH2:32][CH2:31][O:30][C:28]1=[O:29]>CN(C)C=O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:27]3[CH2:32][CH2:31][O:30][C:28]3=[O:29])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1OCCC1Br
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCOC1=O
Temperature: 0 °C

Procedure:
4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (1.0 g) was added to a mixture of sodium hydride (0.158 g of a 60% dispersion in mineral oil) in dimethyl formamide (70 ml) with stirring under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 hour and then α-bromo-γ-butyrolactone (0.60 g) in dimethylformamide (6 ml) was added dropwise with stirring at 0° C. The mixture was stirred at ambient temperature for 18 hours and then quenched with water (100 ml). The mixture was extracted with ethyl acetate. The combined extracts were dried and evaporated to give 2-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-butyrolactone as an oil which was used directly in b).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>P(Cl)(Cl)(Cl)=O>[N:22]1[CH:23]=[CH:24][C:19]([C:17]2[C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[CH2:3][CH2:2][N:1]([C:9]=34)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=2)=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccccc1N1CCc2ccccc21)c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)N=C(c1ccncc1)c1cccc3c1N2CC3
Temperature: 25 °C
Yield: 71.1 %

Procedure:
N-[2-(2,3-dihydro-1H-indol-1-yl)phenyl]-4-pyridinecarboxamide (10 gm) in phosphorous oxychloride (300 ml) was refluxed under nitrogen for 4.5 hours. Themixture was cooled to room temperature. The excess of phosphorous oxychloride was removed under reduced pressure (55° C.). The residue was partitioned between dichloromethane and 10% sodium hydroxide solution (600 ml:600 ml). The organic phase was separated and washed with water (250 ml) and brine (2×500 ml). The solution was dried over anhydrous magnesium sulfate and concentrated to about 10 gm of gum. Purification was effected by flash chromatography (silica, 150 gm, eluted with 1.5% methanol/98.5% dichloromethane, 4 L) to yield 6.7 gm of solid. Recrystallization from hot ethanol (70 ml) yielded 5.24 gm of crystals, m.p. 152°-153° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][CH3:15].[O-]P([O-])([O-])=O.[K+].[K+].[K+].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]>[Cl:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:14][CH3:15])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCNS(C)(=O)=O
Reactant: COC(=O)c1cc(Cl)nc(Cl)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: CCCN(c1cc(C(=O)OC)cc(Cl)n1)S(C)(=O)=O
Temperature: 100 °C

Procedure:
A solution of methyl 2,6-dichloroisonicotinate (4.8 g, 23.3 mmol) and N-propylmethanesulfonamide (3.8 g, 28.0 mmol) in dioxane (190 mL) was degassed with argon. Potassium phosphate tribasic (6.9 g, 32.6 mmol), xantphos (810 mg, 1.40 mmol) and Pd2 dba3 (427 mg, 0.47 mmol) were added, and the reaction mixture was stirred at 100° C., sealed, for 16 h. The reaction mixture was filtered on cellite, concentrated in vacuo, and purified by flash chromatography (2×300 g silica gel, 0 to 35% EtOAc in hexane) to give methyl 2-chloro-6-[(methylsulfonyl)(propyl)amino]isonicotinate. 1H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 7.72 (s, 1H), 3.97 (s, 3H), 3.91 (t, J=7.2 Hz, 2H), 3.14 (s, 3H), 1.68-1.52 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.[C:31]1([N:41]=[C:42]=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[C:31]1([NH:41][C:42]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]3[N:15]=[C:14]([N:16]4[C:20]5[CH:21]=[CH:22][C:23]([C:25]6[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=6)=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:13]=[CH:12][N:11]=3)[CH3:8])[CH2:2]2)=[O:43])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(Nc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1)C1CCCNC1
Reactant: O=C=Nc1cccc2ccccc12
Product: CC(Nc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1)C1CCCN(C(=O)Nc2cccc3ccccc23)C1

Procedure:
The title compound was prepared from 2-[1-(piperidin-3-yl)-ethylamino]-4-[5-(pyridin-4-yl)-benzimidazol-1-yl]pyrimidine according to the procedure described in EXAMPLE 29 using 1-naphthylisocyanate. Mass spectrum (ESI) 569.5 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:16][OH:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:20]([CH3:22])=[CH2:21]>CC(C)=O.B(F)(F)F.CCOCC>[CH3:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[CH2:16][O:17][C:20]([CH3:22])([CH3:21])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: COC(=O)CC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: C=C(C)OC
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
(S)-methyl 4-(tert-butoxycarbonylamino)-5-hydroxypentanoate (24 g, 97.2 mmol) and isopropenyl methyl ether (88.8 g, 854.6 mmol) was dissolved in acetone (2000 mL) and BF3-Et2O (0.82 mL, 5.84 mmol) was added at rt. The mixture was stirred for 1 hr at rt. The reaction was quenched by addition of Et3N (11.6 mL). The reaction solution was washed with aqueous saturated NaHCO3 (200 mL) and evaporated, and (S)-tert-butyl 4-(3-methoxy-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (25.1 g, 90%) was obtained as an oil, which was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][OH:20])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][O:22]C1C=CC(CCl)=CC=1.O>C1(C)C=CC=CC=1>[CH3:21][O:22][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH2:19][OH:20])=[N:11]2)=[CH:9][CH:8]=1
Reactant: COc1ccc(CCl)cc1
Reactant: OCc1nn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Cn2nc(CO)c3ccccc32)cc1
Temperature: 25 °C
Yield: 27.2 %

Procedure:
To a suspension of 60% NaH (2.7 g; 0.07 mol) in toluene (200 ml) was added 1-benzyl-3-hydroxymethylindazole (10 g; 0.07 mol). The mixture was brought to boiling point and left stirring at reflux for 1 hour. 4-Methoxybenzyl chloride (14 g; 0.09 mol) was then added. The mixture was then stirred at reflux for 4 hours. The reaction was completed by cooling the mixture to room temperature and adding water (50 ml). The organic phase was separated out and washed, respectively, with 2N HCl (50 ml) and water (5×50 ml). The solvent was evaporated off under reduced pressure. The crude residue thus obtained was purified by flash chromatography on silica gel, using as eluent a 3/2 hexane/ethyl acetate mixture. The product obtained was crystallized from a 5/1 hexane/ethyl acetate mixture to give 5.1 g of [1-(4-methoxybenzyl)-1H-indazol-3-yl]methanol with a melting point of 95°-97° C.
Reaction SMILES: [OH-].[K+].[C:3](I)([C:6]([C:9]([C:12]([C:15]([C:18]([F:21])([F:20])[F:19])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.CO>[CH:3]([C:6]([C:9]([C:12]([C:15]([C:18]([F:19])([F:20])[F:21])([F:16])[F:17])([F:13])[F:14])([F:11])[F:10])([F:8])[F:7])([F:5])[F:4]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Into a 1 l four-necked flask equipped with a stirrer, a distillation apparatus-equipped refluxing condenser, a dropping funnel and a thermometer, 200 cc of methanol, 131 g of (1.1 mols) of 48% potassium hydroxide and 3 g of tetrabutylphosphonium bromide were charged. The reactor was heated to bring the internal temperature to 60° C. Then, 223 g (0.5 mol) of C6F13I was dropwise added thereto over a period of one hour. After completion of dropwise addition, heating and refluxing were continued for two hours. The conversion at that time was 97.0%. A fraction with a boiling point of up to 60° C. was recovered by distillation from the reactor. The recovered liquid was washed with 300 g of water to recover the fluorocarbon. Thus, 149 g of C6F13H having a purity of 99.9%, was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[N:4][C:5]([O:9][CH2:10][C:11]([N:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)[CH3:14])=[O:12])=[N:6][C:7]=1[CH3:8].[CH3:29][S:30]([OH:33])(=[O:32])=[O:31]>CO>[CH3:29][S:30]([OH:33])(=[O:32])=[O:31].[NH2:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([O:9][CH2:10][C:11]([N:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:17][CH2:16]2)[CH2:14][CH3:29])=[O:12])=[N:4][C:3]=1[CH3:28]
Reactant: Cc1nc(OCC(=O)N(C)C2CCN(Cc3ccccc3)CC2)nc(C)c1N
Agent: CS(=O)(=O)O
Solvent: CO
Product: CCN(C(=O)COc1nc(C)c(N)c(C)n1)C1CCN(Cc2ccccc2)CC1
Yield: 178.5 %

Procedure:
Compound 65 (202 mg) was suspended in methanol (1 mL) and methanesulfonic acid (50.6 mg) was added to the suspension at room temperature (20 to 30° C.). After the compound was dissolved, the mixture was concentrated under reduced pressure. Then, isopropanol (1.0 mL) was added to the resulting residue and the mixture was stirred under reflux. Once the residue was dissolved, the mixture was stirred overnight as it was allowed to cool. Subsequently, the mixture was stirred and cooled with ice for 1 hour and was suction-filtered. The resulting solid was washed with isopropanol and dried to give 232 mg (92% yield) of the desired product as white crystals.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([NH:35][C@H:36](C(O)=O)C)([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH:24]1[C:23]2[CH:22]([CH2:21][O:20][C:18]([NH:35][CH2:36][CH2:2][C:3]([O:5][C:6]3[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=3[F:15])=[O:4])=[O:19])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]=2[CH:27]=[CH:26][CH:25]=1
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCNC(=O)OCC1c2ccccc2-c2ccccc21)Oc1c(F)c(F)cc(F)c1F
Reaction time: 1 h

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (1.7 g, 6.5 mmol) was added dropwise to a solution of FMOC-alanine (2.0 g, 6.4 mmol) and triethylamine (1.0 ml, 7 mmol) in 20 ml of anhydrous CH2Cl2. After 1 hr., CH2Cl2 was removed by evaporation at reduced pressure using rotary evaporator, redissolved in 30 ml ethylacetate/hexane (1:1). Flash chromatography (4×20 cm, hexane/ethyl acetate, 3:1) afforded rude 4 as a white solid. It was recrystallized from hexane/ethyl acetate to give 4 as a white crystalline solid (2.3 g, 78%): 1H NMR (CDCl3, 200 MHz, ppm) 7.73 (d, 2H, J=7.1 Hz, aromatic protons), 7.75 (d, 2H, J=7.7 Hz, aromatic protons), 7.24-7.42 (m, 4H, aromatic protons), 7.01 (m, 1H, C6F4H), 5.21 (br s, 1H, —CONH—), 4.38 (d, 2H, J=7.1 Hz, —CH2OCO—), 4.20 (m, 1H, benzyl proton), 3.58 (m, -2H, NCH 2), 2.93 (t, 2H, J=5.4 Hz, —CH2CO—). Anal. Calcd. for C24H17NO4F4: C, 62.75; H, 3.73; N, 3.05. Found: C, 62.52; H, 3.59; N, 3.01.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][CH:9]1[NH:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:10]1.[F:24][C:25]([F:41])([F:40])[C:26]1[O:30][N:29]=[C:28]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])[N:27]=1>>[CH3:8][CH:9]1[N:14]([C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:28]3[N:27]=[C:26]([C:25]([F:41])([F:40])[F:24])[O:30][N:29]=3)[CH:32]=2)[CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:10]1
Reactant: CC1CN(Cc2ccc(C#N)cn2)CCN1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(Cc2ccc(C#N)cn2)CCN1C(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 21 %

Procedure:
This compound was synthesized from 6-((3-methylpiperazin-1-yl)methyl)nicotinonitrile TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (60 mg, yield 21%) pale yellow viscous liquid. 1H NMR (400 MHz, MeOD) δ 8.85-8.84 (m, 1H), 8.25-8.22 (dt, J=7.4 Hz, 1.6 Hz, 1H), 8.19-8.16 (dd, J=8.2 Hz, 2.1 Hz, 1H), 8.13 (m, 1H), 7.82-7.80 (d, J=8.3 Hz, 1H), 7.72-7.66 (m, 2H), 3.82-3.70 (m, 3H), 3.50 (m, 2H), 2.89 (m, 1H), 2.74 (m, 1H), 2.43-2.41 (m, 1H), 2.31-2.25 (m, 1H), 1.46-1.44 (d, J=6.5 Hz, 3H). MS (ESI) m/z: Calculated for C22H16F3N6O2: 456.15. found: 457.2 (M+H)+
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([CH3:21])[CH:7]=1.C(=O)([O-])O.[Na+].[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1.[BH4-].[Na+]>C1COCC1.CO>[ClH:1].[CH:27]1([CH2:30][NH:2][C@@H:3]2[CH2:5][C@H:4]2[C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:8]([CH3:21])[CH:7]=2)[CH2:29][CH2:28]1
Reactant: O=CC1CC1
Reactant: Cc1cc([C@@H]2C[C@H]2N)ccc1NC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc([C@@H]2C[C@H]2NCC2CC2)ccc1NC(=O)c1ccccc1
Temperature: 0.6000000238418579 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)-2-methylphenyl]benzamide hydrochloride (90.1 mg) and sodium hydrogen carbonate (50.0 mg) in THF (1.49 mL)/methanol (1.49 mL) was added cyclopropanecarbaldehyde (0.029 mL). The reaction mixture was stirred at 0.60° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (22.51 mg) was added. The mixture was stirred at room temperature overnight, and poured into saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (5 mL), and 4N hydrochloric acid/ethyl acetate solution (0.5 mL) was added. The solvent was evaporated under reduced pressure, and the residue was recrystallized from methanol/diisopropyl to give the title compound (55.9 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:7]=[C:6]([C:18]([O:20]CC)=[O:19])[C:5]2=[O:23].[CH2:24]([NH:26][C:27](=[O:47])[NH:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[C:31]([C:38]2[S:39][CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[N:42]=2)[CH:30]=1)[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+].Cl>O1CCOCC1.O.C1(P([Pd-4](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)C=CC=CC=1>[CH:12]1([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:32]4[CH:33]=[N:34][C:29]([NH:28][C:27]([NH:26][CH2:24][CH3:25])=[O:47])=[CH:30][C:31]=4[C:38]4[S:39][CH:40]=[C:41]([C:43]([F:46])([F:44])[F:45])[N:42]=4)=[N:11][CH:10]=3)[C:5](=[O:23])[C:6]([C:18]([OH:20])=[O:19])=[CH:7]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B(O)O)cn1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2cnc(Br)cc2c1=O
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)O)cn(C4CCCCC4)c3cn2)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 15.8 %

Procedure:
To a solution of ethyl 6-bromo-1-cyclohexyl-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (Intermediate 47, 208 mg, 0.5 mmol, 1 equiv.) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazole-2-yl)pyridine-3-ylboronic acid (180 mg, 0.5 mmol, 1 equiv., WO2009106885) in 1,4-dioxane (3 mL) was added tetrakis(triphenylphosphino)palladium(0) (58 mg, 0.05 mmol, 0.1 equiv.) followed by a solution of cesium carbonate (326 mg, 1.0 mmol, 2 equiv.) in water (1 mL). This reaction mixture was stirred at 100° C. for 2 h. 2 M lithium hydroxide (0.5 mL) was added. The reaction mixture was stirred at 100° C. for 9 h, cooled to room temperature, and diluted with water. To this was added 1 N HCl was added until pH 3-4 was reached. The precipitate was collected by filtration, washed with water and hexanes and dried under high pressure. The compound was purified (HPLC) and concentrated to provide 1-cyclohexyl-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylic acid as a solid (46.4 mg, 15%). Calcd for C27H25F3N6O4S [M+H]+: 587.09.
Reaction SMILES: C1OC1C.B(Br)(Br)Br.[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([C:25]#[C:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH:22]=[CH:21][C:20]=2[O:33]C)=[C:15]([NH:35][C:36]([NH:38][C:39]2[C:44]([CH:45]([CH3:47])[CH3:46])=[CH:43][CH:42]=[CH:41][C:40]=2[CH:48]([CH3:50])[CH3:49])=[O:37])[C:14]1=[O:51])[CH2:10][CH2:11][CH3:12].[OH-].[Na+].Cl>C(Cl)Cl>[CH2:9]([N:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([C:25]#[C:26][CH2:27][N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[CH:22]=[CH:21][C:20]=2[OH:33])=[C:15]([NH:35][C:36]([NH:38][C:39]2[C:40]([CH:48]([CH3:50])[CH3:49])=[CH:41][CH:42]=[CH:43][C:44]=2[CH:45]([CH3:47])[CH3:46])=[O:37])[C:14]1=[O:51])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1ccc(-c2cc(C#CCN(CC)CC)ccc2OC)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c1=O
Agent: BrB(Br)Br
Agent: CC1CO1
Agent: Cl
Solvent: ClCCl
Product: CCCCn1ccc(-c2cc(C#CCN(CC)CC)ccc2O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c1=O
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of propylene oxide (0.07 ml, 1.04 mmol) in methylene chloride (10 ml) was added BBr3 (0.29 ml, 3.11 mmol) under ice-cooling, and the mixture was stirred for 30 minutes. To the mixture was added N-[1-butyl-2-oxo-4-[2-methoxy-5-{3-(diethylamino)-1-propynyl}phenyl]-1,2-dihydropyridin-3-yl]-N′-(2,6-diisopropylphenyl)urea (303 mg, 0.518 mmol), and the mixture was stirred under reflux for 4 hours. To the reaction solution was added a 10% aqueous sodium hydroxide solution, and the mixture was acidified with 3N hydrochloric acid. The mixture was extracted with chloroform, and the extract was washed with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:30) to give the title compound (77 mg, <26%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[O:13]>C(#N)C>[CH3:9][C:4]1[N:3]=[C:2]([NH:1][C:24]([NH:23][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:22])=[O:21])=[O:25])[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(N)nc(C)n1
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1cc(C)nc(C)n1

Procedure:
To a suspension of 1.2 g of 4-amino-2,6-dimethylpyrimidine in 30 ml of dry acetonitrile with stirring was added 2.4 of 2-methoxycarbonylbenzenesulfonylisocyanate. The mixture was stirred for two hours at ambient temperature, allowed to stand for sixteen hours and the desired product, which had precipitated, was removed by filtration and washed with butyl chloride to yield 2.4 g, m.p. 125°-127°. The product showed absorption peaks by Nuclear Magnetic Resource at 4.0, 2.62 and 2.9 ppm; consistent for the product.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@@H:4]([C:12]([NH:14][C@H:15]([C:20]([O:22]CC1C=CC=CC=1)=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[NH:11])[NH2:10].O.Cl>O1CCOCC1.CO>[NH:3]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@@H:4]([C:12]([NH:14][C@H:15]([C:20]([OH:22])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[NH:10])[NH2:11]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](CCCNC(=N)N)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](C)[C@H](NC(=O)[C@@H](CCCNC(=N)N)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
41.8 ml of aqueous 1N NaOH are added to a solution of 19 g of Z-D-Arg-Ile-OBzl in a mixture of 70 ml of dioxane, 30 ml of water and 12 ml of methanol, and the mixture is left to stand at room temperature overnight. The next day it is neutralized with about 3.3 ml of 4N HCl. The cloudy solution is filtered with suction through a clarifying layer, and the filtrate is concentrated. The residue is partitioned between 120 ml of n-pentanol and 120 ml of water. The aqueous phase is extracted a further 4 times by shaking with n-pentanol. The n-pentanol phases are concentrated together. The residue is triturated with ethyl acetate, and the precipitate is filtered off with suction.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=2[CH:29]=1.[Cl:30][C:31]1[CH:32]=[C:33]([SH:38])[CH:34]=[CH:35][C:36]=1[Cl:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([S:38][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11]=3[CH:29]=2)[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:7]=1.[C:20]([C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])#[CH:21]>>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([C:21]#[C:20][C:22]([OH:29])([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])=[CH:7][C:6]=1[CH:8]([OH:18])[CH2:9][CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C#CC(O)(CCC)CCC
Reactant: O=C(NCCC(O)c1cc(Br)ccc1Cl)C(F)(F)F
Product: CCCC(O)(C#Cc1ccc(Cl)c(C(O)CCNC(=O)C(F)(F)F)c1)CCC

Procedure:
N-(3-(5-Bromo-2-chlorophenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide was coupled with 4-ethynylheptan-4-ol to give N-(3-(2-chloro-5-(3-hydroxy-3-propylhex-1-ynyl)phenyl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide as a pale yellow oil. Yield (1.03 g, 68%): 1H NMR (400 MHz, DMSO-d6) δ 9.42 (t, J=5.6 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.23 (dd, J=8.0 Hz, 2.0, 1H), 5.57 (d, J=4.0 Hz, 1H), 5.17 (s, 1H), 4.87-4.82 (m, 1H), 3.33-3.28 (m, 2H), 1.87-1.79 (m, 1H), 1.66-1.39 (m, 9H), 0.89 (t, J=7.2 Hz, 6H).