Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18](=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]=[C:13]([NH:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:12]=2)C=CC=CC=1>[Pd].C1COCC1>[NH2:10][C:11]1[CH:16]=[C:15]([NH:17][C:18](=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]=[C:13]([NH:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:12]=1
Reactant: CCCCCCCCCC(=O)Nc1cc(NC(=O)CCCCCCCCC)cc(NC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)Nc1cc(N)cc(NC(=O)CCCCCCCCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A mixture of 2.77 g (4.9 mmol) of [3,5-bis[(1-oxodecyl)amino]phenyl]carbamic acid phenylmethyl ester and 0.6g of 10% palladium on carbon in 60 ml of THF was shaken under a hydrogen atmosphere at room temperature and pressure for 8 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure. The resultant solid was triturated with ether and filtered to give 1.94 g (92% yield, mp 152°-154°) of N,N'-(5-amino-1,3-phenylene) bisdecanamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.C[N:22]1CCOCC1.C(OC(Cl)=O)C(C)C.N>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:22])=[O:14])=[CH:11][CH:10]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CN1CCOCC1
Reactant: Cc1ccc(Sc2ccc(C(=O)O)cc2)c([N+](=O)[O-])c1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Sc2ccc(C(N)=O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The product from Example 30a (0.3 g, 1.04 mmol) was dissolved in THF (15 mL) and treated with N-methylmorpholine (0.131 mL, 1.19 mmol) followed by cooling in an ice bath and addition of isobutylchloroformate (0.148 mL, 1.14 mmol). The resulting mixture was allowed warm to room temperature with stirring for thirty minutes. Subsequent cooling in an ice bath was followed by addition of ammonia gas and warming to room temperature. The title compound was isolated by the addition of water and collection of the solid by vacuum filtration was used without further purification (0.289 g, 96%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([Cl:30])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1Cl
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C(F)(F)F)cc23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])=[CH:9][C:8](=[O:21])[NH:7][C:6]1=[S:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:47]([O:51][C:52]([NH:54][CH2:55][C:56](O)=[O:57])=[O:53])([CH3:50])([CH3:49])[CH3:48].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:10]1[N:5]([CH2:4][CH2:3][NH:2][C:56](=[O:57])[CH2:55][NH:54][C:52](=[O:53])[O:51][C:47]([CH3:48])([CH3:49])[CH3:50])[C:6](=[S:22])[NH:7][C:8](=[O:21])[CH:9]=1
Reactant: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCN)c(OC)c1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CCNC(=O)CNC(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a solution of 1-(2-aminoethyl)-6-(2,4-dimethoxyphenyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one hydrochloride (123 mg, 0.4 mmol)(the product of Example 6) in dry methylene chloride (4 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (182 mg, 0.48 mmol) and tert-butoxycarbonylamino-acetic acid (70 mg, 0.4 mmol) and diisoproplyethylamine (336 mg, 1.6 mmol). After stirring overnight at RT the reaction mixture was concentrated under reduced pressure and the residue purified by preparative thin layer chromatography (1:1 petroleum ether:ethyl acetate) to provide tert-butyl 2-(2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)ethylamino)-2-oxoethylcarbamate (120 mg, 65%).
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>CN(C=O)C.CC(OC)(C)C>[Si:47]([O:46][CH2:45][CH2:44][N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:33][CH2:34][CH2:35][CH3:36])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
To a stirred solution of 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (190 mg, 0.40 mmol) in dry DMF (5 mL) was added K2CO3 (160 mg, 1.16 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (92 mg, 0.38 mmol) at 0° C. The mixture was allowed to warm to room temperature and heated at 50° C. for 24 h. The reaction mixture was cooled to 0° C., diluted with MTBE and quenched with water. The organic layer was separated and the aqueous layer was extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to provide crude product. The crude material was purified by flash chromatography (gradient 10 to 30% ethylacetate/hexane) to provide the title compound (144 mg, 54%). 1H NMR (CD3OD) 8.66 (d, J=1.6 Hz, 1H), 8.30 (dd, J=8.0, 2.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.65 (s, 1H), 7.38-7.29 (m, 5H), 5.20 (s, 2H), 3.99 (s, 3H), 3.83-3.82 (m, 2H), 3.77 (t, J=5.0 Hz, 2H), 3.70 (t, J=5.0 Hz, 2H), 3.49 (br s, 2H), 1.70-1.55 (m, 4H), 1.45-1.26 (m, 4H), 1.05-0.85 (m, 6H), 0.83 (s, 9H), 0.03 (s, 6H); MS(ESI+) m/z 650.2 (M+H)+.
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:16]=3[CH3:17])[C:5]2=[N:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1)CCC>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.O1CCOCC1>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:10]1[C:5]2[N:6]([C:2]([C:30]3[CH:35]=[N:34][CH:33]=[CH:32][N:31]=3)=[CH:3][N:4]=2)[N:7]=[CH:8][CH:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Cc1ccncc1-c1ccnn2c(I)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1ccncc1-c1ccnn2c(-c3cnccn3)cnc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30 %

Procedure:
A microwave vial was charged with a mixture of 3-iodo-8-(4-methylpyridin-3-yl)imidazo[1,2-b]pyridazine, TFA (66 mg, 0.147 mmol), 2-(tributylstannyl)pyrazine (162 mg, 0.440 mmol), tetrakis(triphenylphosphine)palladium(0) (33.9 mg, 0.029 mmol), and dioxane (4 mL) was stirred at RT for 5 min. under nitrogen. The resulting mixture was heated to 114° C. for 15 h in microwave. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep. HPLC to give 18.2 mg (30%) product. 1H NMR (400 MHz, CD3OD) δ ppm 9.86 (1H, d, J=1.76 Hz), 8.97 (1H, s), 8.86 (2H, dd, J=16.12, 5.29 Hz), 8.66-8.79 (1H, m), 8.59 (1H, d, J=2.52 Hz), 8.56 (1H, s), 8.10 (1H, d, J=6.04 Hz), 7.54 (1H, d, J=4.78 Hz), 2.57 (3H, s); LC (Conditions B & C): >95% purity. LC/MS: Rt=1.05 min. LC/MS (Condition A): 289.12.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:14][C:13]=1[CH3:19]
Reactant: N#Cc1cc(F)ccc1F
Reactant: Cc1cc(O)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccc(F)cc2C#N)ccc1N
Temperature: 25 °C
Yield: 98.6 %

Procedure:
In a 3 L, 4-necked flask that had been evacuated and back-filled with argon, 2,5-difluorobenzonitrile (295.3 ml, 812.0 mmol) and 4-amino-3-methylphenol (100.0 g, 812.0 mmol) were dissolved in dry DMSO (2.75 M) with rapid stirring at room temperature. The solution was evacuated/backfilled with argon (3×). Potassium carbonate (185.2 g, 1340 mmol) (−325 mesh) was added. The reaction mixture was evacuated/backfilled with argon (3×) and warmed to 80° C. (internal probe) for 16 hours. TLC indicated complete conversion. The reaction mixture was cooled to room temperature and poured slowly into 2 L of ice water with rapid stirring. The residue in the round bottom flask was taken up in water repeatedly and poured into the ice water until a total volume of 3 L was achieved and all solids were in the ice water. The suspension was stirred rapidly for 2 hours as it came to room temperature. The brown solids were collected by filtration, washed with water (3 L), air dried, dried with latex dam, and dried under high vacuum at 40° C. for 44 hours to provide 194 g (99%) of the desired product as a tan solid. MS (APCI+) m/z 243 (M+1) was detected. 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 1H), 7.18 (m, 1H), 6.65-6.85 (m, 5H), 3.60 (br, 2H), 2.17 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=3[N:16]=2)[C:4](=[O:18])[CH2:3]1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:35])[N:28]2[CH2:31][CH2:32][CH:33]=O)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:35])[N:28]2[CH2:31][CH2:32][CH2:33][NH:1][C@@H:2]2[CH2:6][N:5]([C:7]3[CH:8]=[CH:9][C:10]4[O:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=4[N:16]=3)[C:4](=[O:18])[CH2:3]2)=[CH:23][CH:22]=1
Reactant: COc1ccc2ncc(=O)n(CCC=O)c2c1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCCN[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
6-[(4S)-4-Amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (94.1 mg, 0.379 mol) and 3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propanal (Reference Example 8; 106 mg, 0.456 mmol) were dissolved in chloroform/methanol (10:1, v/v, 6 ml). Molecular sieve 3 A (powder, 1.0 g) was added to the solution and heated under reflux for 3 hours. After cooling, sodium triacetoxyborohydride (145 mg, 0.684 mmol) was added to the reaction mixture and the mixture was stirred overnight at room temperature. After completion of the reaction, the molecular sieve was removed by filtration and a saturated sodium hydrogen carbonate aqueous solution was added to the filtrate and stirred. After separating the organic layer, the aqueous layer was extracted twice with chloroform/methanol (10:1, v/v) and combined with the organic layer. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by thin-layer chromatography (chloroform/methanol) to yield 56 mg (32%) of the title compound in the form of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[CH:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22]I.O>CN(C)C=O.CCCCCC>[Cl:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]([CH3:18])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[C:17][CH3:22])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: CC#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.72 g (10 mmol) of 7-chloro-3-ethynyl-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was dissolved in 20 ml of N,N-dimethylformamide. 1.31 g (30 mmol) of sodium hydride dispersion (55% in oil) was washed with n-hexane and then introduced at room temperature into the above solution. After 10 minutes 0.95 ml (15 mmol) of methyl iodide was added thereto and the mixture was stirred at room temperature for a further 3 hours. The reaction mixture was poured into 300 ml of water and extracted four times with methylene chloride. The organic extracts were washed four times with water and dried over magnesium sulphate. After chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate, there was obtained 7-chloro-4,5-dihydro-5-methyl-3-(1-propynyl)-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 243°-244°.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:17](=[O:18])[CH2:16][C:15](=[O:19])[N:14]=[C:13]1[CH3:20].C([O-])([O-])=O.[K+].[K+].[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30]Br>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[F:27][C:28]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:29]=1[CH2:30][O:19][C:15]1[N:14]=[C:13]([CH3:20])[N:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:17](=[O:18])[CH:16]=1
Reactant: COC(=O)c1ccc(C)c(N2C(=O)CC(=O)N=C2C)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
A mixture of methyl 4-methyl-3-(2-methyl-4,6-dioxo-5,6-dihydropyrimidin-1(4H)-yl)benzoate (0.1 g, 0.00036 mol, from Step 2), K2CO3 (0.075 g, 0.00054 mol) and 2,4 difluorobenzylbromide (0.075 g, 0.00036 mol) in DMF (2.0 mL) containing 18-crown-6 (0.005 g) is stirred at room temperature for 1 h under argon atmosphere. DMF is distilled in vacuo and the residue is purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=401) are combined and concentrated to a small volume (˜20 mL). After cooling, 5% NaHCO3 solution (10 mL) is added and the solution is extracted with dichloromethane (3×20 mL). The combined organic extracts are dried (Na2SO4), filtered, and concentrated to dryness to afford the title compound (0.12 g, 82%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 8.04 (d, 1H, J=1.6 Hz), 7.87 (d, 1H, J=1.16 Hz), 7.55 (m, 2H), 7.00 (m, 2H), 5.79 (s, 1H), 5.38 (s, 2H), 3.89 (s, 3H), 2.14 (s, 3H), and 2.12 (s, 3H); ES-HRMS m/z 401.1346 (M+H calcd for C21H19N2O4F2 requires 401.1307).
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:17]1[O:18][C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1)[CH2:13][CH2:14][CH2:15][OH:16])=O)C1C=CC=CC=1>CO.[Pd]>[OH:16][CH2:15][CH2:14][CH2:13][C@@H:12]([NH2:11])[C:17]1[O:18][C:19]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1
Reactant: O=C(N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 5 h
Yield: 69.4 %

Procedure:
A mixture of (1R)-N-benzyloxycarbonyl-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (12 g) and 10% Pd/C (2 g) in methanol (20 ml) was stirred under H2 for 5 hours. The catalyst was filtered off and filtrate was evaporated. The residue was recrystallized with ether to give (1R)-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (5.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][CH:46]([OH:50])[CH2:47][CH2:48][CH3:49])[CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:50][CH:46]([CH2:45][CH2:44][N:41]2[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]2)[CH2:47][CH2:48][CH3:49])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: CCCC(O)CCN1CCN(C)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC(CCN1CCN(C)CC1)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 29.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-(4-methylpiperazino)-3-hexanol (46 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (25 mg, yield 25%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:1]1[CH:2]=[CH:3][C:4]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)cc1
Yield: 28.6 %

Procedure:
p-Toluenesulfonyl chloride (0.52 mol, 100 g), N-bromosuccinimide (0.62 mol, 110.3 g), and benzoyl peroxide (5 g) were heated to reflux in carbon tetrachloride (500 ml) for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with isopropyl ether to afford 40.1 g of title product as a white solid; m.p. 70°-73° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]=[C:6]2[CH2:12][C:13]([OH:15])=O.[C:16]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]=[C:6]2[CH2:12][C:13]([N:29]1[CH2:28][CH2:27][N:26]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:31][CH2:30]1)=[O:15]
Reactant: COc1ccc2c(c1)C(CC(=O)O)=CC2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CC(=O)N1CCN(c3cccc4ccccc34)CC1)=CC2
Reaction time: 1 h
Yield: 86.4 %

Procedure:
2.0 g (0.012 mol) of N,N'-carbonyldiimidazole are added in small portions to a solution of 2.45 g (0.012 mol) of 5-methoxy-1H-indene-3-acetic acid in 12 ml of tetrahydrofuran, which has been placed under an argon atmosphere, and the mixture is stirred for 1 h. A solution of 2.55 g (0.012 mol) of 1-(naphth-1-yl)piperazine in 10 ml of tetrahydrofuran is added, and the mixture is left to stand overnight. The solvent is evaporated under reduced pressure. The residual oil is taken up in water and diethyl ether, and the solid obtained is collected by filtration and dried. 4.13 g of a product are obtained which is used as it is in the following step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][S:19][C:20]1[N:25]=[C:24](I)[CH:23]=[CH:22][N:21]=1>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]([C:22]3[CH:23]=[CH:24][N:25]=[C:20]([S:19][CH3:18])[N:21]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CSc1nccc(I)n1
Reactant: Fc1ccc(-c2nc3nc(Cl)ccc3[nH]2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
KN(TMS)2 (1.42 g 7.16 mmol) in toluene (7 ml) is added at 0° C. to a solution of 5Chloro-2-(4fluorophenyl)imidazo[4,5-b]pyridine (1.9 g 6.66 mmol) in DMF (25 ml). After stirring 1 h at room temperature, 2-methylthio-4-iodopyrimidine (1.8 g 7.1 mmol) in toluene (7 ml) is added dropwise and heated for 20 h at 120° C. The reaction mixture is poured on water and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness to yield the crystalline crude product, which after recrystallisation from ethyl acetate yields the title compound as colorless crystals (1.76 g 67%).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Cl:7]Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10]>C(Cl)Cl>[Cl:7][CH2:1][CH:2]([OH:6])[CH2:3][C:4]([NH:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:15])=[O:5]
Reactant: CCOC(=O)CN
Reactant: C=C1CC(=O)O1
Reactant: ClCl
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)CC(O)CCl
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
5.08 ml diketene are dissolved in 40 ml CH2Cl2. The solution is cooled to -30° C. and chlorine is passed through for 90 min. The solution is then added rapidly dropwise to a solution of glycine ethyl ester in 160 ml CH2Cl2 prepared as in the preceding example. After stirring for 30 min, the solvent is evaporated in vacuo, the residue is taken up in ethyl acetate and the salts filtered off. The solvent is evaporated, the oily residue is dissolved in 150 ml ethanol, cooled in ice, and 1.26 g NaBH4 is added in portions. After 30 min a few drops of dilute hydrochloric acid are added, the solvent is evaporated, the residue is taken up in ethyl acetate, washed with brine and dried. The solvent is evaporated and the residue chromatographed on silica, eluting with ethyl acetate. The compound is obtained as a white powder, m.p. 53°-4° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)oc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCO[C@@H]1CN(c2nc(C(=O)O)c(C)o2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 50.3 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (112i) (0.2 g, 0.42 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (2 mL) and THF (3 mL), to obtain 90 mg of the title compound as a colorless solid (51%).