Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=2[CH:10]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].O>CN(C)C=O>[C:20]1(=[O:30])[N:24]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[O:7][C:8]3[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=3[CH:10]=2)[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCOC(=O)c1ccc2cc(CCCCBr)oc2c1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(CCCCN3C(=O)c4ccccc4C3=O)oc2c1

Procedure:
A solution of ethyl 2-(4-bromobutyl)benzofuran-6-carboxylate (3.25 g., 0.01 mole) and potassium phthalimide (2.04 g., 0.011 mole) in dimethylformamide (25 ml.) is stirred at 25°-27° C. for 18 hours. The solution is poured into water. The precipitated ethyl 2-(4-phthalimidobutyl)benzofuran-6-carboxylate is collected by filtration.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H].ClCCl>[Pd].C(OCC)(=O)C.C(O)(=O)C>[NH2:15][C:13]1[CH:14]=[C:9]([C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH:10]=[C:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:12]=1
Reactant: O=C(c1cc(-c2ccccc2)cc([N+](=O)[O-])c1)N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)N2CCOCC2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Palladium on carbon (10 wt %, 67.5 mg, 0.063 mmol) was added to a solution of morpholin-4-yl(5-nitrobiphenyl-3-yl)methanone (198 mg, 0.634 mmol) in ethyl acetate (5.7 mL) and acetic acid (0.57 mL). The mixture was fitted with a hydrogen balloon and stirred for 3 hours at room temperature. Dichloromethane was added, and the mixture was filtered through CELITE, rinsed with dichloromethane rinse and washed with saturated aqueous NaHCO3 (30 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide (5-aminobiphenyl-3-yl)(morpholin-4-yl)methanone as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.61-7.51 (m, 2H), 7.44 (t, J=7.4 Hz, 2H), 7.37 (dd, J=8.4, 6.2 Hz, 1H), 6.97 (s, 1H), 6.96-6.91 (m, 1H), 6.75-6.63 (m, 1H), 3.89 (s, 2H), 3.85-3.37 (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([NH:23][C:24](=[O:26])[CH3:25])([C:18]([O:20]CC)=[O:19])[CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:2].[OH-].[K+]>C(O)C.O>[C:24]([NH:23][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:27])([CH2:6][C:7]#[C:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[C:18]([OH:20])=[O:19])(=[O:26])[CH3:25]
Reactant: CCOC(=O)C(CC#CCNC(=O)OC(C)(C)C)(NC(C)=O)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(CC#CCNC(=O)OC(C)(C)C)(NC(C)=O)C(=O)O
Yield: 90 %

Procedure:
Ex-8e) Following the procedure described in Tetrahedron Lett Vol.21, 4263, (1980) partial saponification of 10.2 g of ethyl-2-acetylamino-6-t-butyloxycarbonylamino-2-ethoxycarbonyl-4-hexynoate is carried out in ethanol with 1.5 equivalent of KOH in water at 20-25° C. for 3 h to give 2-Acetylamino-6-t-butyloxycarbonylamino-2-ethoxycarbonyl-4-hexynoic acid in 90% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)C>[C:25]1([NH:31][C:32]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][C:11]4[C:20]5[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=5)[N:14]=[CH:13][CH:12]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Solvent: CCOCC
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(=O)Nc4ccccc4)c3)c2cc1OC
Yield: 32.1 %

Procedure:
4-(1H-Indol-5-yloxy)-6,7-dimethoxyquinoline (25 mg, 0.0780 mmol) and phenyl isocyanate (0.013 ml, 0.117 mmol) were used for reaction in the same manner as Example 330, the obtained crystals were suspended in diethyl ether:ethanol=10:1, and then the crystals were filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (11 mg, 0.0250 mmol, 32.09%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH3:12][O:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])=[O:15]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:14]([O:13][CH3:12])=[O:15])(=[O:24])=[O:23])=[O:27])[N:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nc(OC)n1
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)nc(OC)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine, 25 ml of anhydrous methylene chloride and 2.4 g of 2-methoxycarbonylbenzenesulfonylisocyanate was stirred at ambient temperature for 16 hours. It was then filtered to remove unreacted amine and the filtrate evaporated at temperatures up to 40° under reduced pressure. The residue was triturated with butyl chloride and filtered to yield the desired compound which melted above 170° with decomposition.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][NH:17][C:18](=[O:32])[N:19]3[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)C>Cl.C(O)C>[CH2:25]([N:19]1[C:20]2[C:15](=[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:23]([F:24])=[CH:22][CH:21]=2)[CH2:16][NH:17][C:18]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc3c2CNC(=O)N3Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: O=C1NCc2c(ccc(F)c2N2CCNCC2)N1Cc1ccccc1
Temperature: 80 °C

Procedure:
4-(1-Benzyl-6-fluoro-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester (141 mg) was dissolved in 4 mL 2 N HCl/ethanol and heated to 80° C. for 20 minutes, then cooled to room temperature. Diethyl ether was added, precipitating 115 mg: of 1-benzyl-6-fluoro-5-piperazin-1-yl-3,4dihydro-1H-quinazolin-2-one hydrochloride. MP: 285.6-290.0° C. MS: 341 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N+:7]([O-:8])=[C:6]([CH2:9][C:10]([O:12]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:5]([C:22]#[N:23])=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:42])[NH:30][C:31]1[C:35]2[CH:36]=[C:37]([CH2:40][NH2:41])[CH:38]=[CH:39][C:34]=2[O:33][N:32]=1)([CH3:27])([CH3:26])[CH3:25].CO>CCOC(C)=O.CCCCCC>[C:22]([C:5]1[C:6]([CH2:9][C:10]([NH:41][CH2:40][C:37]2[CH:38]=[CH:39][C:34]3[O:33][N:32]=[C:31]([NH:30][C:29]([O:28][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:42])[C:35]=3[CH:36]=2)=[O:12])=[N+:7]([O-:8])[C:2]([Cl:1])=[CH:3][CH:4]=1)#[N:23]
Reactant: N#Cc1ccc(Cl)[n+]([O-])c1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)Nc1noc2ccc(CN)cc12
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nc1noc2ccc(CNC(=O)Cc3c(C#N)ccc(Cl)[n+]3[O-])cc12
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-3-cyano-2-(4-nitro-phenoxycarbonylmethyl)-pyridine 1-oxide (83.6 mg, 0.25 mmol), as prepared in Example 6f, and (5-aminomethyl-benzo[d]isoxazol-3-yl)-carbamic acid tert-butyl ester (78.8 mg, 0.3 mmol) in CDCl3 (3 mL) was stirred in an ice-water bath which was allowed to rise to rt overnight. A lot of precipitate formed. TLC showed the disappearance of 6-chloro-3-cyano-2-(4-nitro-phenoxycarbonylmethyl)-pyridine 1-oxide. A small amount of methanol was added to dissolve the solid. The solution was applied onto a prep TLC (2 mm, 20×20 cm) and developed with EtOAc/Hexane (4:1). A white solid was obtained (103 mg). LC/MS (ESI) (M+H+ 458.1)
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)[CH3:12]>C(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[NH:3]1[CH:7]=[C:6]([CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[CH3:12])[N:5]=[CH:4]1
Reactant: CC(Br)c1cccc2cccnc12
Reactant: C[Si](C)(C)n1ccnc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(c1c[nH]cn1)c1cccc2cccnc12
Temperature: 0 °C
Yield: 48 %

Procedure:
Titanium tetrachloride (3.28 ml, 29.9 mmol) was added to anhydrous chloroform (25 mL) at 0° C. 1-Trimethylsilanyl-1H-imidazole (4.38 ml, 29.9 mmol) in chloroform (25 ml) was added slowly (6 to 7 m) to the TiCl4 solution. The resulting orange solid mixture was stirred at 0° C. for 30 m followed by the addition of (13) (3.53 g, 15.0 mmol) in chloroform (15 mL). The mixture was warmed to room temperature and stirred overnight. The mixture was quenched with water (60 mL). The two layers were separated and the organic layer was extracted twice with water (40 mL). The pooled aqueous layer was neutralized with 4 M NaOH to pH>8. The basic aqueous layer was to extracted with dichloromethane numerous times. The pooled organic layers were washed with brine once, and dried over magnesium sulfate. The mixture was filtered, and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 2 to 5% saturated ammonia methanol in dichloromethane to give 8-(1-(1H-imidazol-4-yl)ethyl)quinoline (14) as an off white solid (1.61 g, 7.22 mmol, 48% yield.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24](O)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[N:30]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][O:22][CH3:23])=[C:19]([C:24]([N:33]4[CH2:34][CH2:35][CH2:36][N:30]([CH2:37][CH2:38][OH:39])[CH2:31][CH2:32]4)=[O:25])[C:18]([CH2:27][O:28][CH3:29])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: OCCN1CCCNCC1
Reactant: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)O
Product: COCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(COC)c1C(=O)N1CCCN(CCO)CC1

Procedure:
In analogy to the procedure described for example 1, 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-bis-methoxymethyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 2-[1,4]diazepan-1-yl-ethanol gave the title compound as brown oil. MS: 539.3 (MH+, 1 Cl).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[CH:24]=[N:23][C:22]([CH2:25]Br)=[CH:21][N:20]=1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[CH:24]=[N:23][C:22]([CH2:25][NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:21][N:20]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: NC1CCC1
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(CNC2CCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
In a dried 100 mL round bottom flask was added cyclobutylamine (740 mg, 889 μl, 10.4 mmol, Eq: 3), K2CO3 (480 mg, 3.47 mmol, Eq: 1.00) and THF at rt. under argon. To the mixture was added a solution of (5-Bromomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (1 g, 3.47 mmol, Eq: 1.00) in THF dropwise. The resulting reaction mixture was stirred vigorously at room temperature under argon overnight. The reaction was concentrated, diluted with water/DCM and extracted with DCM (2×30 mL). Combined organic extracts were concentrated to give a solid. The crude product was purified by LC chromatography (50 g spherical silica column) eluting with 5 to 10% MeOH in 1/1 EtOAc/Hex to afford 348 mg (36%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10](N)[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[CH:5]=[CH:4][N:3]=1.B(Br)(Br)Br.C(Cl)Cl.C([O-])(O)=[O:26].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:26])[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(-c2cc(N)cc([N+](=O)[O-])c2)ccn1
Reactant: O=C([O-])O
Agent: BrB(Br)Br
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-c2cc(O)cc([N+](=O)[O-])c2)ccn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
To 0° C. flask charged with 65.B (2.85 g, 11.7 mmol) was added a solution of BBr3/CH2Cl2 (1.0 M, 25 mL). The solution was allowed to warm to rt and stirred for 45 mins. The resulting mixture was treated with MeOH (7 mL), neutralized with solid NaHCO3 to PH=7 and concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel using 0-10% of MeOH/CH2Cl2 for elution gave the title product 65.C as solid (1.83 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[C:3]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[N:4][CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncc(CO)cc2Cl)C1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncc(C=O)cc2Cl)C1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 91.3 %

Procedure:
A mixture of tert-butyl (3R)-3-{[3-chloro-5-(hydroxymethyl)-2-pyridinyl]amino}-1-piperidinecarboxylate (10.0 g) and MnO2 (25.4 g) in CHCl3 (200 ml) was stirred at 60° C. for 3.5 hours. After removal of the insoluble material, and the solvent was evaporated in vacuo to give tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-piperidinecarboxylate (9.08 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Si:11]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Yield: 99.4 %

Procedure:
A solution of 3.52 g of 6-hydroxyindole, 4.78 g of tert-butyldimethylsilyl chloride, and 4.5 g of imidazole in 16 ml of dimethylformamide is stirred at ambient temperature overnight. The reaction medium is diluted with ethyl acetate and the organic phase is then washed with 2 times 50 ml of distilled water. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off in a rotary evaporator to obtain 6.5 g of 6-(tert-butyl-dimethylsilanyloxy)-1H-indole.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][C@@H:11]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH2:20][C:21]([OH:23])=O)=[O:18])=[O:14])[CH3:12])=[O:9])[CH3:7])=[O:4].Cl.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C.O>[NH:1]1[C:21](=[O:23])[CH2:20][NH:19][C:17](=[O:18])[CH2:16][NH:15][C:13](=[O:14])[C@@H:11]([CH3:12])[NH:10][C:8](=[O:9])[C@H:6]([CH3:7])[NH:5][C:3](=[O:4])[CH2:2]1
Reactant: C[C@H](NC(=O)CN)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1NC(=O)CNC(=O)CNC(=O)CNC(=O)[C@@H](C)NC1=O
Temperature: -25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
This compound was synthesized by the method of Veber, D. F. et al, J. Org. Chem., 44, 3101-5 (1979). To a solution of Gly-Ala-DAla-Gly-Gly.circle-solid.HCl prepared as in Example 33D (12.9 g, 35.0 mmol) in anhydrous DMF (4400 ml) was added enough TEA to adjust the pH to ~8 (measured by spotting the reaction mixture on moistened Hydrion paper) and the resulting mixture was cooled to -25° C. To this mixture was added DPPA (9.20 ml, 43.0 mmol) dropwise over 5 min. The reaction was stored at -25° C. (internal temperature) for 48 h thereafter. During this time the pH was monitored periodically (as described above) and maintained at ~8 by the addition of TEA. After this time the reaction mixture was allowed to stand at 0° C. for 48 h. Again the pH was monitored periodically and maintained at ~8 by the addition of TEA. After this time the reaction mixture was diluted with water (4400 ml) and stirred with Bio-Rad AG 501-X8 (mixed-bed) resin (200 g) for 6 h. The resin was separated by filtration and the solution was concentrated to dryness. Trituration of the residue with refluxing THF (250 ml) for 3 h, filtration of the hot THF and drying at high vacuum afforded 6.61 g (60% yield) of the product as a white powder: 1H NMR (DMSO-d6) δ 1.15-1.32 (m, 6H), 3.45-4.00 (m, 6H), 4.10-4.38 (m, 2H), 7.81 (d, J=7.8 Hz, 1H), 7.97 (t, J=6.6 Hz, 1H), 8.10 (m, 2H), 8.18 (d, J=7.5 Hz, 1H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][N:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=34)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[N:18]=[CH:19][N:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=34)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3ncn4cc(F)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3ncn4cc(F)ccc34)nc12
Yield: 92.4 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-fluoroimidazo[1,5-a]pyridin-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (95 mg, 197 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (449 mg, 303 μL, 3.94 mmol) at room temperature. After 16 h the reaction was concentrated. The residue was dissolved in dichloromethane (3 mL), methanol (1.5 mL) and ammonium hydroxide (0.45 mL). After 1 h the reaction was concentrated. The residue was triturated with water and filtered. The solid was washed water and ether then dried under vacuum to give N-tert-butyl-2-(6-fluoroimidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (64 mg, 182 μmol, 92%) as a yellow solid. MS: (M+H)+=353; 1H NMR (CD3OD) δ: 9.10 (s, 1H), 8.48 (d, J=5.1 Hz, 1H), 8.45 (s, 1H), 8.42 (m, 1H), 8.25 (s, 1H), 7.03 (m, 1H), 1.62 (s, 9H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][C:6]1([CH2:19][O:20][CH3:21])[CH2:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1>O1CCOCC1>[F:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][C:6]1([CH2:19][O:20][CH3:21])[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: COCC1(Cc2ccccc2F)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: COCC1(Cc2ccccc2F)CCCNC1
Reaction time: 4 h

Procedure:
Hydrochloric acid in dioxane (1.5 mL, 4M) was added to a flask containing tert-butyl 3-(2-fluorobenzyl)-3-(methoxymethyl)piperidine-1-carboxylate (0.415 g, 1.23 mmol). 1,4-dioxane (1.5 mL) was added to the reaction mixture. The reaction was allowed to stir for 4 hours. Upon reaction completion, the reaction was concentrated, and 337 mg of crude product was recovered and progressed to the next step without further purification.
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[C:6]1[CH:11]=[CH:10][CH:9]=C[C:7]=1[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:15]=1.[CH3:39][C:40]([OH:42])=[O:41].C(Cl)Cl>CCCCCCC.CCOC(C)=O.[Zn]>[F:29][C:27]([F:28])([F:30])[C:24]1[CH:23]=[CH:22][C:21]([CH:20]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:16]2[C:15]([CH2:14][S:13][C:12]3[CH:7]=[CH:6][CH:11]=[CH:10][CH:9]=3)=[C:39]([CH:19]=[CH:18][CH:17]=2)[C:40]([OH:42])=[O:41])=[CH:26][CH:25]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)C(c1ccc(C(F)(F)F)cc1)c1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCOC(=O)C(c1ccc(C(F)(F)F)cc1)c1cccc(C(=O)O)c1CSc1ccccc1
Yield: 77 %

Procedure:
The titled compound was prepared according to the method described for example 1 above from 2-{3-[1-(4-Trifluoromethyl-phenyl)-ethoxycarbonylmethyl]phenylsulfanylmethyl}-benzoic acid 2,2,2-trichloro-ethyl ester (157 mg, 0.0.259 mmol), zinc (339 mg, 5.18 mmol), HOAc, 97% (1.48 mL, 25.9 mmol) and DCM (12 mL). The crude was submitted to flash chromatography using heptane and EtOAc (70/30-60/40) as eluent to give the titled compound (94 mg, 77%) as an oil; 1H NMR (400 MHz, CDCl3): δ 1.53 (s, 3H), 3.60 (dd, 2H), 4.54 (dd, 2H), 5.91 (m, 1H), 7.07-7.12 (m, 1H), 7.15-7.20 (m, 2H), 7.21-7.32 (m, 3H), 7.35-7.42 (m, 3H), 7.58 (d, 2H), 7.98 (d, 1H); Mass spectrum: M−H+ 473.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)(=O)C>[C:22]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH2:13][CH2:14][C:15](=[O:21])[NH:16]3)[CH2:2][CH2:3]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1
Solvent: CC(=O)O
Product: CC(=O)N1CCN(CCCOc2cccc3c2CCC(=O)N3)CC1

Procedure:
20 grams of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril are mixed with 15 ml of acetic anhydride and 10 ml of acetic acid and heated for 5 hours under refluxing conditions. The reaction mixture is concentrated under reduced pressure to dryness. The residue is recrystallized from Ethanol to obtain 5-[3-(4-acetylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 143°-145° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][C:33]=1[C:41]([F:44])([F:43])[F:42]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([Cl:31])=[C:33]([C:41]([F:44])([F:42])[F:43])[CH:34]=2)[CH:25]=1
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3ccc(Cl)c(C(F)(F)F)c3)c2)c1

Procedure:
In a manner similar to that described in Example 25, methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate and 4-chloro-3-(trifluoromethyl)benzoic acid were coupled to give the title compound as a white solid (74 mg).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[C:9]1([CH2:18][CH2:19][OH:20])[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=1.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[C:1]([Si:5]([CH3:8])([CH3:7])[O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:18][CH2:19][OH:20])=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccc(CCO)cc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CCO)cc1
Reaction time: 0.75 h

Procedure:
tert-Butyldimethylchlorosilane (9.68 mL) was added to a solution of 2,2′-(1,4-phenylene)diethanol (example 5, step a) (8.64 g) and imidazole (10.21 g) in dry DMF (100 mL) cooled in an ice bath. After 45 min, the reaction mixture was diluted with ethyl acetate, washed three times with water and evaporated in vacuo. Purification was by silica gel chromatography, eluting with 5:1 isohexane:ethyl acetate to give the subtitled compound as a colourless oil. Yield 6.20 g.