Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][C:8]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])=[CH:7][C:6]=1[Br:31].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[Br:31][C:6]1[CH:7]=[C:8]([CH:14]2[C:23]3[C:22](=[O:24])[CH2:21][CH:20]([CH2:25][CH2:26][CH3:27])[CH2:19][C:18]=3[NH:17][C:16]([CH3:28])=[C:15]2[C:29]#[N:30])[CH:9]=[C:10]([O:11][CH2:12][CH3:13])[C:5]=1[O:4][CH2:3][CH2:2][NH:1][S:40]([CH3:39])(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCN)c(OCC)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCNS(C)(=O)=O)c(OCC)c1
Reaction time: 17 h

Procedure:
A mixture of the product of step c (130.7 mg), triethylamine (93 μl) and methanesulfonyl chloride 21 μl in dichloromethane (3 ml) was stirred for 17 h. The mixture was diluted with dichloromethane and washed with 0.5N aqueous HCl. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B). Yield: 57.1 mg. MS-ESI: [M+H]+=566.0/568.0; HPLC: Rt=12.49 min. (method 1). Diast. ratio: 4:1
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[O:6].[NH:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1.[I-].[K+]>CN(C)C=O>[O:27]=[C:19]1[N:18]([CH:15]2[CH2:14][CH2:13][N:12]([CH2:2][CH2:3][NH:4][C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)=[O:6])[CH2:17][CH2:16]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20]1
Reactant: O=C(NCCCl)c1ccco1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6.9 parts of N-(2-chloroethyl)-2-furancarboxamide, 9.8 parts of 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 6.6 parts of potassium iodide and 135 parts of N,N-dimethylformamide is stirred first for 3 hours at reflux and further overnight at room temperature. The reaction mixture is evaporated. The residue is taken up in water and the whole is alkalized. The product is extracted with 4-methyl-2-pentanone. The layers are separated and the aqueous phase is set aside. The organic phase is washed with water, dried, filtered and evaporated. The solid residue is crystallized from 2-propanone. The product is filtered off and dried, yielding a first fraction of 1 part of N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-2-furancarboxamide; mp. 228.9° C. The aqueous phase, which was set aside (see above), is allowed to stand overnight. The precipitated product is filtered off and crystallized from methanol, yielding a second fraction of 4 parts of N-{2-[ 4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-2-furancarboxamide; mp. 231.7° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=O)[C:11](=[O:14])[O:12][CH3:13])[CH3:9])=[CH:4][CH:3]=1.[CH3:26][C:27]([S@@:30]([NH2:32])=[O:31])([CH3:29])[CH3:28]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:15][CH2:16]/[C:17](=[N:32]/[S@:30]([C:27]([CH3:29])([CH3:28])[CH3:26])=[O:31])/[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:11](=[O:14])[O:12][CH3:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: COC(=O)N(CCC(=O)c1ccc(F)cc1)[C@@H](C)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(CC/C(=N/[S@@](=O)C(C)(C)C)c1ccc(F)cc1)[C@@H](C)c1ccc(Br)cc1
Temperature: 70 °C
Yield: 77.6 %

Procedure:
To a solution of (S)-methyl 1-(4-bromophenyl)ethyl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (982 mg, 2 mmol) and (S)-2-methylpropane-2-sulfinamide (265 mg, 2 mmol) in anhydrous THF (20 mL) at rt was added Ti(OEt)4 (1 g, 4 mmol). The reaction mixture was heated at 70° C. for 24 h. After cooling to rt, the reaction mixture was poured into brine with vigorous stirring. The resulting suspension was filtered through a pad of celite and the solid was washed with brine. The combined organic phases were dried, filtered and concentrated to give methyl (1S)-1-(4-bromophenyl)ethyl((Z)-3-((S)-tert-butylsulfinylimino)-3-(4-fluorophenyl)propyl)carbamate (794 mg, 65%). 1H NMR (CD3OD): 1.24 (m, 9H), 1.58 (d, 4H), 1.61 (m, 1H), 2.95 (m, 1H), 3.48 (m, 2H), 3.66 (m, 1H), 3.80 (m, 3H), 4.58 (m, 1H), 3.78 (m, 3H), 5.36 (m, 1H), 7.18 (m, 3H), 7.30 (m, 2H), 7.50 (m, 2H), 7.96 (m, 2H).
Reaction SMILES: [C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH2:9])[CH3:8])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C1C=CC=CC=1>[C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH3:8])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OOC(C)(N)CC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=CC(=O)OOC(C)(CC)NS(C)(=O)=O
Yield: 67.5 %

Procedure:
To a solution of 15.9 g of ethyl-β-amino-β-ethoxy acrylate in 60 ml of benzene was added 10.3 g of triethylamine, and a solution of 11.5 g of methanesulfonyl chloride in 40 ml of benzene was dropped thereinto with stirring. After the dropping, the resulting mixture was stirred at room temperature for 5 hours. The crystals formed were separated. The filtrate was concentrated under reduced pressure and the concentrated residue crystallized by cooling. When the crystals were washed with n-hexane and dried, 16 g of prismatic crystals of a melting point of 103° to 104° C. was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[CH2:35]([OH:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH2:35]([O:42][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: Cc1ccccc1
Product: Brc1ccc(OCc2ccccc2)nc1

Procedure:
A suspension of 2,5-dibromopyridine (2.0 g, 8.4 mmol), dibenzo-18-crown-6 (0.14 g, 0.05 equiv), benzyl alcohol (1.1 mL, 1.3 equiv), and potassium hydroxide (1.1 g, 2.4 equiv) in toluene (30 mL) were heated at reflux for 3 h in an apparatus fitted with a Dean-Stark trap. The suspension was cooled, concentrated, suspended in water, and extracted into methylene chloride. The combined organic phases were washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.9 g (85%) which was used without purification. Mass spec.: 264.25 (MH)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8](=[O:10])[CH3:9].O>CN(C)C=O>[N:1]1([CH:7]([CH2:11][CH2:12][CH2:13][CH3:14])[C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCCCC(Br)C(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(C(C)=O)n1ccnc1

Procedure:
30 g of imidazole was dissolved in 80 ml of N,N-dimethylformamide. To this solution, 30 g of 3-bromo-2-heptanone was gradually added under stirring, and stirred at a temperature of from 50° to 60° C. for 4 hours. Then, the mixture was poured into water and extracted with chloroform. The extraction solution was treated by a usual manner, and the obtained oily product was purified by distillation, whereby 3-(imidazole-1-yl)-2-heptanone was obtained. The boiling point was 116°-119° C./2 mmHg.
Reaction SMILES: FC(F)(F)C(O)=O.C[N:9]([CH:11]=[C:12]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)[C:13]([O:15]CC)=O)C.[CH:23]1([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[C:37]([NH:39]N)[N:36]=[CH:35][N:34]=3)[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24]1>C(OCC)(=O)C>[CH:23]1([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:34]=[CH:35][N:36]=[C:37]([N:39]4[C:13](=[O:15])[C:12]([N:18]5[CH:22]=[CH:21][N:20]=[CH:19]5)=[CH:11][NH:9]4)[CH:38]=3)[CH2:29][CH2:28]2)[CH2:24][CH2:25][CH2:26]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnc1
Reactant: NNc1cc(N2CCN(C3CCC3)CC2)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1c(-n2ccnc2)c[nH]n1-c1cc(N2CCN(C3CCC3)CC2)ncn1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
16 μl (23 mg, 0.2 mmol) of trifluoroacetic acid are added to a mixture of 211 mg (1.0 mmol) of the compound from Example 5A and 250 mg (1.0 mmol) of the compound from Example 9A in 4 ml of ethyl acetate, and the mixture is stirred at 100° C. for 20 h. The reaction mixture is concentrated under reduced pressure, more ethyl acetate and trifluoroacetic acid (the same amounts as above) are added and the mixture is stirred at 100° C. for 20 h. The reaction mixture is cooled to RT, and the precipitated solid is filtered off and washed with diethyl ether. The residue is pre-purified by column chromatography on silica gel (mobile phase dichloromethane/methanol/ammonia 10/2/0.2) and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 137 mg (36% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][CH2:29][CH:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:38](Cl)(=[O:40])[CH3:39]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]([C:38](=[O:40])[CH3:39])[CH2:29][CH:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC(C)c4ccccc4)cc3)cc2)CC1
Reactant: CC(=O)Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(CC(C)c4ccccc4)C(C)=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-(4′-{3-methyl-4-[(2-phenyl-propylamino)-methyl]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester and acetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:5]=1.Cl[Sn]Cl>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Yield: 89.9 %

Procedure:
To a solution of 3-(5-methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester (4 g, 14.7 mmol) in methanol/ethyl acetate was added SnCl2 (11.15 g, 58.8 mmol) at room temperature. The reaction mixture was refluxed for 3 hours and then cooled. Solvent was removed under reduced pressure and the residue was dissolved in H2O and basified by addition of Na2CO3 to pH=9. The mixture was extracted with CH2Cl2, and the organic phase was washed with water, brine, and dried over Na2SO4. The solvent was removed under reduced pressure to give 3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (3.2 g, 90%) as white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl(O)(=O)(=O)=[O:23]>C(OC(=O)CCCCC)(=O)CCCCC>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]([OH:21])[C@H:12]([NH:15][C:16]([CH:18]([Cl:20])[Cl:19])=[O:17])[CH2:13][F:14])=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:11]([O-:21])(=[O:23])[CH2:8][CH2:7][CH2:6][CH2:5][CH3:10]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: CCCCCC(=O)OC(=O)CCCCC
Agent: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: CCCCCC(=O)[O-]
Reaction time: 3 h

Procedure:
100 g of florfenicol was suspended in 500 g of hexanoic anhydride in one liter round bottom flask equipped with an overhead stirrer and a drying tube. To this suspension was added 3 ml of perchloric acid, while stirring vigorously, with a pipette. A clear solution was obtained in a few minutes. Stirring was continued for another 3 hours during which the product, florfenicol hexanoate pro-drug was recrystallized. The solid product was filtered using Buckner funnel under vacuum, washed thoroughly with hexane. The product was finally recrystallized in ethanol and the recrystallized product was washed with hexane and dried to obtain around 117 g of solid florfenicol hexanoate.
Reaction SMILES: [NH2:1][C@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[NH:29][C:30]([C:33](O)=[O:34])=[CH:31][N:32]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:33]([C:30]3[NH:29][C:28]([CH2:27][NH:26][C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[N:32][CH:31]=3)=[O:34])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CC(C)(C)OC(=O)NCc1ncc(C(=O)O)[nH]1
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cnc(CNC(=O)OC(C)(C)C)[nH]1

Procedure:
(R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (108 mg, 0.42 mmol) was coupled with 2-(tert-Butoxycarbonylaminomethyl)-1H-imidazole-5-carboxylic acid (100 mg, 0.42 mmol) using the method of Example 34(d). After extraction a quantitative yield of the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][CH:27]([NH2:31])[CH2:28][O:29][CH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:31][CH:27]([CH3:26])[CH2:28][O:29][CH3:30])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: COCC(C)N
Product: COCC(C)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyisopropylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.80 (1H, br s), 10.80 (1H, br s), 10.05 (1H, br s), 8.18 (0.45H, s), 8.14(0.55H, s), 7.35-7.24 (3H, m), 7.15-7.08 (2H, m), 4.15-4.07 (1H, m), 3.98 (2H, s), 3.40-3.35 (5H, m), 1.15 (0.45H, d, J=6.6 Hz), 1.09 (0.55H, d, J=6.6 Hz); HRMS calcd for C20H20FN3O4+H+: 386.1516. Found 386.1513.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[N:5]=2.[Cl:34][CH2:35][C:36](Cl)=[O:37]>CN(C)C=O.C(OCC)(=O)C>[Cl:34][CH2:35][C:36]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=3)[CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[N:5]=2)=[O:37]
Reactant: O=C(Cl)CCl
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-ethylphenyl}-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.327 mmol) in N,N-dimethylformamide (4.0 mL) was added chloroacetyl chloride (34 μL, 0.425 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-ethylphenyl]-3-(1-cyano-1-methylethyl)benzamide as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:7]=1[O:17][CH:18]([CH3:20])[CH3:19])[CH3:2].[Li][CH2:22]CCC.CI>C1COCC1>[CH2:15]([O:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:7]([O:17][CH:18]([CH3:20])[CH3:19])=[C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])[C:11]=1[CH3:22])[CH3:16]
Reactant: [Li]CCCC
Reactant: CCOCOc1ccc(OC(C)C)c(OCOCC)c1
Solvent: CI
Solvent: C1CCOC1
Product: CCOCOc1ccc(OC(C)C)c(OCOCC)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 78.5 %

Procedure:
A solution of 4c (190 mg, 0.67 mmol) in anhydrous THF (530 μL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 410 μL, 1.00 mmol) in anhydrous THF (440 μL) at room temperature. After one hour, the solution was cooled to −78° C. and methyl iodide (170 μL, 2.67 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 6:1 Hexane:EtOAc) to afford 5c as a yellow oil (157 mg, 79%): 1H NMR (CDCl3, 500 MHz) 6.70 (d, J=9.0 Hz, 1H), 6.61 (d, J=9.0 Hz, 1H), 5.10 (s, 2H), 5.08 (s, 2H), 4.34 (quintet, J=6.1 Hz, 1H), 3.78 (q, J=7.1 Hz, 2H), 3.67 (q, J=7.1 Hz, 2H), 2.13 (s, 3H), 1.23 (d, J=6.1 Hz, 6H), 1.24-1.15 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 150.3, 146.6, 145.3, 122.7, 113.7, 110.1, 97.3, 94.0, 71.5, 65.4, 64.2, 29.4, 22.2, 15.2, 15.2, 9.9; IR (film) νmax 2924, 2853, 2359, 2339, 1591, 1483, 1113, 1057, 974 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C16H26O5, 299.1858; found, 299.1909.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH:15](O)[CH3:16].[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[SH:24].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.O>[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[S:24][CH:15]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[CH:14]2)[CH3:16]
Reactant: CC(O)c1cccc2cc(-c3nccs3)[nH]c12
Reactant: Cn1ccnc1S
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CC(Sc1nccn1C)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of 1-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]ethanol (0.089 g), 1-methyl-1H-imidazole-2-thiol (0.046 g) and tributylphosphine (0.458 g) in tetrahydrofuran (7 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.584 g) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.110 g, yield 89%) as colorless crystals.
Reaction SMILES: [C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=2)[C@@H:15]([C@H:17]2[CH2:22][CH2:21][CH2:20]C[N:18]2C(C2C=CC=CC=2)C2C=CC=CC=2)[OH:16])=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2].N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@@H]1N(C(C2C=CC=CC=2)C2C=CC=CC=2)C[C@@H](O)C1)[OH:61].FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.[Li+].[OH-]>CCO.O>[C:1]([NH:4][C@:5]1([C@@H:54]([CH2:56][CH3:57])[CH3:55])[CH2:9][CH2:8][N:7]([C@@H:10]([CH2:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:11]([NH:13][C@@H:14]([CH2:36][C:37]2[CH:38]=[C:39]([F:44])[CH:40]=[C:41]([F:43])[CH:42]=2)[C@H:15]([OH:16])[C@H:17]2[CH2:22][C@H:21]([OH:61])[CH2:20][NH:18]2)=[O:12])[C:6]1=[O:53])(=[O:3])[CH3:2]
Reactant: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2CCCCN2C(c2ccccc2)c2ccccc2)C1=O
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@H](O)CN1C(c1ccccc1)c1ccccc1
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC[C@@H](C)[C@@]1(NC(C)=O)CCN([C@@H](CCc2ccccc2)C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)[C@H]2C[C@H](O)CN2)C1=O
Temperature: 25 °C
Yield: 84 %

Procedure:
Step 15 (A): (3S,5R)-5-((1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl)-1-benzhydrylpyrrolidin-3-ol. To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4S)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)oxazolidin-2-one (Preparation K, 60 mg, 0.129 mmol) in EtOH (5 mL) was added a solution of LiOH (62 mg, 2.58 mmol) in H2O (1.25 mL). This reaction mixture was stirred at reflux for 4 h. After cooling down to rt, the mixture was concentrated to remove EtOH and H2O was added followed by 1N HCl (8 mL) solution and pH 7 buffer. The mixture was extracted with ethyl acetate and the organic phase was washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo to give the title compound (47.3 mg, 84% yield) as an opaque oil: 1H NMR (CDCl3, 300 MHz) δ 2.32-2.39 (1H, m), 2.49-2.62 (3H, m), 2.79-2.80 (1H, m), 3.18 (1H, d, J=12 Hz), 3.49-3.58 (2H, m), 4.28 (1H, t, J=6 Hz), 4.63 (1H, s), 5.55 (1H, s), 5.96 (4H, brd s), 6.62-6.68 (3H, m), 7.20-7.36 (6H, m), 7.77 (4H, d, J=6 Hz). HPLC retention time: 1.20 min (method A). MS (ESI) (M+H)+ 439.16.
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][O:5][C:3]1=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14](S(C)(=O)=O)[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:1][CH:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][O:5][C:3]2=[O:4])[N:13]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CC1(C)COC(=O)C1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(OC2C(=O)OCC2(C)C)n1
Temperature: 25 °C
Yield: 97 %

Procedure:
13.0 g of 2-hydroxy-3,3-dimethyl-γ-butyrolactone and 24.0 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine were mixed in 80 ml of N,N-dimethylformamide in the presence of 27.6 g of potassium carbonate at a temperature of from 90° to 100° C. for 3 hours. The reaction solution was cooled to room temperature, then, poured into ice water and extracted with ethyl ether. The extract was washed twice with water and dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration and then the filtrate was concentrated to obtain 26.0 g of the desired product.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([N:37]1[CH2:44][CH:43]2[O:45][CH:39]([CH2:40][NH:41][CH2:42]2)[CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:27][N:26]([CH3:28])[C:25]([C:7]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:41]4[CH2:40][CH:39]5[O:45][CH:43]([CH2:44][N:37]([CH2:30][C:31]6[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=6)[CH2:38]5)[CH2:42]4)=[O:22])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CN(Cc6ccccc6)CC(C4)O5)cn3)nc2n1C1CCCC1
Yield: 43.4 %

Procedure:
Following general amide formation method 1, 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (200 mg, 0.507 mmol, 1.0 eq) was combined with 3-benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane (162 mg, 0.558 mmol, 1.1 eq) (Reference: PCT Int. Appl. 2006137769, 2 Dec. 2006) which gave 2-[5-(7-Benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as solid (131 mg) in 39% yield.