Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Brc1ccc(NCc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4-bromoaniline (Aldrich; 1.3 equiv.) in methanol (0.4 M) was treated with 3-pyridinecarboxaldehyde (Aldrich; 1.0 equiv.). The solution was heated to reflux for 2 hours. The reaction was cooled to 0° C. and treated slowly with sodium borohydride (3.4 equiv.). After 1 hour the cooling bath was removed and stirring continued overnight. The reaction was concentrated in vacuo. The residue was partitioned between DCM and water. The aqueous phase was back-extracted once with DCM. The combined organics were washed with water and brine. The organic layer was concentrated to a white solid, which was purified via recrystallization from 1.2:4 ethyl acetate/hexanes to give the title compound. Anal Calcd for C12H11BrN2.0.1H2O: C, 54.40; H, 4.26; N, 10.57. Found: C, 54.30; H, 4.12; N, 10.44. MS found 262.84, 264.83 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[N:4][N:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH2:24])=[N:20]1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[CH2:18][N:19]1[CH:23]=[N:22][C:21]([NH:24][CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)[CH2:8][CH2:9]2)=[N:20]1
Reactant: Nc1ncn(Cc2cccc(Cl)c2)n1
Reactant: Cc1nnc(N2CCC(=O)CC2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nnc(N2CCC(Nc3ncn(Cc4cccc(Cl)c4)n3)CC2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(5-methyl-[1,3,4]oxadiazol-2-yl)-piperidin-4-one (91 mg, 0.5 mmol) and 1-(3-chloro-benzyl)-1H-[1,2,4]triazol-3-ylamine (104 mg, 0.5 mmol) in dry toluene (8 mL) and acetic acid (0.4 mL) was heated under reflux at a Dean-Stark trap for 12 hours. The reaction mixture was cooled to room temperature, ethanol (5 mL) was added, followed by sodium borohydride (19 mg, 0.5 mmol) and stirred at room temperature overnight. The reaction mixture was extracted with water and ethyl acetate, the organic layers were combined, dried over Na2SO4, filtered and the solvents were evaporated. The residue was purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a white solid (91 mg, 49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39].[OH-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:37](=[O:40])[CH2:38][CH3:39])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Reaction time: 8 h
Yield: 39 %

Procedure:
N-(4-Fluorophenyl)-N′-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]malonamide (20.2 mg) was dissolved in N,N-dimethylformamide (0.5 ml), and then triethylamine (0.042 ml) and propionyl chloride (0.013 ml) were added dropwise thereto under a nitrogen atmosphere at room temperature, followed by stirring overnight. To the reaction mixture was added a 1 N aqueous solution of sodium hydroxide (1.5 ml), followed by stirring and extracting with ethyl acetate. The organic layer was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then dried in vacuum to provide the titled compound (9.0 mg, 39%) as pale yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23]>>[CH3:19][O:20][CH2:21][C:22]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:23]
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1nc2c(OC)ccc(N3CCOCC3)c2s1

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and methoxyacetyl chloride the title compound was obtained as a light yellow solid (37%), MS: m/e=338 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)([CH3:17])[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][CH2:8]1.O[Li].O.Cl>O.C1COCC1>[Cl:25][C:20]1[CH:19]=[C:18]([C:4]([CH3:17])([CH2:5][CH2:6][N:7]2[CH2:8][CH2:9][N:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH2:11][CH2:12]2)[C:3]([OH:26])=[O:2])[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: COC(=O)C(C)(CCN1CCN(S(C)(=O)=O)CC1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(CCN1CCN(S(C)(=O)=O)CC1)(C(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.15 g (2.7 mmol) 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-2-methyl-butyric acid methyl ester and 0.171 g (4.08 mmol) LiOH.H2O in 25 mL water and 25 mL THF was stirred at room temperature for 16 h. The mixture was treated with 4N HCl aq. and evaporated to dryness. The residue was used without further purification in the subsequent step. MS(m/e): 409.2 (MH+).
Reaction SMILES: [H-].[Na+].CS(C)=O.[I-].[CH3:8][S+](C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:14]=1>C(OCC)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:8][O:20]2)=[CH:15][CH:14]=1
Reactant: C[S+](C)C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(I)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Clc1ccc(C2(c3ccc(I)cc3)CO2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
Sodium hydride (60% dispersion in oil, 128 mg, 3.2 mmol) was placed under N2 then DMSO (5 mL) was added. Trimethylsulfonium iodide (0.66 g, 3.2 mmol) was added as a solid after 15 min, followed after a further 30 min by (4-chloro-phenyl)-(4-iodo-phenyl)-methanone. The mixture was stirred at room temperature for 24 hours then diluted with ethyl acetate and washed with 1:2 water/brine, water and brine (×2). The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (1.01 g, 97%), which was used without further purification. LCMS (PS-A2) Rt 4.07 min [M−H]+ 355.
Reaction SMILES: [SH3+].S1CCCC1.[C:7]([C:10]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[CH:11]=1)(=[O:9])[CH3:8].[Br:24]Br>C(Cl)Cl.C(OCC)C>[Br:24][CH2:8][C:7]([C:10]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[CH:11]=1)=[O:9]
Reactant: BrBr
Reactant: CC(=O)c1ccc2c(ccc3ccccc32)c1
Agent: [SH3+]
Solvent: C1CCSC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CBr)c1ccc2c(ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Preparation of a sulfonium salt according to Formula 3 wherein X- is CF3SO3- and R1, R2, and S combined are tetrahydrothiophene is as follows. To a stirred solution of 5 grams (22.6 mM) of 2-acetylphenanthrene in a mixture of 30 ml of methylene chloride and 30 ml of diethyl ether cooled in an ice/acetone bath was added 3.5 grains (22 mM) of bromine dropwise over 15 minutes. The red bromine color was immediately discharged upon addition to the stirred solution. The cooling bath was removed and the stirred mixture warmed to room temperature over 30 minutes, then the mixture was stirred at room temperature for 2 hours. The reaction mixture was stripped of solvent on a rotary evaporator, then was suspended in 50 ml diethyl ether and evaporated to dryness. This process was repeated twice more to remove the byproduct hydrogen bromide from the solid product. The residual solid was triturated with 15 ml cold diethyl ether, filtered, and dried in a vacuum oven to yield 4.35 grams of 2-(bromoacetyl)-phenanthrene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH:16]=O.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].CC(O)=O.C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:11])[CH2:7][CH2:8][CH2:9][NH:10][CH2:16][CH:15]([O:18][CH3:19])[O:14][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C=O)OC
Reactant: CC(C)(C)OC(=O)CCCN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COC(CNCCCC(=O)OC(C)(C)C)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution (0° C.) of 2.94 g (15.00 mmol) of 4-aminobutyric acid ter-butylester; hydrochloride in 75 ml of MeOH were added 2.51 ml (18.00 mmol) of dimethoxyacetaldehyde (45% solution in TBME), 3.86 ml (15.00 mmol) of triethylamine, 16.75 g (135.00 mmol) of magnesium sulfate, 3.43 ml (60.00 mmol) of AcOH and 1.29 g (19.50 mmol) of sodium cyanoborohydride (1.99 g, 31.6 mmol). The reaction was stirred 2 h at RT, another 0.39 ml (1.50 mmol) of dimethoxyacetaldehyde (45% solution in TBME) was added and after 1.5 h, the reaction mixture was partitioned between aqueous saturated NaHCO3 and EtOAc/Et2O (1:1) (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield after evaporation of the solvent 1.87 g (50%) of the titled compound as light yellow oil. MS: 248.18 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].CCOCC.C([O:19][N:20]1[C:24]2[CH:25]=[C:26]([C:29]([NH:31][C@H:32]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]4[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=4)=[CH:42][CH:41]=3)[CH2:33][C@@H:34]([OH:38])[C:35]([OH:37])=[O:36])=[O:30])[CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1)C1C=CC=CC=1.CC(C)=O.C1COCC1>[Pd].CC(O)=O>[C:1]([O:4][CH2:5][O:37][C:35](=[O:36])[C@H:34]([OH:38])[CH2:33][C@H:32]([NH:31][C:29]([C:26]1[CH:27]=[CH:28][C:23]2[N:22]=[N:21][N:20]([OH:19])[C:24]=2[CH:25]=1)=[O:30])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=2)=[CH:42][CH:41]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCBr
Reactant: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O)c1ccc2nnn(OCc3ccccc3)c2c1
Agent: [Pd]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)OCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
Bromomethyl acetate (6.7 μL, 68.3 μmol) and Et2O (11.7 μL, 84 μmol) were added to a solution of (2R,4R)-4-[(3-benzyloxy-3H-benzotriazole-5-carbonyl)amino]-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid (30.0 mg, 52.5 μmol) in acetone (1.0 mL, 13.6 mmol) and the resulting mixture was stirred at 45° C. for 1 hour. A drop of AcOH was added to neutralize the reaction and the mixture was concentrated to yield a clear yellow liquid. The crude liquid was purified (C18 column chromatography, 55 g column, using 40-90% MeCN in water with 0.05% TFA) to yield a white solid. The solid was dissolved in THF (1.0 mL, 12.3 mmol) and 10% Pd/C, 50% wet (0.45 mmol/g loading; 5.8 mg, 2.6 μmol) was added to the solution, which was stirred under hydrogen for 1 hour. The mixture was filtered and the filtrate was concentrated to yield a clear colorless liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (10.0 mg, purity 99%). MS m/z [M+H]+ calc'd for C27H25ClN4O7, 553.14. found 553.1.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([O:21][C@@H:22]2[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]2[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:10][N:11](C(OCC)=O)[C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:1]([C:8]1[C:9]([O:21][C@@H:22]2[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:53])([CH3:55])[CH3:54])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:37])[CH3:36])[C@H:23]2[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:27])[CH3:28])=[N:10][NH:11][C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c1Cc1ccccc1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a solution of 4-benzyl-1-ethoxycarbonyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole (0.15 g) in methanol (3 mL) was added sodium bicarbonate (0.032 g) under stirring at room temperature. The mixture was stirred at room temperature for 12 hours. In addition, to the mixture was added potassium carbonate (0.053 g), and the mixture was stirred for 2 hours. The reaction mixture was poured into water to precipitate the solid. The solids were collected by filtration. The obtained solids were washed with water and dried under reduced pressure to give 4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.098 g).
Reaction SMILES: C=O.[NH2:3][C:4]1[N:5]=[C:6]([NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[S:7][C:8]=1[C:9]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[F:20])=[O:10].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(C(C)C)CC)(C)C>>[NH2:3][C:4]1[N:5]=[C:6]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:24][CH2:23]2)[S:7][C:8]=1[C:9]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[F:20])=[O:10]
Reactant: COc1ccc(F)c(F)c1C(=O)c1sc(NC2CCNCC2)nc1N
Reactant: CS(=O)(=O)Cl
Agent: C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)c(F)c1C(=O)c1sc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Yield: 90 %

Procedure:
[4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(2,3-difluoro-6-methoxy-phenyl)methanone methanone (0.05 g, 0.14 mmol) (Example 8) was treated with methanesulfonyl chloride in a manner similar to Example 9 except that diisopropylethyl amine was additionally used as a catalyst to give 50 mg (90% yield) of [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)thiazol-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone. 1H NMR (DMSO−d6, 300 MHz) δ1.57 (m, 2H, CH2), 1.92 (m, 2H, CH2), 2.85 (m, 5H, SCH3 & NCH2), 3.53 (m, 2H, NCH2), 3.6-4.0 (broad,1H, CH), 3.88(s, 3H, OCH3), 6.72 (m,1H, Aromatic), 7.42 (m,1H, Aromatic), 7.6 (2× brd, 1H, NH), 7.8 (brd, 1H, NH), 7.99 (m, 1H, Aromatic), 9.0 (brd, 1H, NH). LR/LC/MS: (M+H): compatible with 446. Ki CDK1=0.001 μM; Ki CDK2=0.001 μM; Ki CDK4=0.002 μM.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](=[O:24])[CH2:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][C:15]=2[CH3:23])[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH2:40][CH2:39][CH2:38]2>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11](=[O:24])[CH2:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:41]3[C:42]4[C:37](=[CH:36][C:35]([CH3:34])=[CH:44][CH:43]=4)[CH2:38][CH2:39][CH2:40]3)=[O:19])=[CH:16][C:15]=2[CH3:23])[CH2:9][CH2:10]1
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCN(CCC(C)(C)C)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(c1)CCCN2C(=O)c1ccc(CCC(=O)N2CCN(CCC(C)(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 6 %

Procedure:
DMAP (51 mg, 0.42 mmol) and WSCD (161 mg, 0.84 mmol) were added to a solution of 4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid from Example E44 (150 mg, 0.42 mmol) in dichloromethane (10 ml) and triethylamine (0.176 ml, 1.26 mmol) and the mixture was stirred for 30 min at room temperature. 6-Methyl-1,2,3,4-tetrahydro-quinoline (67 mg, 0.46 mmol) was added and the mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was redissolved in EtOAC, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (12 mg, 6%).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([OH:16])[S:14][CH:15]=1)[C:6]([O:8]CC)=[O:7])[CH3:2].C(O)C.[OH-].[K+].Cl>O>[CH2:1]([O:3][N:4]=[C:5]([C:11]1[N:12]=[C:13]([OH:16])[S:14][CH:15]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)OCC)c1csc(O)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCON=C(C(=O)O)c1csc(O)n1

Procedure:
To a solution of 10 g. of ethyl α-ethoxyimino-(2-hydroxythiazol-4-yl)acetate in 30 ml. of ethanol is added a solution of 11.47 g. of KOH in 50 ml. of water at room temperature and the mixture is stirred for 25 minutes. The reaction mixture is condensed under reduced pressure and is made acidic with 10% aq. HCl. Ethyl acetate extract of the reaction mixure is extracted with 10% aq.NaHCO3. The aqueous layer is then made acidic with 10% aq.HCl and extracted again with ethyl acetate. From the ethyl acetate extract, after being washed, dried and condensed is obtained a crystalline substance. Recrystallization from benzene-ethanol gives α-ethoxyimino-(2-hydroxythiazol-4-yl)acetic acid. 7.5 g.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]=1>[Pd].C(O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncc[nH]2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ncc[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Palladium on carbon (10 wt %, 0.100 g) was added to a solution tert-butyl 4-(1H-imidazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.300 g, 1.20 mmol) in ethanol (20 mL), and the mixture stirred under a hydrogen atmosphere at room temperature for 2 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to afford tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (0.300 g, 99%) as an off-white solid. MS (ESI, pos. ion) m/z 252 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1N2CN3CN(C2)CN1C3.O.FC(F)(F)[C:24](O)=[O:25]>>[OH:10][C:9]1[CH:8]=[C:7]([CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[OH:1])[CH:24]=[O:25]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1cccc(O)c1O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: N#Cc1cc(C=O)cc(O)c1O

Procedure:
A solution containing 1.35 g of 2,3-dihydroxybenzonitrile and 1.4 g of hexamethylene tetramine in 20 ml of trifluoroacetic acid was refluxed for 1.5 h. Water was added and the product was filtered. Yield 0.9 g (55%), m.p. 211°-215° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][Cl:10].[CH2:11]([O:18][C:19]1([OH:54])[CH2:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([OH:33])[C:30]([C:42]([N:44]2[CH2:52][C:51]3[C:46](=[CH:47][CH:48]=[C:49]([OH:53])[CH:50]=3)[CH2:45]2)=[O:43])=[CH:29][CH:20]1[C:21]([N:23]([CH2:25][CH2:26][CH2:27][CH3:28])[CH3:24])=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[CH2:11]([O:18][C:19]1([OH:54])[CH2:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([OH:33])[C:30]([C:42]([N:44]2[CH2:52][C:51]3[C:46](=[CH:47][CH:48]=[C:49]([O:53][CH2:8][CH2:9][Cl:10])[CH:50]=3)[CH2:45]2)=[O:43])=[CH:29][CH:20]1[C:21]([N:23]([CH2:25][CH2:26][CH2:27][CH3:28])[CH3:24])=[O:22])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClCCBr
Reactant: CCCCN(C)C(=O)C1C=C(C(=O)N2Cc3ccc(O)cc3C2)C(O)(OCc2ccccc2)CC1(O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(C)C(=O)C1C=C(C(=O)N2Cc3ccc(OCCCl)cc3C2)C(O)(OCc2ccccc2)CC1(O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
235 mg (1.7 mmol) of potassium carbonate and 580 μl (7 mmol) of 1-bromo-2-chloroethane are added to a solution of 400 mg (0.708 mmol) of 2,4-bisbenzyloxy-N-butyl-2,4-dihydroxy-5-(5-hydroxy-1,3-dihydroisoindole-2-carbonyl)-N-methylbenzamide in 3 ml of acetonitrile. The suspension is stirred for 16 h at 80° C., cooled to 22° C. and filtered. The residue is washed with acetonitrile, and the combined filtrates are evaporated to dryness in vacuo: 408 mg (92%) of 2,4-bisbenzyloxy-N-butyl-5-[5-(2-chloroethoxy)-1,3-dihydroisoindole-2-carbonyl]-2,4-dihydroxy-N-methylbenzamide (“A10a”), MW 627.2; Rt 2.371 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.ClC1C=CC(C(C2N(C)C=NC=2)=O)=CN=1.FC1N=CC(C(Cl)=O)=CC=1.FC1N=CC([C:43]([N:45]([O:47][CH3:48])C)=O)=CC=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:45]([O:47][CH3:48])[CH3:43])=[O:9])=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1ccc(F)nc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cn1cncc1C(=O)c1ccc(Cl)nc1
Agent: O=C(Cl)c1ccc(F)nc1
Product: CON(C)C(=O)c1ccc(Cl)nc1

Procedure:
The title compound was prepared using 6-chloropyridine-3-carbonyl chloride (Intermediate 22, step a) in place of 6-fluoropyridine-3-carbonyl chloride according to the procedure described for Intermediate 21, step b.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[C:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[C:9]([C:19]([OH:21])=O)[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([F:18])[CH:13]=1)#[N:6].C1(C)C=CC=CC=1.C(Cl)Cl.Cl.[CH3:41][NH:42][O:43][CH3:44]>>[C:5]([C:7]1[C:8]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[C:9]([C:19]([N:42]([O:43][CH3:44])[CH3:41])=[O:21])[S:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([F:18])[CH:13]=1)#[N:6]
Reactant: CNOC
Reactant: N#Cc1c(-c2ccnc(F)c2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
Thionyl chloride (6.2 mL, 85 mmol) was added to a mixture of 4-cyano-3-(2,4-dichlorophenyl)-5-(2-fluoropyridin-4-yl)thiophene-2-carboxylic acid (2.94 g, 7.48 mmol) in Toluene (22 mL, 210 mmol) and the mixture was heated at 90° C. for 1 h. The reaction mixture was evaporated and the residue was coevaporated with toluene twice to thick oil. This oil in DCM (20 g, 200 mmol) was added to a mixture of N,O-Dimethylhydroxylamine Hydrochloride (2.92 g, 29.9 mmol) and TEA (7.0 mL, 5.0E1 mmol) in DCM (100 mL, 2000 mmol) in a ice bath. After 2 h, the mixture was washed by water and brine. The DCM layer was collected and dried and evaporated in vacuum to afford crude intermediate, which was purified by column chromatography to afford the title compound (2.41 g, 73.9%). LCMS: (FA) ES+, 436, 438. 1H NMR (400 MHz, d1-chloroform) δ: 8.41 (1H, d, J=5.26 Hz), 7.72-7.63 (1H, m), 7.54 (1H, d, J=1.96 Hz), 7.39 (2H, dd, J=7.70, 1.99 Hz), 7.29 (1H, d, J=8.26 Hz), 3.76 (3H, s), 3.27 (3H, s)