Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:10])=[O:9].Cl>CO>[Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cccc3ccccc23)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2c(Cc3cccc4ccccc34)sc3ncccc23)c1Cl
Yield: 63.8 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-(naphthylmethyl)thieno[2,3-b]pyridine-3-sulfonamide (58 mg, 0.10 mmoles), methanol (2 ml) and 4N HCl (2 ml). Recrystallization from EtOAc/hexanes provided 30 mg (61%) of the title compound as a yellow crystalline solid, m.p. 165-168° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[CH:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(CCN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [trans-2-phenylcyclopropyl]amine (668 mg, 5.02 mmol), 1,1-dimethylethyl 4-(2-oxoethyl)-1-piperidinecarboxylate (1.04 g, 4.58 mmol) and AcOH (1 μL, 0.017 mmol) in chloroform (5 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (1.03 g, 4.86 mmol) was added and stirring continued for 18 hours. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with THF—CHCl3 (2×50 mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 12 g column) to yield the desired product. This product was further purified via reverse phase column chromatography on Gilson ((C18 column: 0.1% Formic acid H2O/CH3CN, 95-5%) affording the title compound (222 mg, 13% yield) as a yellow oil: LC-MS (ES) m/z=345 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=O.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][CH2:22][C:23]([CH3:25])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:25][C:23]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]2=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:22]=1[CH2:21][C:20]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CCC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1cccc(Cl)c1)CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(Cl)c1)CCCC3
Yield: 76.7 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3-chlorophenyl)methanone (0.291 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.296 g (76%) of the title compound as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:24]([C:21]1[N:22]=[CH:23][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:19][CH:20]=1)#[N:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C#N)cn3)cc(C)c21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Oc2cnc(C#N)cn2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
[6-(5-Cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (100 mg, 0.28 mmol) was dissolved in THF (4 mL) and cooled to 0° C. To this was added LHMDS (1M in THF, 0.28 mL, 0.28 mmol) and stirred at 0° C. for 1 h. Another portion of LHMDS (1M in THF, 0.28 mL, 0.28 mmol) was added at 0° C. The reaction was stirred at 0° C. for 2 h and was allowed to warm up to room temperature. The reaction was stirred at room temperature for 6 h. The solvent was removed. Preparative HPLC (C18 column) gave the title compound (33 mg, 36%) as a white solid. MS (ESI) m/z: 326 [M+1]+; 1H NMR (300 MHz, CD3OD) δ 8.56 (1H, s), 8.50 (1H, s), 7.28 (1H, s), 7.15 (1H, s), 5.65 (1H, dd), 3.18 (1H, dd), 2.35 (3H, s), 2.30 (1H, m).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(F)(F)F.CCOCC.[CH2:17]([O:21][C:22](=[O:39])[CH:23](OC(=O)C)[NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[CH2:17]([O:21][C:22](=[O:39])[CH:23]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOC(=O)C(NC(=O)OCc1ccccc1)OC(C)=O
Reactant: Oc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCOC(=O)C(NC(=O)OCc1ccccc1)c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 1.73 g. (0.010 mol.) of phenol and 0.2 ml. of boron trifluoride etherate in 20 ml. of methylene chloride was added dropwise with stirring over a 15 minute interval 3.37 g. (0.011 mol.) of N-benzyloxycarbonyl-2-acetoxyglycine n-butyl ester. After three hours the reaction mixture was cooled and the precipitate collected by filtration to give N-benzyloxycarbonyl-2-(4-hydroxyphenyl)glycine n-butyl ester, m.p. 143°-144°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([NH2:21])=O)[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([O:22][C:23]([F:26])([F:25])[F:24])[CH:3]=1>C1COCC1>[NH2:21][CH2:19][C@H:16]1[CH2:15][CH2:14][C@H:13]([CH2:12][NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[O:22][C:23]([F:25])([F:26])[F:24])(=[O:10])=[O:9])[CH2:18][CH2:17]1
Reactant: NC(=O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Solvent: C1CCOC1
Product: NC[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)CC1
Temperature: 0 °C

Procedure:
To a solution of trans-4-[(4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-methyl]-cyclohexanecarboxylic acid amide (4.2 g, 9.2 mmol) in THF (40 mL) was added a solution of 1 M BH3 in THF (32 mL, 32 mmol) over 40 min. The mixture was refluxed for 2 hr. After cooling to 0° C., the mixture was quenched with water (7 mL). To the resulting mixture were added 4 M HCl in EtOAc (28 mL) and MeOH (28 mL) and the mixture was concentrated. To the residue was added MeOH (28 mL) and the mixture was once again concentrated. The resulting HCl-salt was recrystallized from Et2O and subsequently neutralized with 1 M aqueous sodium hydroxide. The aqueous layer was extracted with CH2Cl2 (twice), the organic layers combined, dried over sodium sulfate, and concentrated under reduced pressure to give trans-N-(4-aminomethyl-cyclohexylmethyl)-4-bromo-2-trifluoromethoxy-benzenesulfonamide as a white solid (3.0 g, 74%).
Reaction SMILES: [CH3:1][CH:2]([CH:27]([CH3:30])[CH2:28][CH3:29])[C:3]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:26])=[CH:11][N:12]3[C:19](=[O:20])[C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][N:16]=[C:13]32)=[CH:8][CH:7]=1)=[O:4].[OH-].[Na+:32]>CO>[CH3:1][CH:2]([CH:27]([CH3:30])[CH2:28][CH3:29])[C:3]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:26])=[CH:11][N:12]3[C:19](=[O:20])[C:18]([C:21]([O-:23])=[O:22])=[CH:17][N:16]=[C:13]32)=[CH:8][CH:7]=1)=[O:4].[Na+:32]
Reactant: CCOC(=O)c1cnc2c3cc(NC(=O)C(C)C(C)CC)ccc3c(C)cn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)C(C)C(=O)Nc1ccc2c(C)cn3c(=O)c(C(=O)[O-])cnc3c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 10-(2,3-dimethylpentanoylamino)-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (520 mg) and 1N aqueous sodium hydroxide (3.6 ml) in aqueous methanol (25 ml) was stirred at room temperature for 2 days. Methanol was added to the reaction mixture until nearly all the precipitate was dissolved. The solution was concentrated to a half volume under reduced pressure and then filtered. The filtrate was diluted with water and allowed to stand in a refrigerator. The resultant precipitate was collected, washed with water and dried to give sodium 10-(2,3-dimethylpentanoylamino)-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (210 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:10]([C:14]1[N:19]=[C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])[CH2:24][CH2:25]2)[CH:17]=[C:16]([CH:31]2[CH2:34][CH2:33][CH2:32]2)[N:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3cnccn3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
0.28 g of 2-pyrazinecarboxylic acid (2.26 mmol) and 0.78 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.27 mmol) were dissolved in 30 ml of dichloromethane. Addition of 1.19 g of diisopropylethylamine (9.26 mmol), 0.155 g of hydroxybenzotriazole (HOBt, 1.15 mmol), and 0.487 g of N-ethyl-N′-(3-dimethyl-aminopropyl)-carbodiimide hydrochloride (EDCl, 2.54 mmol) at 0° C. was followed by stirring for 16 h at room temperature. After the addition of 0.24 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride the mixture was stirred for further 4 h. 50 ml of dichloromethane were added. The organic layer was washed with water and saturated aqueous sodium chloride. The dichloromethane phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (5%). Evaporation of the solvent yielded 0.568 g of the title compound as a white solid.
Reaction SMILES: C(OC(=O)C(N=NC1C=CC=CC=1N(C1C=CC=C(C(F)(F)F)C=1)C(OCC)=O)(NC(=O)CCl)C(OCC)=O)C.C(OC(=O)[C:45]([N:56]=[N:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[N:64]([C:70]1[CH:75]=[CH:74][CH:73]=[C:72]([CH3:76])[C:71]=1[CH3:77])[C:65]([O:67][CH2:68][CH3:69])=[O:66])([NH:51][C:52](=O)[CH2:53][Cl:54])[C:46]([O:48]CC)=[O:47])C>>[CH2:68]([O:67][C:65]([N:64]([C:70]1[CH:75]=[CH:74][CH:73]=[C:72]([CH3:76])[C:71]=1[CH3:77])[C:59]1[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=1[N:57]1[C:52]([CH2:53][Cl:54])=[N:51][C:45]([C:46]([OH:48])=[O:47])=[N:56]1)=[O:66])[CH3:69]
Reactant: CCOC(=O)N(c1ccccc1N=NC(NC(=O)CCl)(C(=O)OCC)C(=O)OCC)c1cccc(C)c1C
Agent: CCOC(=O)N(c1cccc(C(F)(F)F)c1)c1ccccc1N=NC(NC(=O)CCl)(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)N(c1ccccc1-n1nc(C(=O)O)nc1CCl)c1cccc(C)c1C

Procedure:
using 98.50 g (0.168 mol) of [2-(N-ethoxycarbonyl-3-(trifluoromethyl)-phenylamino)-phenylazo]-(2-chloroacetamido)-malonic acid diethyl ester there is obtained crude 1-[2-[N-ethoxycarbonyl-3-(trifluoromethyl)-phenylamino]-phenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid which sinters from 88° and melts at 100°-108° with decomposition; using 91.10 g (0.166 mol) of [2-(N-ethoxycarbonyl-2,3-dimethylphenylamino)-phenylazo]-(2-chloroacetamido)-malonic acid diethyl ester there is obtained crude 1-[2-(N-ethoxycarbonyl-2,3-dimethylphenylamino)-phenyl]-5-(chloromethyl)-1H-1,2,4-triazole-3-carboxylic acid which melts at 188°-190° with decomposition;
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.[SH:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:6]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH:21]=[CH:22][C:2]([S:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:3][C:4]=2[N:8]=1
Reactant: COC(=O)CS
Reactant: CC(C)(C)Cc1nc2cc(Br)ccc2n1CC1CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CSc1ccc2c(c1)nc(CC(C)(C)C)n2CC1CCOCC1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A mixture of 5-bromo-2-(2,2-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole (Step C, 300 mg, 0.82 mmol), N,N-diisopropylethylamine (286 μL, 1.64 mmol), methyl mercaptoacetate (73 μL, 0.82 mmol), tris(dibenzylideneacetone)dipalladium(0) (37.5 mg, 0.041 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (47.4 mg, 0.082 mmol) in 1,4-dioxane was microwaved at 120° C. for 30 min. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2 then 1:1 as eluent) to afford the title compound (318 mg, 99%) as a yellow viscous oil.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH2:32][CH2:33][C@@H:34]([OH:36])[CH3:35].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:32][CH2:33][C@@H:34]([OH:36])[CH3:35])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: C[C@H](O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNC[C@H](C)O)c4)cc23)CC1
Yield: 30.2 %

Procedure:
Following the general procedure of example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol), (2S)-1-amino-2-propanol (6.5 mg, 0.087 mmol) and NaBH(OAc)3 (58 mg, 0.261 mmol) were reacted to give the title compound (13.1 mg, 23%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Reactant: NCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), 4-aminobutyric acid (185 mg, 1.79 mmol) and NaOMe solution (2.7 mL, 1.34 mmol, 0.5 M in MeOH) was refluxed for 24 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 1. The organic layer was dried over MgSO4 and concentrated to give 32 mg of the title compound as an off-white solid. MS: (+) m/z 407.31 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:21][S:22]([N:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1)(=[O:24])=[O:23]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][CH:5]=[C:4]([NH:31][CH:28]2[CH2:29][CH2:30][N:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:26][CH2:27]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1ccc(Cl)nc1N
Reactant: CS(=O)(=O)N1CCC(N)CC1
Product: COc1ccc(F)c(F)c1C(=O)c1ccc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 39) and 1-methanesulfonyl-piperidin-4-ylamine (Step A. Example 6) using the procedure described in Step B. Example 6. HRMS, observed: 441.1407, Calcd for (M+H)+: 441.1403. Ki for cdk4=0.017 μM, cdk1=0.060 μM, cdk2=0.054 and IC50 for HCT116 cell line=2.6 μM.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([F:12])[C:5]=1[F:13])[CH3:2].[NH2:14]OS(O)(=O)=O>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:14])=[C:6]([F:12])[C:5]=1[F:13])[CH3:2]
Reactant: NOS(=O)(=O)O
Reactant: CCOc1ccc(C=O)c(F)c1F
Product: CCOc1ccc(C#N)c(F)c1F

Procedure:
4-Ethoxy-2,3-difluorobenzaldehyde (obtainable according to Example 7) is reacted with hydroxylamine -O-sulfonic acid according to J. Streith and C. Fizet, Helv. Chim. Acta 59, 2796 (1976), m.p.: 45° C.
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH2:14][N:13]1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[O:11])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][NH:9][C:10]([C@H:12]1[C@@H:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][CH2:15][CH2:14][N:13]1[S:24]([C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)(=[O:26])=[O:25])=[O:11]
Reactant: COc1ccc(S(=O)(=O)N2CC=C[C@H](c3ccccc3)[C@@H]2C(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N2CCC[C@H](c3ccccc3)[C@@H]2C(=O)NO)cc1
Reaction time: 1 h

Procedure:
To a solution of (+)-(2R*-3R*)-N-benzyloxy-1-(4-methoxybenzenesulfonyl)-3-phenyl-1,2,3,6tetrahydropyridine-2-carboxamide (35 mg, 0.073 mmol) in ethanol (5 ml) is added 10% palladium on carbon (10 mg, 5 mol). The flask is evacuated and backfilled with hydrogen (repeated two times). The reaction mixture is then stirred for 1 hour at which time it is filtered through Celite™ and concentrated. The product (+)-2R*-3R*)-N-hydroxy-1-(4-methoxybenzenesulfonyl)-3-phenylpiperidine-2-carboxamide was collected as a white solid. Melting point 163° C. (dec). Mass spectrum [PBMS w/C.I. (NH3)]: m/Z 390 (m+H2), (m+NH4). 1H NMR (CD3OD) δ7.73 (d, J=8.9 Hz, 2 H), 7.31-737 (m, 5 H), 7.04 (d, 8.9 Hz, 2 H0, 4.89 (s, H2O), 4.34 (d, J=5.4 Hz,1 H), 3.86 (s, 3 H), 3.74-3.63 (m, 2 H), 3.31 (bs, CD3OD), 2.99-2.90 (m, 1 H), 2.58-2.52 (m, 1 H), 1.94-1.88 (m, 1 H), 1.67-160 (m, 2 H).
Reaction SMILES: [CH2:1]([C:5]1(C=O)[NH:9][CH:8]=[CH:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[CH2:2][CH2:3][CH3:4].C[Li].[O:22]1CC[CH2:24][CH2:23]1>>[CH2:1]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]([CH:23]([OH:22])[CH3:24])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCOC1
Reactant: CCCCC1(C=O)NC=CN1Cc1ccccc1Cl
Agent: [Li]C
Product: CCCCc1ncc(C(C)O)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-carboxaldehyde (Example 1(iii)) (1.1 g, 3.97 mmol) was dissolved in dry tetrahydrofuran (15 mL), cooled to -78° C. under argon and a solution of methyl lithium (3.64 ml of 1.2 M in diethyl ether, 4.57 mmol) was added dropwise. The mixture was stirred for 1.5 hours, quenched with ammonium chloride solution, warmed to ambient temperature and extracted with ethyl acetate. The washed, dried, concentrated product was flashed chromatographed over silica gel with ethyl acetate to provide 1.07 g (92%) of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(α-hydroxy)ethyl-1H-imidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[C:15]([C:27]([O:29][CH3:30])=[O:28])N=[N:13][C:12]=2[C:31]([O:33][CH3:34])=[O:32])=[C:5]([O:35][CH2:36][O:37][CH3:38])[CH:4]=1.CCOC(C)=O.C(Cl)Cl>CC(O)=O.CO.C(Cl)(Cl)Cl.[Zn]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)=[C:15]([C:27]([O:29][CH3:30])=[O:28])[NH:13][C:12]=2[C:31]([O:33][CH3:34])=[O:32])=[C:5]([O:35][CH2:36][O:37][CH3:38])[CH:4]=1
Reactant: COCOc1cc(OC)c(OC)cc1-c1c(C(=O)OC)nnc(C(=O)OC)c1-c1ccc(OC)c(OC)c1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COCOc1cc(OC)c(OC)cc1-c1c(C(=O)OC)[nH]c(C(=O)OC)c1-c1ccc(OC)c(OC)c1
Reaction time: 4 h
Yield: 62 %

Procedure:
A solution of 7 (1.01 g, 1.91 mmol, 1.0 equiv) in HOAc (25 mL) under Ar at 25° C. was treated with activated Zn dust (1.25 g, 19.1 mmol, 10 equiv), stirred for 4 h, and then treated with additional Zn dust (1.25 g, 10 equiv). After 14.5 h, the slurry was diluted with 10% MeOH/CHCl3 (25 mL) and stirred 3 h at 25° C. The mixture was filtered through Celite, rinsed with 10% MeOH/CHCl3, and the filtrate was washed with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated in vacuo. Chromatography (SiO2, 4.5×15 cm, 25% EtOAc/CH2Cl2) afforded 8 (0.61 g, 62% yield) as an orange oil. An analytically pure sample could be prepared by recrystallization from EtOAc-hexanes: mp 162-163° C.; MALDIHRMS (DHB) m/z 515.1800 (M+, C26H29NO10 requires 515.1791).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25]Cl)[CH3:22]>CN(C)C=O>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][N:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:18][C:6]1=2)[CH3:22]
Reactant: CCN(CC)CCCl
Reactant: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN1c2ccccc2N(C)C(=O)c2ccc(C)nc21
Reaction time: 0.5 h

Procedure:
A mixture consisting of 7.2 gm of 6,11-dihydro-2,6-dimethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, 70 ml of dimethyl formamide and 1.9 gm of 50% sodium hydride in mineral oil was stirred at 30° to 50° C. in a nitrogen atmosphere for 30 minutes. Thereafter, a solution of 6.8 gm of 2-diethylaminoethyl chloride in 30 ml of dimethyl formamide was added dropwise, and the mixture was stirred at 100° C. for 2 hours and then evaporated in vacuo. The residue was admixed with an aqueous potassium carbonate solution, and the mixture was extracted with ether. The evaporation residue of the combined ether extracts, which were dried with sodium sulfate, was purified in a silica gel column and recrystallized from petroleum ether (b.p. 100°-140° C.), yielding 62% of theory of the compound of the formula ##STR13## which had a melting point of 91°-93° C.