Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:46]([O:53][C:54]1C(C(O)=O)=NC(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)=N[C:59]=1O)[C:47]1C=CC=CC=1.[Si](OCCNC1CCOCC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:45]1[CH2:59][CH2:54][O:53][CH2:46][CH2:47]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Reactant: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNC1CCOCC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)C1CCOCC1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) (300 mg, 0.66 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-(tetrahydro-pyran-4-yl)-amine (8j) (257 mg, 0.99 mmol). The yield was 320 mg, 70%, of a colorless sticky mass.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]2[C:8]3[C:9]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[N:10][C:11]4[C:16]([C:7]=3[C:6](=[N:26][OH:27])[C:5]=2[CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.Cl.COC1C=CC2C3C(N4CCNCC4)=NC4C(C=3C(=O)C=2C=1)=CC=CC=4.C(C1OC1)Cl>>[N:31]1([CH2:30][CH2:29][O:27][N:26]=[C:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[C:9]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:8]=3[C:23]3[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][C:5]2=3)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc2c(c1)C(=NO)c1c-2c(N2CCNCC2)nc2ccccc12
Reactant: ClCCN1CCCC1
Agent: COc1ccc2c(c1)C(=O)c1c-2c(N2CCNCC2)nc2ccccc12
Agent: Cl
Solvent: ClCC1CO1
Product: COc1ccc2c(c1)C(=NOCCN1CCCC1)c1c-2c(N2CCNCC2)nc2ccccc12

Procedure:
9-Methoxy-6-(piperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one O-2-(pyrrolidin-1-yl)ethyl oxime (6u) was prepared substantially according to the procedures as set forth in the above Synthesis Example 18, except that compound 6p and 1-(2-chloroethyl)pyrrolidine·HCl were used in place of compound 5x and epichlorohydrin, respectively, giving the title compound at a yield of 43%.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:27])=[CH:25][CH:26]=2)[NH2:23])=[C:13]([CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:12]=1[OH:36])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[C:24]([CH3:27])=[CH:25][CH:26]=2)=[C:13]([CH2:30][CH2:31][C:32]([F:34])([F:33])[F:35])[C:12]=1[OH:36])(=[O:10])[CH3:9]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(=O)c1ccc(OCCCOc2ccc(C)c(N)c2)c(CCC(F)(F)F)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)ccc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1.9 ml (21 mmol) of methyl chlorooxalate in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 7.5 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methylaniline and 3.0 g of triethylamine in 60 ml of methylene chloride in the course of about 5 minutes. The reaction mixture is subsequently stirred at room temperature for 90 minutes and poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether gives methyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methylphenyl}}-oxamate.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:16])[CH2:8][CH:9]([CH3:15])[C:10](OCC)=[O:11].[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:16]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][C:24]([F:35])([F:34])[F:23])=[CH:27][CH:28]=2)[C:10](=[O:11])[CH:9]([CH3:15])[CH2:8]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)CC(N)c1ccccc1-c1ccccc1
Product: CC1CC(c2ccccc2-c2ccccc2)N(Cc2ccc(OC(F)(F)F)cc2)C1=O

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-([1,1′-biphenyl]-2-yl)-4-amino-2-methylbutanoate with commercially available 4-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.03 min.; [M+H]+: 425.99 g/mol.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[N:10]=2)[CH:5]=[C:4]([C:16]([O:18]CC)=[O:17])[C:3]1=[O:21].O.[OH-].[Li+].O.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[N:10]=2)[CH:5]=[C:4]([C:16]([OH:18])=[O:17])[C:3]1=[O:21]
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)nc2n(C)c1=O
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)c(C(=O)O)cc2ccc(C(F)(F)F)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
1.24 g (4.1 mmol) of ethyl 1-methyl-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in 1,4-dioxane (50 mL), and 0.35 g (8.3 mmol) of lithium hydroxide monohydrate and 10 mL of water were added thereto at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was washed with ethyl acetate. The aqueous phase was acidified with citric acid, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried, and concentrated. The residue was washed with normal-hexane, and thus 1.02 g of the title compound was obtained as colorless crystals (yield: 91%).
Reaction SMILES: C([O:8][C:9](=[O:23])[C@H:10]([CH:20]([CH3:22])[CH3:21])[NH:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[O:17]1[CH2:18][CH2:19][N:14]([C:12]([NH:11][C@H:10]([C:9]([OH:23])=[O:8])[CH:20]([CH3:22])[CH3:21])=[O:13])[CH2:15][CH2:16]1
Reactant: CC(C)[C@H](NC(=O)N1CCOCC1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)N1CCOCC1)C(=O)O

Procedure:
2.7 g (8.4 mmol) of N-morpholinocarbonyl-(L)-valine-benzyl ester are dissolved in 75 ml of ethyl acetate and the solution is hydrogenated for 3 h in the presence of 500 mg of 10% palladium on carbon at 1 atm hydrogen pressure and RT. The catalyst is filtered off and, after concentrating the solvent by evaporation, the title compound is obtained in the form of a colourless oil. 1H-NMR (300 MHz, CD3OD): 4.15 (m, 1H), 3.65 (m, 4H), 3.40 (m, 4H), 2.12 (m, 1H), 0.95 (2d, 6H).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:10]([CH3:27])[O:9][N:8]=1)(=O)=O.CN(C=O)C.[N-:33]=[N+:34]=[N-:35].[Na+]>O>[N:33]([CH2:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[O:26])=[C:10]([CH3:27])[O:9][N:8]=1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1onc(COS(C)(=O)=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1onc(CN=[N+]=[N-])c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottomed flask was added (4-chlorophenyl)(2-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)phenyl)methanone (47.2 mg, 0.144 mmol), DCM, and Et3N (40.1 μl, 0.288 mmol). The solution was cooled to 0° C. before addition of Ms-Cl (13.47 μl, 0.173 mmol). The reaction was stirred at 0° C. for 30 min before addition of water. The layers were separated and the aqueous was extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated to afford crude (4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methyl methanesulfonate. To a round bottomed flask was added (4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazol-3-yl)methyl methanesulfonate (58.4 mg, 0.144 mmol), DMF, and sodium azide (28.1 mg, 0.432 mmol). The reaction was stirred at room temperature for 2 h before diluting with water and extracting the aqueous with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude (2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl) (4-chlorophenyl)methanone. To a round bottomed flask was added (2-(3-(azidomethyl)-5-methylisoxazol-4-yl)phenyl)(4-chlorophenyl)methanone (50.8 mg, 0.144 mmol), toluene (3 mL), and trimethylphosphine solution (216 μl, 1M in toluene, 0.216 mmol). The reaction was stirred at room temperature over 2 days before purifying via Biotage (EtOAc/hex) to afford 6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,3-e]azepine. LC/MS m/z 309 [M+H]+; 1H NMR (400 MHz, Acetone) δ 7.70-7.76 (m, 1H), 7.63-7.70 (m, 1H), 7.32-7.49 (m, 6H), 5.10 (br. s, 1H), 4.10 (br. s, 1H), 2.68 (s, 3H).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][CH:21]([CH2:24][N:25]3[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][CH3:34])[CH2:27][CH2:26]3)[C:20]2=[O:35])=[CH:15][CH:14]=1>C(OCC)(=O)C>[C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:23][CH2:22][C@@H:21]([CH2:24][N:25]3[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][O:33][CH3:34])[CH2:29][CH2:30]3)[C:20]2=[O:35])=[CH:15][CH:14]=1
Reactant: COCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1
Agent: O=C(O)[C@@H](O)c1ccccc1
Solvent: CCOC(C)=O
Product: COCCN1CCN(C[C@@H]2CCN(c3ccc(Cl)cc3)C2=O)CC1
Yield: 35.7 %

Procedure:
Under heating, 152 mg of (S)-(+)-mandelic acid was added to a solution of 352 mg of 1-(4-chlorophenyl)-3-(4-(2-methoxyethyl)piperazin-1-yl)methyl-2-pyrrolidinone in 3 mL of ethyl acetate. After cooling, the precipitated crystals were filtered and dried in vacuo to give 180 mg of the title compound.
Reaction SMILES: [CH:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\CCCC.[CH3:18][C:19](OC(C)=O)=[O:20].N1C=CC=CC=1.C(O)CCCCCC/C=C\CCC>>[C:19]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH3:12])(=[O:20])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC/C=C\CCCCCCCCCC=O
Agent: CCC/C=C\CCCCCCCO
Solvent: c1ccncc1
Product: CCC/C=C\CCCCCCCOC(C)=O
Yield: 90 %

Procedure:
By acetylation of compound 2: According to the procedure for compound 6, Ac2O (0.29 mL, 3.0 mmol), pyridine (0.14 mL, 1.8 mmol), and alcohol 12 (0.28 g, 1.5 mmol) were reacted to provide 13 (19 g, 90% yield, 86% Z as determined by 1H-NMR) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[C:35](=[N:37]O)[NH2:36]>>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=1[C:35]1[N:37]=[C:24]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:12]2)[O:25][N:36]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: NC(=NO)c1c(F)cccc1F
Product: CCc1ccc(C2CC(c3nc(-c4c(F)cccc4F)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 57 mg (0.33 mmol) of 2,6-difluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 57 mg (52% of theory)
Reaction SMILES: Cl.Cl.[C:3]1([C:9]2[C:10]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][C:34](O)=[O:35])=[O:30])([CH3:27])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:35]=[C:34]([N:21]1[CH2:20][CH2:19][N:18]([C:10]2[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:14][N:13]=[C:12]3[NH:15][CH:16]=[CH:17][C:11]=23)[CH2:23][CH2:22]1)[CH2:33][CH2:32][NH:31][C:29](=[O:30])[O:28][C:24]([CH3:26])([CH3:25])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: c1ccc(-c2cnc3[nH]ccc3c2N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
5-Phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri dine dihydrochloride (0.10 g, 0.285 mmol, see Example 19), 3-(tert-butoxycarbonylamino)propanoic acid (0.0646 g, 0.342 mmol), HOBT-H2O (0.0610 g, 0.399 mmol), and EDCI (0.0709 g, 0.370 mmol) were placed in DCM (5 mL) at room temperature. DIEA (d 0.742; 0.248 mL, 1.42 mmol) was then added, and the reaction was stirred at room temperature for 18 hours. The reaction was then poured into Na2CO3 and extracted with DCM. The combined organic fractions were dried, filtered, concentrated and purified (500:10 DCM:MeOH) to give tert-butyl 3-oxo-3-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propylcarbamate (0.055 g, 43.0% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([CH3:29])=[C:15]([NH:21][C@H:22]([C@H:26]([OH:28])[CH3:27])[C:23](O)=[O:24])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:23](=[O:24])[C@H:22]([NH:21][C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[C:13]([Cl:12])[C:14]=2[CH3:29])[C@H:26]([OH:28])[CH3:27])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: NNC(=O)c1ccc(Cl)cc1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Cl)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Yield: 92.7 %

Procedure:
4-Chloro-N′-((2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide was prepared using 4-chlorobenzoic hydrazide (4.42 mmol, 1.1 equiv.) and (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (4.02 mmol, 1.0 equiv.) according to the procedure as described for intermediate 5a. The crude off-white solid was recrystallized using hot methylene chloride to provide the desired product as a white solid (1.57 g, 93% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.94 (br. s, 1H), 9.48 (br. s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.55 (m, 3H), 6.73 (d, J=8.5 Hz, 1H), 5.59 (br. d., J=7.1 Hz, 1H), 4.25 (m, 1H), 4.13 (m, 1H), 2.35 (s, 3H), 1.37 (d, J=6.4 Hz, 3H); LRMS (ESI+) exact mass calcd for C19H18Cl2N4O3 [M]+421.28. found 421.3; TLC Rf=0.32, 100% EtOAc, vanillin stain.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[C:35]([Cl:37])[C:34](Cl)=[N:33][CH:32]=1>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:33][CH:32]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)c(Cl)c1

Procedure:
The title compound was prepared in analogy to Example 174 from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 172) with methyl-5,6-dichloronicotinate [CAS Reg. No. 56055-54-0]. MS (m/e)=571.2 [M+H+].
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH2:8][CH2:7]1.[NH2:19][NH2:20]>C(O)(C)C>[Cl:18][C:14]1[CH:13]=[C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][NH:19][NH2:20])[CH2:7][CH2:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: ClCCCN1CCN(c2cccc(Cl)c2)CC1
Reactant: NN
Agent: Cl
Solvent: CC(C)O
Product: NNCCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 75 °C
Yield: 94.4 %

Procedure:
1-(3-Chloropropyl)-4-(3-chlorophenyl)piperazine hydrochloride (20.0 g, 0.065 mol) is suspended in isopropanol (65 ml) and anhydrous hydrazine (31.7 g, 0.988 mol) is added. The reaction mixture is heated at 70-80° C. for 2.5 hours and cooled to room temperature. The upper layer is separated and concentrated under reduced pressure. The residue is dissolved in isopropanol (50 ml) and the upper layer is separated, dried (Na2SO4), and concentrated to yield 16.5 g (94.5% yield) of 1-(3-chlorophenyl)-4-(3-hydrazinopropyl)piperazine (85% pure) as a viscous oil. The product is used directly without further purification or stored at room temperature in toluene or isopropanol solution by adding 1% MgO.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(OCC)C.[OH:16][S:17](O)(=[O:19])=[O:18].O=S(=O)=O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:17]([OH:19])(=[O:18])=[O:16])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: CCOCC
Product: Nc1ccc(S(=O)(=O)O)cc1C(=O)O
Yield: 57 %

Procedure:
A solution of 2-aminobenzoic acid (2g, 15 mM) in oleum (30 ml) was heated at 80°, under argon atmosphere for 2 hours. The mixture was poured into diethyl ether (400 ml) and the resulting precipitate was filtered, washed with diethyl ether and dried under vacuum to give 2-amino-5-sulphobenzoic acid (1.8 g, 57%).
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)=[CH:22][CH:21]=3)=[CH:13][C:12]=12.N1CC(C2C=CC(C(NCC3C=CN4C=CN=C4C=3)=O)=CC=2)C1>>[N:8]1[CH:9]=[CH:10][N:11]2[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19](=[O:31])[C:20]3[CH:21]=[CH:22][C:23]([CH:26]4[CH2:30][CH2:29][N:28]([S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH2:27]4)=[CH:24][CH:25]=3)=[CH:13][C:12]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNC2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CNC2)cc1
Product: CC(C)S(=O)(=O)N1CCC(c2ccc(C(=O)NCc3ccn4ccnc4c3)cc2)C1

Procedure:
The title compound was prepared as described in Example 557C, substituting propane-2-sulfonyl chloride for propane-2-sulfonyl chloride and N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(pyrrolidin-3-yl)benzamide for 4-(azetidin-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)benzamide. 1H NMR (501 MHz, DMSO-d6) δ ppm 9.04 (t, J=6.0 Hz, 1H), 8.47 (d, J=6.9 Hz, 1H), 7.87 (m, 3H), 7.50 (d, J=1.2 Hz, 1H), 7.43 (m, 2H), 7.37 (s, 1H), 6.84 (dd, J=7.0, 1.6 Hz, 1H), 4.49 (d, J=5.9 Hz, 2H), 3.77 (m, 1H), 3.52 (m, 2H), 3.42 (m, 2H), 3.25 (m, 1H), 2.30 (m, 1H), 2.04 (m, 1H), 1.25 (dd, J=6.8, 1.4 Hz, 6H); MS (ESI(+)) m/e 427 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][CH2:42][C:43]([NH:45][C@@H:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:47](=[O:48])[C@H:46]([C:50]([CH3:52])([CH3:51])[CH3:53])[NH:45][C:43](=[O:44])[CH2:42][O:41][CH3:40]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COCC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.3 %

Procedure:
A solution containing the product from Example 2C (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 55B (0.038 mmol), DEPBT (0.016 g, 0.054 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.184 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.011 g, 38% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.81 (s, 9 H), 0.84 (s, 9 H), 1.52 (m, 2 H), 2.56 (m, 1 H), 2.74 (m, 3 H), 3.26 (s, 3 H), 3.49 (s, 3 H), 3.66 (m, 1 H), 3.82 (m, 3 H), 4.03 (m, 1 H), 4.16 (m, 1 H), 4.31 (d, J=9.56 Hz, 1 H), 4.83 (d, J=5.88 Hz, 1 H), 6.62 (d, J=9.56 Hz, 1 H), 7.14 (m, 8 H), 7.31 (m, 1 H), 7.85 (m, 6 H), 8.63 (d, J=4.41 Hz, 1 H).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[N:23]=[CH:22][CH:21]=[CH:20][C:8]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[O:10].[H-].[Na+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>O.ClCCl>[Cl:6][C:7]1[N:23]=[CH:22][CH:21]=[CH:20][C:8]=1[C:9]([N:11]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=[O:10]
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cccc(NC(=O)c2cccnc2Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(C(=O)c2cccnc2Cl)c2cccc(OC)c2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83.1 %

Procedure:
N,N-Dimethylformamide was added to the compound (972.4 mg, 3.1736 mmol) prepared in step 1 and the mixture was cooled to 0° C. Sodium hydride (380 mg, 9.52 mmol) was slowly added and the resulting mixture stirred at 0° C. for 20 minutes. p-Methoxybenzyl chloride (0.646 ml, 4.76 mmol) was added at 0° C. and the mixture stirred for 3 hours at room temperature. Once the reaction was completed, dichloromethane and water was added, the organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=2.5:1) to obtain the title compound (1.01 g, yield: 84%, ivory oil).
Reaction SMILES: [N:1]1[C:2]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.C=O.[BH3-][C:21]#N.[Na+]>[Cl-].[Cl-].[Zn+2].C(OCC)C.CO>[CH3:21][N:7]1[CH2:8][CH2:9][N:4]2[N:3]=[C:2]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[N:1]=[C:5]2[CH2:6]1
Reactant: CC(C)(C)OC(=O)Nc1nc2n(n1)CCNC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CN1CCn2nc(NC(=O)OC(C)(C)C)nc2C1
Yield: 94 %

Procedure:
Following the procedure in Example 191i, and starting with 270d (500 mg, 2.1 mmol, 1.0 eq.), paraformaldehyde (630 mg, 21.0 mmol, 10.0 eq.), ZnCl2/diethyl ether (2.1 mL, 2.1 mmol, 1.0 M), NaBH3CN (390 mg, 6.3 mmol, 3.0 eq.), and methanol (20 mL) afforded 270e as a yellow solid (500 mg, 94%). MS-ESI: [M-tBu]+ 198.0.