Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:27][C:6]2=[N:7][C:8]([CH3:26])=[C:9]([CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[C:5]2[C:4]=1[CH3:28])[CH3:2].[OH-].[Na+]>CO.C(O)C>[CH2:1]([C:3]1[S:27][C:6]2=[N:7][C:8]([CH3:26])=[C:9]([CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20])[C:10]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[C:5]2[C:4]=1[CH3:28])[CH3:2]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc(CC)c(C)c2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc2sc(CC)c(C)c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 51.4 %

Procedure:
To a solution of methyl 2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.119 g; 0.301 mmol) in methanol (6.4 mL) and ethanol (3.2 mL) was added a 5% sodium hydroxide solution (8.2 mL; 10.25 mmol). The reaction mixture was heated under reflux for 5.5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.059 g (51%) of the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](Br)[C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]([C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1)([CH3:13])([CH3:12])[CH3:11].O.CC(=O)OCC>CCO>[Br:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH:18][N:17]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1cnc(Br)nc1Br
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2nc(Br)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A mixture of 2,4-dibromo-5-chloropyrimidine (500 mg, 1.85 mmol) and 5-tert-butyl-1H-pyrazol-3-amine (216 mg, 2.2 mmol, 1.2 eq) in EtOH (100 mL) was stirred at rt for 2 h. After addition of water and extraction with EA (3×), the combined organic layers were dried (Na2SO4), filtered, concentrated and purified by silica gel chromatography (EA/PE 1:2) to afford 2-bromo-N-(5-tert-butyl-1H-pyrazol-3-yl)-5-chloropyrimidin-4-amine (450 mg, 85%). LC-MS (m/z)=288 [M+H]+
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl[CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][N:15]=1>>[CH3:21][O:20][C:18]1[C:17]([CH3:22])=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:19]=1
Reactant: COc1cc(CCl)ncc1C
Reactant: Sc1ncnc2ccccc12
Product: COc1cc(CSc2ncnc3ccccc23)ncc1C
Yield: 3.7 %

Procedure:
The title compound(0.24 g) was prepared from 4-mercaptoquinazoline(3.5 g) and 2-chloromethyl-4-methoxy-5-methylpyridine(4.1 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:19][CH2:20][CH3:21])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])=[CH:8][C:7]([OH:18])=[CH:6][CH:5]=2.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([CH3:28])([O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:19][CH2:20][CH3:21])[C:2]([CH3:1])=[C:10]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[CH3:27])[CH3:23]
Reactant: CCCn1c(C)c(-c2ccccc2C)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(C)c(-c2ccccc2C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 2-methyl-3-(2-methyl-phenyl)-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[C:9]2[C:4](=[CH:5][C:6]([C:23]3[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:7][N:8]=2)[N:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[F:32][C:29]([F:30])([F:31])[C:28]1[C:23]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][N:14]=4)=[CH:11][CH:2]=[N:3]3)=[N:8][CH:7]=2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(Nc2cc(Cl)nc3cc(-c4ncccc4C(F)(F)F)cnc23)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: FC(F)(F)c1ccc(Nc2ccnc3cc(-c4ncccc4C(F)(F)F)cnc23)nc1

Procedure:
Stir a mixture of 2-chloro-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl) pyridin-2-yl]-[1,5]naphthyridin-4-amine (94 mg), ammonium formate (126 mg), 10% palladium on carbon (25 mg) in methanol (10 mL) at 50° C. for 2 hours. Cool, filter through Celite and evaporate to dryness. Purify by preparative thin layer chromatography, eluting with dichloromethane/methanol/ammonium hydroxide mixture to give the title compound. MS 436 (M+1). 1H NMR δ (CDCl3) 8.95-8.93 (2H, m), 8.63-8.57 (2H, m), 8.34-8.32 (1H, m), 8.26 (1H, s), 8.18 (1H, dd), 7.91 (1H, dd), 7.57-7.52 (2H, m).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[CH3:16][O:1][CH2:2][CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: CI
Reactant: O=C(O)c1ccc(SCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCSc1ccc(C(=O)O)cc1
Temperature: 27.5 °C
Reaction time: 0.25 h
Yield: 60.2 %

Procedure:
To a stirred solution of 4-(2-Hydroxy-ethylsulfanyl)-benzoic acid (7 g, 0.0352 mol) in DMF (140 mL) was added Sodium hydride (4.2 g, 0.088 mmol) at 5-10° C. under nitrogen atmosphere. Reaction mixture was stirred for 15 min at 25-30° C. and then Methyl iodide (6.6 mL, 0.1057mol) was added to at 10-15° C. Stirring continued for 3 hr after removing cooling. Reaction mixture was then quenched in aqueous NaOH solution and stirred for 30 min. Aqueous layer was washed with ethyl acetate (200 mL). Aqueous layer was then acidified using dil.HCl. Product obtained was filtered which on drying afforded 4.5 g of desired product in 60% yield.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].C(OCC)(=O)C.CCCCCC>CS(C)=O>[CH3:21][C:19]1[CH:20]=[CH:15][C:16]([N+:22]([O-:24])=[O:23])=[C:17]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:18]=1
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1cc(C)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 99.9 %

Procedure:
To a suspension of NaH (3.22 g, 80.6 mmol) in DMSO (20 mL) was added diethyl malonate (12.9 g, 12.2 mL, 80.6 mmol) dropwise. The reaction mixture was heated at 60° C. for 30 min. A solution of 2-fluoro-4-methyl-1-nitro-benzene (5.00 g, 32.2 mmol) in DMSO (6 mL) was added and the reaction mixture heated at 60° C. for 2 h. The reaction was quenched with saturated ammonium chloride (20 mL), acidified (pH˜1) with 1N HCl and extracted into ether. The product was dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel chromatography (0-60% ethyl acetate/hexane) provided diethyl 2-(5-methyl-2-nitrophenyl)malonate as a yellow solid (9.50 g, 99% yield). LC/MS m/z 296.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 8.05 (d, J=8.4 Hz, 1H), 7.46 (dd, J=1.2, 8.4 Hz, 1H), 7.30 (d, J=1.2 Hz, 1H), 5.36 (s, 1H), 4.22-4.14 (q, 1H), 2.43 (s, 3H), 1.18 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][N:19]([CH:28]=[O:29])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]([N:10]2[C@H:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[N+:54]1([O-:61])[C:55]([NH2:60])=[CH:56][CH:57]=[CH:58][CH:59]=1>C(#N)C>[CH:1]1([CH2:6][C@H:7]([CH2:18][N:19]([CH:28]=[O:29])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:60][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][N+:54]=3[O-:61])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cccc[n+]1[O-]
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)O)OCc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1N=CC[C@H]1C(=O)Nc1cccc[n+]1[O-])OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (88 mg, 0.219 mmol) in acetonitrile (4 mL) at 0° C. was added 4-methylmorpholine (0.053 mL, 0.482 mmol), followed by 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (DMTMM) (86 mg, 0.263 mmol). The solution was stirred for 15 min, and then 2-pyridinamine 1-oxide (31.4 mg, 0.285 mmol) was added. The reaction mixture was warmed up to room temperature and stirred overnight. The solvent was evaporated away, and residue was dissolved in DCM. The solution was washed with 5% aq. NaHSO4 followed by water. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford a crude oil, which was purified by RP-HPLC to provide (5S)-1-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-N-(1-oxido-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide as a colorless gum (67 mg, 62%). LCMS: (M+H)+: 494.0.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]=O)[N:4]([CH3:9])[N:3]=1.[Cl-].[CH3:11][C:12]1[N:17]2[N:18]=[C:19]([CH2:21][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=[C:16]2[C:15]([CH3:41])=[N:14][CH:13]=1>>[Br:1][C:2]1[N:6]=[C:5](/[CH:7]=[CH:21]/[C:19]2[N:20]=[C:16]3[C:15]([CH3:41])=[N:14][CH:13]=[C:12]([CH3:11])[N:17]3[N:18]=2)[N:4]([CH3:9])[N:3]=1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: Cn1nc(Br)nc1C=O
Agent: [Cl-]
Product: Cc1ncc(C)n2nc(/C=C/c3nc(Br)nn3C)nc12
Yield: 67.1 %

Procedure:
Was prepared in the same manner as described in Example 1g) using 3-bromo-1-methyl-1H-1,2,4-triazole-5-carbaldehyde (218 mg, 1.15 mmol, Eq: 1.00) and ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (527 mg, 1.15 mmol, Eq: 1.00) as starting materials. Chromatography afforded 2-[(E)-2-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (258 mg/67.3%) as a white solid. MS: m/e=336.0334.1 (M+H+), mp: 199.4° C.
Reaction SMILES: [CH3:1][C@@H:2]([O:11][CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:26])=[CH:17][CH:16]=1)[C:3](N1CCOCC1)=[O:4].C1C[O:39]CC1.[OH-].[Li+]>CO.O>[CH3:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]([C:21]2[N:20]([CH2:19][C:18]3[CH:34]=[CH:35][C:15](/[CH:14]=[CH:13]/[CH2:12][O:11][C@H:2]([CH3:1])[C:3]([OH:4])=[O:39])=[CH:16][CH:17]=3)[CH:24]=[CH:23][CH:22]=2)=[O:26])=[CH:32][CH:31]=1
Reactant: Cc1ccc(C(=O)c2cccn2Cc2ccc(/C=C/CO[C@H](C)C(=O)N3CCOCC3)cc2)cc1
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)c2cccn2Cc2ccc(/C=C/CO[C@H](C)C(=O)O)cc2)cc1
Yield: 85 %

Procedure:
The compound of Example 68-1 (213 mg, 0.45 mmol) was dissolved in methanol (1 ml) and THF (1 ml) and thereto was added 2N aqueous lithium hydroxide (0.9 ml), followed by stirring under reflux for 7 hours. The reaction mixture was diluted with water and washed with diethyl water. The aqueous layer was adjusted to around pH4 with 5% aqueous potassium hydrogen sulfate solution and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo to give the subject compound (155 mg, 85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:10](=[O:20])[C:9]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:25](I)[CH:26]=[CH2:27]>CN(C)C=O>[CH2:27]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:9]([C:21]#[N:22])[C:10]1=[O:20])[CH:26]=[CH2:25]
Reactant: C=CCI
Reactant: COc1ccc2[nH]c(=O)c(C#N)c(-c3cccc(F)c3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c(C#N)c(-c2cccc(F)c2)c2cc(OC)ccc21
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.00 g, 3.40 mmol) in 20 mL of N,N-dimethylformamide at 0° C. was added sodium hydride (163 mg of 60% dispersion in mineral oil, 4.08 mmol). After 30 minutes, allyl iodide was added (0.342 mL, 3.74 mmol), and the reaction was stirred for 2 hours. The reaction was quenched with water and partitioned between EtOAc and water, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was subjected to flash chomatography through SiO2 (5-60% EtOAc/hexane) to provide the first eluting product as the titled compound. 1H NMR, difference nOe, and HMQC NMR spectral data for the product were consistent with the titled compound. ESI+MS: 335.1 [M+H]+.
Reaction SMILES: Br[C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14][CH2:15][Si:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[O:4].[I-:28].[Na+]>CC(C)=O>[I:28][C:2]([CH3:27])([CH3:26])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH2:14][CH2:15][Si:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[O:4]
Reactant: [I-]
Reactant: CCO[Si](CCCSCCCCCCOC(=O)C(C)(C)Br)(OCC)OCC
Agent: [Na+]
Solvent: CC(C)=O
Product: CCO[Si](CCCSCCCCCCOC(=O)C(C)(C)I)(OCC)OCC

Procedure:
The 6-(3-(triethoxysilyl)propylthio)hexyl 2-bromo-2-methylpropanate (5 g) obtained through the procedures of Example 1 was mixed with sodium iodide (20 g) and dry acetone (100 mL), and the mixture was allowed to react in a nitrogen atmosphere at 75° C. for 10 hours. After the reaction, extraction was performed to give 6-(3-(triethoxysilyl)propylthio)hexyl 2-iodo-2-methylpropanate of the chemical formula below (compound 6).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:29][CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:10]3[N:11]([C:13]([C:16]4[CH:27]=[CH:26][C:19]([C:20](NC5CC5)=[O:21])=[C:18]([CH3:28])[CH:17]=4)=[CH:14][N:15]=3)[N:12]=2)=[CH:4][CH:3]=1.Br.[OH2:39]>>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:29][CH2:30][CH2:31][C:32]([F:33])([F:35])[F:34])[C:10]3[N:11]([C:13]([C:16]4[CH:27]=[CH:26][C:19]([C:20]([OH:21])=[O:39])=[C:18]([CH3:28])[CH:17]=4)=[CH:14][N:15]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O
Reactant: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Oc4ccc(Cl)cc4)nn23)ccc1C(=O)NC1CC1
Agent: Br
Product: Cc1cc(-c2cnc3c(NCCC(F)(F)F)cc(Oc4ccc(Cl)cc4)nn23)ccc1C(=O)O

Procedure:
A mixture comprising 300 mg (566 μmol) 4-{6-(4-chlorophenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-N-cyclopropyl-2-methylbenzamide and 13.4 mL hydrobromic acid was heated at 120° C. for 2.5 days. Water was added, the precipitate filtered off to give the crude title compound that was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:4]1)(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)NC1CCCC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 3-(hydroxymethyl)cyclohexylcarbamate (7.9 mmol), methanesulfonyl chloride (23.7 mmol) and triethylamine (119 mmol) in DCM (100 ml) was stirred at rt overnight. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>>[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][O:2][CH3:1])=[CH:6][CH:7]=1)(=[O:14])[CH3:13]
Reactant: CON=Cc1ccc(NC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(NC(C)=O)cc1

Procedure:
Reduction of 4-acetamidobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a waxy solid (100% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 2.16 (3H, s, CH3), 3.49 (3H, s, OCH3), 4.00 (2H, s, NCH2), 7.26 (1H, broad s, NH), 7.29 (2H, m, aromatics), 7.46 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 186-188° C. (dec.). Anal. calcd. for C10H14N2O2—HCl—H2O: C, 50.87; H, 6.66; N, 11.87. Found: C, 50.77; H, 6.44; N, 12.16.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=O)=[CH:4][CH:3]=1.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:13][C:14]([OH:15])=[N:16][CH:9]=2)=[CH:6][CH:7]=1
Reactant: NCC(N)=O
Reactant: O=CC(=O)c1ccc(F)cc1
Product: Oc1cnc(-c2ccc(F)cc2)cn1
Yield: 42 %

Procedure:
The title compound was prepared according to the method described for Preparation 25 using (4-fluoro-phenyl)-oxo-acetaldehyde and 2-amino-acetamide to afford the title compound as a pale yellow oil (2.33 g, 42%).
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:21][C@@H:20]([C:29](=[O:49])[N:30]([CH:46]4[CH2:48][CH2:47]4)[CH2:31][C:32]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:50]([N:57]=[C:58]=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CC#N>[CH:46]1([N:30]([CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=2)[C:29]([C@@H:20]2[CH2:21][C@H:22]([N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[C:58]([NH:57][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:59])[CH2:23][NH:18][CH2:19]2)=[O:49])[CH2:48][CH2:47]1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCC(C)C)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Reactant: O=C=NCc1ccccc1
Solvent: CC#N
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](N(CC(C)C)C(=O)NCc3ccccc3)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example ??? using (3R,5S)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-isobutylamino-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester and benzylisocyanate. MS: 574 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.34 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:10][CH2:9]1.Cl[C:31]1[N:40]=[C:39]2[C:34]([C:35](=[O:47])[C:36]([C:44]([OH:46])=[O:45])=[CH:37][N:38]2[CH:41]2[CH2:43][CH2:42]2)=[CH:33][C:32]=1[F:48]>>[C:26]([NH:25][CH2:24][C@@H:22]1[O:21][C:20](=[O:29])[N:19]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:13][CH2:12][N:11]([C@@H:14]4[CH2:18][CH2:17][N:16]([C:31]5[N:40]=[C:39]6[C:34]([C:35](=[O:47])[C:36]([C:44]([OH:46])=[O:45])=[CH:37][N:38]6[CH:41]6[CH2:43][CH2:42]6)=[CH:33][C:32]=5[F:48])[CH2:15]4)[CH2:10][CH2:9]3)=[C:2]([F:1])[CH:3]=2)[CH2:23]1)(=[O:28])[CH3:27]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN([C@@H]4CCNC4)CC3)c(F)c2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN([C@@H]4CCN(c5nc6c(cc5F)c(=O)c(C(=O)O)cn6C5CC5)C4)CC3)c(F)c2)C(=O)O1

Procedure:
This compound was synthesized in analogy to the procedure described in Example 19 using 0.0 90 g N-{(5S)-3-[3-fluoro-4-(4-{(3R)-pyrrolidin-3-yl}-piperazin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.22 mmol) and 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (0.22 mmol).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:22]([CH2:32][CH2:33][CH3:34])=[N:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:22]([CH2:32][CH2:33][CH3:34])=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCCc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-propyl-1H-pyrazol-4-yl]propionate (610 mg), 1N aqueous sodium hydroxide solution (2.6 ml), ethanol (3 ml), and tetrahydrofuran (3 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The crystals obtained were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-propyl-1H-pyrazol-4-yl]propionic acid (480 mg, yield: 80%). This was recrystallized from ethyl acetate-hexane. Melting point: 153–154° C.
Reaction SMILES: [N:1]#[C:2]Br.[Cl:4][C:5]1[C:14]2[NH:13][S:12](=[O:16])(=[O:15])[N:11]([CH:17]([CH3:19])[CH3:18])[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>ClCCCl>[Cl:4][C:5]1[C:14]2[N:13]([C:2]#[N:1])[S:12](=[O:16])(=[O:15])[N:11]([CH:17]([CH3:18])[CH3:19])[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)N1C(=O)c2cccc(Cl)c2NS1(=O)=O
Reactant: N#CBr
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)N1C(=O)c2cccc(Cl)c2N(C#N)S1(=O)=O
Temperature: 20 °C
Reaction time: 48 h

Procedure:
127 parts of cyanogen bromide are added to 274.5 parts of 8-chloro-3-isopropyl-2,1,3-benzothiadiazin-4-one-2,2-dioxide dissolved in 1,500 parts of 1,2-dichloroethane at 5°-10° C. and 121 parts of triethylamine are then added dropwise at the same temperature. The reaction mixture is then stirred for 48 hours at room temperature (20° C.), after which it is washed twice with water and three times with normal aqueous sodium hydroxide solution and dried, and the solvent is evaporated off under reduced pressure. The residue is recrystallized twice from isopropanol and gives 90 parts of 8-chloro-1-cyano-3-isopropyl-2,1,3-benzothiadiazin-4-one-2,2-dioxide of melting point 123°-124° C.